Lipid-Polymer Hybrid Nanoparticles for Solubility Enhancement of Tetrahydrocurcumin in a Noval Discriminative Dissolution Medium

Lipid-Polymer Hybrid Nanoparticles for Solubility Enhancement of Tetrahydrocurcumin in a Noval Discriminative Dissolution Medium | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Lipid-Polymer Hybrid Nanoparticles for Solubility Enhancement of Tetrahydrocurcumin in a Noval Discriminative Dissolution Medium Habibur Rahman, Lakshman Prathap, Hariprasad Ranganathan, Telny Thomas, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6623006/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Sep, 2025 Read the published version in BioNanoScience → Version 1 posted 9 You are reading this latest preprint version Abstract A promising strategy to overcome the problems in treatment with pharmaceutical active ingredients involves the development of suitable drug carrier systems using nanoparticles (NPs). Tetrahydrocurcumin (THC) is an active metabolite of curcumin, which comes under BCS Class II due to its less solubility. A novel, integrated system known as lipid-polymer hybrid nanoparticles (LPH-NPs) has been introduced in an effort to mitigate limitations associated with unpredictable physicochemical properties. The particle size, zeta potential, encapsulation efficiency and morphology were characterized for the prepared formulation. In-vitro drug release, release kinetics and stability of the prepared LPH-NPs were evaluated. The particle sizes of all the prepared 27 LPH-NPs formulations were found to be in the range of 98.06 to 158 nm. The formulation F14 has shown the maximum encapsulation efficiency (80.3%) with less particle size (129.8 nm) and PDI (0.085). Also the zeta potential was found to be -36.4 and it confirms the stability of the formulation. The TEM and AFM morphological images of formulation F14 showed spherical, smooth-surfaced, and uniform sized particles. The formulations F13, F14, F15, F16, F17 and F18 showed maximum drug release of 93.1, 95.1, 91.6, 86.2, 89.7 and 87.3%, respectively when compared to pure drug THC. The drug release from the formulation and kinetic results was clearly indicative of sustained release of THC. The obtained drug release results evident that the solubility of THC is improved with LPH-NPs. Hence the developed formulation would enable the increased oral bioavailability of THC. Curcumin hybrid nanoparticles lipid nanoparticles polymeric nanoparticles tetrahydrocurcumin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Oral delivery of drugs is the simplest and easiest way for administering the drug [1]. However, promising experimental findings acquired in vitro sometimes provide unsatisfactory outcomes in vivo due to inadequate solubility, absorption, fast metabolism, elimination, and increased fluctuations in plasma levels [2,3]. Developing newer avenues in drug delivery systems is the need of the hour to tackle the challenges arising due to the above-mentioned factors [4,5]. In the current scenario, oral delivery of drugs is continually seeking newer avenues to tackle the challenges arising due to the above-mentioned factors [6,7]. The major problem associated with the oral administration of an active pharmacological agent is bioavailability, which mainly depends on the aqueous solubility of the agent [8]. Generally, dissolution is an important factor for the poor water-soluble compounds because these molecules are absorption rate limited [9]. The therapeutic effectiveness of a drug molecule depends upon bioavailability and mainly on its solubility [10]. Drug’s bioavailability and solubility mainly determines the therapeutics effectiveness of a drug molecule [11]. The critical area of research in pharmaceutical development was solubility improvement of poorly water-soluble drugs. Various formulation strategies, such as the use of surfactants [12], solid dispersions [13,14] and nanotechnology [15], have been explored to enhance dissolution rates and consequently bioavailability. Particularly in tetrahydrocurcumin (THC) absorption, dissolution is a crucial rate-limiting step [16,17]. THC is an active metabolite of curcumin, which is categorized under BCS Class II [18]. THC has been reported to be responsible for several of the pharmacological activities of curcumin [19]. Similar to curcumin, THC processes several significant pharmacological activities as an antioxidant, anti-cancerogenic, and anti-angiogenic characteristic and prevents type II diabetes [20]. However, THC was also demonstrated to be more efficient than curcumin in alleviating diabetes, hypertension, and hepatotoxicity in rat models [21]. Hence, developing an appropriate dissolution medium is essential to forecasting variations in THC formulation’s bioavailability; we have recently proposed a dissolution method for a quality control analysis of THC in table formulations [22,23]. Developing suitable drug carrier systems is an effective means to address these problems. Depending on the specific needs of the therapy, which determines the drug's in vivo fate, these carriers ought to facilitate a controlled and localized release of the drug [24]. The carrier system's size varies from a few nanometers to a micrometer and is determined by its desired administration route [25]. In the last decade, nanoparticles (NPs) have garnered significant interest due to their ability to deliver drugs to therapeutic sites at appropriate times and doses [26,27]. Of all the common nanoparticulate systems, lipid nanoparticles (L-NPs) and biodegradable polymeric nanoparticles (P-NPs) have emerged as the two leading classes of nanocarriers for drugs, which is evidenced by increasing numbers of clinical trials, research publications, and authorized and approved drug products [28,29]. Both classes have advantages and constraints in terms of their physicochemical and biological characteristics. Historically, lipids have been employed for several decades in different drug delivery systems, including liposomes, solid lipid NPs, nanostructured lipid carriers, and lipid-drug conjugates [30,31]. In case most of the liposomes' lipid components are from natural sources, they are biocompatible, biodegradable, nontoxic or mildly toxic, flexible, and non-immunogenic for systemic and non-systemic administration [32]. However, according to various perspectives, a few drawbacks of liposomal drug products include their chemical and physical stability, repeatability from batch to batch, sterilization, drug entrapment, and manufacturing scale-up [33]. Smaller particle size, tissue penetration, a wider range manufacturing methods, the availability of different polymers, enhanced stability in biological fluids, versatile drug loading, and release behaviours are all generally advantages of P-NPs [34]. The usage of toxic organic solvents during the manufacturing process, poor drug encapsulation for hydrophilic drugs, drug leakage prior to reaching target tissues, polymer cytotoxicity, polymer degradation, and problems with scale-up are some of P-NPs' drawbacks [35]. To address some of the drawbacks of L-NPs and P-NPs, a novel, integrated system called lipid-polymer hybrid nanoparticles (LPH-NPs) has been developed [36]. To put it briefly, LPH-NPs provide a theoretically more efficient delivery mechanism by combining the biomimetic properties of lipids with the architectural benefit of the polymer core [37]. In light of the promising activity profile of THC, there is a stressing need to improve the solubility and absorption for capitalizing the full potential of THC for various therapies [38]. The present investigation was focused on developing novel LPH-NPs loaded with THC for improved oral delivery system to enhance the solubility followed by bioavailability of THC [39]. To our knowledge, this is the first study proposed to develop a novel LPH-NPs system for THC to enhance its physicochemical properties. Hence this study was aimed to prepare a stable and convenient delivery system. LPH-NPs system with maximum drug loading has been developed to study the in-vitro drug release behaviour in a developed dissolution medium to optimize the solubility enhancement. 2. Materials and methods 2.1 Materials THC was obtained as a gift sample from Sami Labs, Bangalore, India. Poly lactic-co-glycolic acid (PLGA), PLGA 50:50 and lecithin were purchased from Sigma-Aldrich, Mumbai, India. Egg-L-α-phosphatidylcholine (Egg-PC) and 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-poly (ethylene glycol) (DSPE-PEG) 2000 were purchased from Avanti Polar Lipids, Alabama, USA. Sodium lauryl sulphate (SLS) was purchased from Sangrose Laboratories Pvt. Ltd., Kerala, India. 2.2 Preparation of lipid polymer hybrid nanoparticles The LPH-NPs were prepared by the High-speed homogenization technique. The stock solutions of PLGA with the drug (THC) in acetonitrile were prepared (Table 1 ). The stock solutions of Egg-PC (1 mg/mL) and DSPE-PEG (1 mg/mL) were prepared with 4% ethanol. Egg-PC and DSPE-PEG solutions were added together, and the volume was brought up to 4 mL with water. To produce the NPs, 400 µL of PLGA solution was added to the aqueous solution, the volume was brought up to 7 mL with water, and the resultant mixture was then sonicated for 5 mins in a bath sonicator and homogenized using high speed homogenization for 10 mins at 20,000 rpm. The developed NPs were further centrifuged (Eppendorf 5415, Germany). The supernant solution was removed and the sediments were re-suspended in water [40,41]. Table 1 Batch specification of THC-loaded LPH-NPs Formulation THC (mg) DSPE-PEG (mL) Egg-PC (mL) F1 8 125 6.25 F2 8 125 12.50 F3 8 125 18.75 F4 8 250 6.25 F5 8 250 12.50 F6 8 250 18.75 F7 8 375 6.25 F8 8 375 12.50 F9 8 375 18.75 F10 10 125 6.25 F11 10 125 12.50 F12 10 125 18.75 F13 10 250 6.25 F14 10 250 12.50 F15 10 250 18.75 F16 10 375 6.25 F17 10 375 12.50 F18 10 375 18.75 F19 12 125 6.25 F20 12 125 12.50 F21 12 125 18.75 F22 12 250 6.25 F23 12 250 12.50 F24 12 250 18.75 F25 12 375 6.25 F26 12 375 12.50 F27 12 375 18.75 2.3 Characterizations of LPH-NPs 2.3.1 Particle size analysis The samples of the prepared LPH-NPs were analysed for particle size and its poly dispersive index (PDI) by photon correlation spectroscopy technique using Zetasizer Nano ZS90, Malvern, United Kingdom [42]. 2.3.2 Zeta potential measurement The zeta potential of the prepared LPH-NPs which is loaded with THC was analyzed using Malvern Zeta sizer. Suitable dilutions of the dispersions were prepared using water and the zeta potential was measured. Typically, 1 ml of LPH-NPs was diluted in 10 ml of water to achieve a 1 mg/ml final concentration of THC. The 1 ml of diluted formulations was placed in zetasizer to determine the zeta potential [43]. 2.3.3 Determination of encapsulation efficiency Typically, the prepared formulation(s) 2 ml was taken and centrifuged at 14,000 rpm for 45 min at 4°C. The supernatant was collected, diluted and the absorbance was measured using UV-visible spectrophotometer (UV-1601 PC Shimadzu Spectrophotometer, Japan) [44]. 2.3.4 Transmission electron microscopic analysis (TEM) A drop of lipid dispersion was placed onto 300-mesh, carbon-coated copper grids and allowed to adsorb. Excess dispersion was removed using blotting paper. The sample was then stained with 1% phosphotungstic acid for 30–60 seconds. After staining, the nanoparticles were allowed to dry under ambient conditions and the dried NPs being examined using transmission electron microscopy (TEM; JEM-1230, JEOL, Tokyo, Japan) at an acceleration voltage of 120 kV. 2.3.5 Atomic force microscopic analysis (AFM) The shape and surface of the produced LPH-NPs were examined using atomic force microscopy (AFM). The dispersions were diluted with purified water and placed on a cover slip, dried under desiccator for 24 h. The sample was analyzed by AFM (SPM-9700, Shimadzu, Tokyo, Japan) at room temperature with 1 Hz scanning. 2.4 In-vitro drug release profiles 2.4.1 Development of dissolution medium In our previous study, a UV-visible spectroscopy-based dissolution method for THC was developed and successfully validated; the developed method was used in this study to evaluate the release of THC from LPH-NPs [22]. 2.4.2 In-vitro drug release studies The in vitro drug release was evaluated by placing 2 ml of the formulation inside a semi-permeable dialysis membrane, which was then set in a beaker with 60 ml of 1% SLS in buffer solution (pH 7.4) as the release medium. This setup was maintained on a magnetic stirrer, rotating at 100 rpm at a temperature of 37°C. At specific time intervals, namely 0.5, 1, 2, 4, 8, 24, 48, 72, and 96 hours, 3 ml of samples were taken and replaced with buffer solution to maintain the sink conditions. The cumulative concentrations of the drug in the samples were determined by measuring absorbance through UV-visible spectrophotometry and then interpolating the results based on the calibration curves [45]. 2.4.3 In-vitro drug release kinetics Kinetic models representing the drug release profile were generated using DD Solver software. The release data of the formulations were analyzed using different kinetic models, and the model that established the best fit-based on the regression coefficient and release exponent (n)-was selected to characterize the drug (THC) release pattern from the nanoparticles. 2.5 Lyophilisation The prepared NPs were made to undergo lyophilisation in the LYODEL freeze dryer. The free-flowing powder was prepared by incorporating the cryoprotectant, mannitol to the liquid formulation and made to undergo freeze drying for 24 h. 2.6 Stability studies To evaluate the stability of the formulations, the particle size analysis and entrapment efficiency studies were conducted for 3 months. The stability studies were conducted out accordance to ICH guidelines. The SLN formulations were stored at two distinct conditions, i.e., 5 ± 3°C (refrigeration conditions) and 25 ± 2°C (room temperature). 2.7 Statistical analyses Two-way ANOVA was used to analyse the level of statistical significance between groups. A significance level (P) of less than 0.05 was deemed statistically significant. The mean ± SD of at least of three samples was used to represent all data. Using GraphPad Prism version 5, significant differences across groups were determined. 3. Results and discussion 3.1 Preparation of LPH-NPs formulations The polymer DSPE-PEG was chosen to prepare the core-shell NPs [46]. The nanoformulation was prepared using DSPE-PEG in order to achieve optimum drug encapsulation efficiency, improved stability, and prolonged blood circulation (Table 1 ). Lecithin was used to prepare the lipid monolayer and outer shell of the polymeric core NPs. The different ratios of polymers and the drug were chosen and optimized the suitable ratio to prepare a reliable LPH-NPs formulation (Fig. 1 ). 3.2 Characterization of LPH-NPs formulations In this study, we have prepared 27 LPH-NPs formulations and optimized the formulations with a suitable range of particle size, PDI, and zeta potential with maximum drug loading. The physicochemical properties were further characterized for the prepared LPH-NPs. Overall, the particle sizes of all the prepared 27 LPH-NPs formulations were found to be in the range of 98.06 to 158 nm (Table 2 ). Noticeably, the particle sizes for formulations F1 to F9 ranged from 124.4 to 138.4 nm. Formulations F10 to F18 exhibited sizes between 98.6 and 158 nm, whereas formulations F19 to F27 showed sizes from 129.5 to 153.9 nm. The changes observed in the particle size were due to the selection of varying concentrations of the core and coating materials. Particularly, in this study, we observed increasing concentration of THC increased the particle size of LPH-NPs formulations. The PDI of all the prepared formulations was found to be mono dispersed and within the acceptable range (PDI less than 0.5) (Table 2 ). This shows that the developed formulations were stable. Every formulation had an anionic charge in its zeta potential. The zeta potential of formulations F10 through F18 was determined to be stable and within an acceptable range. (Table 2 ). On the other hand, formulations F1 to F9 and F19 to F27 were found to be less stable when compared to formulations F10 to F18. According to the study that was already published, a steady nanoformulation should have a zeta potential that is either higher or lower than to ± 30 mV [47]. The encapsulation efficiency of the prepared nanoformulations F1 to F9 was found to be 67.2 to 79.6% and formulations F10 to F18 was found to be 68.4 to 80.3%. The encapsulation efficiency of formulations F19 to F27 was found to be 55.6 to 62.5%. Among the prepared formulations, F10 to F18 has shown the maximum encapsulation efficiency. Noticeably, formulation F14 has shown the maximum encapsulation efficiency (80.3%) with less particle size (129.8 nm) and PDI (0.085) (Fig. 2 A). The stability of the formulation is confirmed by the obtained zeta potential value (-36.4) (Fig. 2 B) (Table 2 ). Hence, formulation F14 was chosen as the best formulation among the 27 formulations and was used for further characterizations and in-vitro drug release studies. The TEM image of formulation F14 showed spherical, smooth-surfaced, and uniform nanosized particles against a light background (Fig. 3 A). The image confirmed that NPs were free from drug crystals and monodispersed without the formation of any aggregates. The TEM image also evident that the size of drug-loaded NPs was in agreement with the obtained DLS results. The AFM report reveals that the THC-loaded LPH-NPs formulation was found to be uniform and spherical shaped with slightly smooth surfaces (Fig. 3 B). The average height of the NPs was found to be 99.02 nm which in agreement with the values obtained in the case of TEM and DLS methods (Fig. 3 C). The histogram of size distribution of THC-loaded LPH-NPs shows particle size ranging from 40–170 nm (Fig. 3 D). Table 2 Characterization of physicochemical properties of THC-loaded LPH-NPs Formulation Particle size (nm) PDI Zeta potential (mV) % Encapsulation Efficiency F1 138.4 0.128 -30.8 69.5 F2 135.8 0.159 -25.6 67.2 F3 132.0 0.208 -26.0 70.3 F4 133.4 0.144 -28.5 79.6 F5 132.1 0.105 -25.0 78.2 F6 135.4 0.156 -25.1 77.0 F7 124.4 0.150 -17.9 72.4 F8 128.0 0.112 -18.6 74.3 F9 126.2 0.127 -18.2 74.4 F10 100.8 0.122 -31.2 68.4 F11 98.06 0.126 -25.9 72.4 F12 104.6 0.096 -24.4 74.3 F13 127.3 0.064 -36.8 79.4 F14 129.8 0.085 -36.4 80.3 F15 129.2 0.085 -33.7 79.6 F16 130.6 0.054 -30.8 75.3 F17 158.0 0.117 -24.5 77.2 F18 141.9 0.062 -27.7 76.8 F19 129.5 0.075 -19.9 56.9 F20 136.8 0.135 -22.8 57.3 F21 140.4 0.065 -19.7 56.8 F22 137.8 0.110 -13.2 61.8 F23 143.8 0.101 -11.6 62.5 F24 131.3 0.110 -23.5 62.4 F25 153.9 0.145 -26.4 57.9 F26 143.5 0.103 -31.3 55.6 F27 145.2 0.112 -24.3 58.7 3.3 In-vitro drug release studies 3.3.1 Method development Based on our previously reported study, by using a surfactant to increase its solubility and maintain the sink conditions, we attempted to develop an appropriate dissolution medium for the in-vitro release of THC. The presence of the anionic surfactant SLS and the solubility of THC in various pH media were explored, and the effect of different media on the drug's solubility was evaluated [22]. 3.3.2 Drug release Among all the prepared LPH-NPs, formulations F13, F14, F15, F16, F17, and F18 were chosen for in-vitro drug release studies based on the formulation which has maximum drug encapsulation efficiency. The drug release study was conducted for 8 hours for all formulations and pure drug THC. The formulations F13, F14, F15, F16, F17 and F18 showed maximum drug release of 93.1, 95.1, 91.6, 86.2, 89.7 and 87.3%, respectively when compared to pure drug THC (Fig. 4 ). The extent of THC release was found to be higher in formulation F14. However, all of the selected formulations showed a sustained release pattern of the drug THC [48]. 3.3.3 In-vitro release kinetic models The dissolution data of the formulation F14 were subjected to release kinetic models of zero-order, first-order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas to predict the release mechanism of LPH-NPs formulation. The dissolution kinetics suggested that the release profile follows Quasi-Fickian diffusion mechanism explained by Korsmeyer-Peppas model (Table 3 ). The results indicates that the drug release was controlled by drug diffusion and the mechanism of polymer matrix relaxation or swelling [49]. Table 3 Release kinetics of formulation F14 Formulation (R 2 ) Correlation coefficient Zero order First order Higuchi Hixson-Crowell Korsmeyer-Peppas F14 0.9735 0.8768 0.7724 0.9111 0.9869 3.4 Stability studies The stability testing of the best formulation selected, F14, were conducted for three months in accordance with ICH guidelines [50]. Particle size, PDI, zetapotential, entrapment efficiency, and morphology were evaluated over three months after the freeze-dried formulations were kept at room temperature (24°C). The freeze-dried formulation was distributed in distilled water and sonicated for 2 min prior to the measurement. The findings from the stability studies revealed that there were no significant changes in the particle size, PDI, zeta potential, and entrapment efficiency of the formulation (Table 4 ) [51]. The TEM (Fig. 5 A) and AFM (Fig. 5 B) images also showed the same spherical, smooth-surfaced, and uniform nanosized particles upon storage for 3 months. The AFM histogram result showed that the average height (105.46 nm) (Fig. 5 C) and distribution (60–170 nm) (Fig. 5 D) of the NPs was found to be in close with the distribution and height values of the NPs before start the storage. The storage stability studies revealed that the formulation was stable upon storage for 3 months with no changes in morphology and are free from aggregations. Based on the obtained results, it is evident that formulation F14 containing 250 µl of DSPE-PEG, 12.5 µl of lecithin, and 10 mg of THC did not undergo any significant physicochemical changes during the time of storage at room temperature. Table 4 Stability profile of THC-loaded LPH-NPs F14 formulation Formulation F14 Initial day of preparation (Liquid NPs) After 3 months of storage (Freeze-dried powder NPs) PS (nm) PDI ZP (mV) % EE PS (nm) PDI ZP (mV) % EE Room Temperature (24 ° C) 129.8 0.085 -36.4 80.3 129.3 0.090 -36.2 80.1 4. Conclusion A proto-type LPH-NPs formulation for THC was successfully developed, and their physicochemical properties have been characterized. The drug release from the formulation was clearly indicative of sustained release of THC. The dissolution medium of 1% SLS in pH 7.4 showed that the developed medium was discriminative for THC. Considering this, it can be finalized that the developed dissolution method is simple, cost effective, and appropriate for the routine quality control analysis of THC although there is no official monograph and validated method available. The developed formulation showed good stability during storage. The dissolution kinetics suggested that the release profile follows Quasi-Fickian diffusion mechanism explained by the Korsmeyer-Peppas model. The obtained drug release results evident that the solubility of THC is improved with LPH-NPs. Hence the developed formulation might enable the increased oral bioavailability of THC. Further studies are needed in the future to determine the pharmacokinetics of the THC-loaded LPH-NPs. Declarations Author contributions Habibur Rahman: Conceptualization, Supervision, Writing- Review and Editing, Lakshman Prathap: Writing- Original draft, Review and Editing, Dinesh Babu: Writing- Review and Editing, Ranganathan Hariprasad: Writing- Review and Editing, Sivaselvakumar Muthusamy: Review and Editing, Telny Thomas: Review and Editing, Arjunan Karuppaiah: Supervision, Writing- Review and Editing. Conflicts of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest. Data availability The data of current research study is available with corresponding author on reasonable request it may be provided. Supplementary information Supplementary data is not available Ethical approval There is no animal experiment was performed in the study Data availability The data of current research study is available with corresponding author on reasonable request it may be provided. Acknowledgements The authors would like to thank PSG College of Pharmacy for providing all the necessary amenities to carry out this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References Park H, Barbier J, Hammond RP (2003) Crystal structure and polymorphism of PbAlBO4. Solid State Sci 5:565–571 Kim J, De Jesus O. (2025) Medication Routes of Administration. In StatPearls. http://www.ncbi.nlm.nih.gov/pubmed/19499570 Sharma M, Sharma R, Jain D. K. (2016) Nanotechnology Based Approaches for Enhancing Oral Bioavailability of Poorly Water Soluble Antihypertensive Drugs. 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Colloids and Surfaces B: Biointerfaces 237: 113858. https://doi.org/10.1016/j.colsurfb.2024.113858 Karuppaiah A, Siram K, Selvaraj D, Ramasamy M, Babu D, Sankar V (2020) Synergistic and enhanced anticancer effect of a facile surface modified non-cytotoxic silver nanoparticle conjugated with gemcitabine in metastatic breast cancer cells. Materials Today Communications, 23:100884. https://doi.org/10.1016/j.mtcomm.2019.100884 Wilhelm Romero K, Quirós M I, Vargas Huertas F, Vega-Baudrit J R, Navarro-Hoyos M, Araya-Sibaja A. M (2021) Design of Hybrid Polymeric-Lipid Nanoparticles Using Curcumin as a Model: Preparation, Characterization, and In Vitro Evaluation of Demethoxycurcumin and Bisdemethoxycurcumin-Loaded Nanoparticles. Polymers 13(23): 4207. https://doi.org/10.3390/polym13234207 Mircioiu C, Voicu V, Anuta V, Tudose A, Celia C, Paolino D, Fresta M, Sandulovici R, Mircioiu I (2019) Mathematical Modeling of Release Kinetics from Supramolecular Drug Delivery Systems. Pharmaceutics 11(3):140. https://doi.org/10.3390/pharmaceutics11030140 González-González O, Ramirez I O, Ramirez B I, O’Connell P, Ballesteros M P, Torrado J J, Serrano D R (2022) Drug Stability: ICH versus Accelerated Predictive Stability Studies. Pharmaceutics, 14(11): 2324. https://doi.org/10.3390/pharmaceutics14112324 Selvaraj K, Lee S.-J, Song K.-B, Yoo B.-K, Karuppaiah A (2025) Fabrication of Mastic Gum Resin Tethered Phospholipid Nanocarriers for the Evaluation and Enhancement of Anti-inflammatory and Anti-bacterial Effects. Current Pharmaceutical Design: 31. https://doi.org/10.2174/0113816128353794241225083428 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 15 Sep, 2025 Read the published version in BioNanoScience → Version 1 posted Editorial decision: Revision requested 12 Jun, 2025 Reviews received at journal 10 Jun, 2025 Reviewers agreed at journal 02 Jun, 2025 Reviews received at journal 19 May, 2025 Reviewers agreed at journal 13 May, 2025 Reviewers invited by journal 13 May, 2025 Editor assigned by journal 13 May, 2025 Submission checks completed at journal 13 May, 2025 First submitted to journal 08 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6623006","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":456127338,"identity":"6c1046e8-2c83-4a25-96f0-0d5146a97728","order_by":0,"name":"Habibur Rahman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBACAwYexgMMDBJyIM6BB0RqYTjAkGBhDNaSQIKWisQGEI8oLebsZw8c+PhDIn1+2OGHQFvs5HQbCGix7MlLODgjQSJ34+00A6CWZGOzA4QcdiDH4DAPSMvsBJCWA4nbCGo5/8bg8J8EiXTD2ekfiNRyA2gLQ4JEgrx0DrG23HiXcLAnTcJwg3ROwYEEA2L8cj734IMfNnXy8rPTN3/4UGEnR1ALQi9YpQGxykFAvoEU1aNgFIyCUTCiAAChHEtG6xWtFQAAAABJRU5ErkJggg==","orcid":"","institution":"PSG College of Pharmacy","correspondingAuthor":true,"prefix":"","firstName":"Habibur","middleName":"","lastName":"Rahman","suffix":""},{"id":456127339,"identity":"88caa73b-c045-4e13-b0b4-03f69b408b09","order_by":1,"name":"Lakshman Prathap","email":"","orcid":"","institution":"PSG College of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Lakshman","middleName":"","lastName":"Prathap","suffix":""},{"id":456127340,"identity":"fc56cd08-3f26-461a-99bb-19c2552fb758","order_by":2,"name":"Hariprasad 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Research","correspondingAuthor":false,"prefix":"","firstName":"Sivaselvakumar","middleName":"","lastName":"Muthusamy","suffix":""},{"id":456127344,"identity":"8d957a96-781c-4227-abac-4a9d8b61584f","order_by":6,"name":"Arjunan Karuppaiah","email":"","orcid":"","institution":"PSG College of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Arjunan","middleName":"","lastName":"Karuppaiah","suffix":""}],"badges":[],"createdAt":"2025-05-08 18:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6623006/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6623006/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12668-025-02145-5","type":"published","date":"2025-09-15T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82890590,"identity":"4861bda8-0810-4769-bceb-c64a9f2d1581","added_by":"auto","created_at":"2025-05-16 12:09:28","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":138105,"visible":true,"origin":"","legend":"\u003cp\u003ePhotographs of LPH-NPs formulations\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6623006/v1/0232dd7e9f701fb7a8477c83.jpeg"},{"id":82888283,"identity":"0193c510-2826-4ea8-9196-90da161b3329","added_by":"auto","created_at":"2025-05-16 12:01:28","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":101828,"visible":true,"origin":"","legend":"\u003cp\u003eDynamic light scattering analysis for THC-loaded LPH-NPs formulation F14, (A) Particle size distribution, (B) Zetapotential distribution\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6623006/v1/b9991a668d1fcda4e3f305ad.jpeg"},{"id":82890593,"identity":"c40a9426-a2dc-43cc-8ca7-02ece58074e0","added_by":"auto","created_at":"2025-05-16 12:09:28","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":324904,"visible":true,"origin":"","legend":"\u003cp\u003eMorphology of THC-loaded LPH-NPs formulation F14, (A) TEM image, (B) AFM image 2D view, (C) AFM image 3D view, (D) AFM histogram image\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6623006/v1/1332a177137b9be895d2ee94.jpeg"},{"id":82888287,"identity":"7f3e14e4-b86a-451b-a005-bffb1c3e5110","added_by":"auto","created_at":"2025-05-16 12:01:28","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":145839,"visible":true,"origin":"","legend":"\u003cp\u003eDrug release profile of THC-loaded LPH-NPs\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6623006/v1/4f1696444f16e1a8603de3ca.jpeg"},{"id":82888295,"identity":"89a31052-7d40-4930-8aeb-54706869e729","added_by":"auto","created_at":"2025-05-16 12:01:28","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":370341,"visible":true,"origin":"","legend":"\u003cp\u003eMorphology of THC-loaded LPH-NPs formulation F14 after storage of 3 months at 24\u003csup\u003eo\u003c/sup\u003eC (A) TEM image, (B) AFM image 2D view, (C) AFM image 3D view, (D) AFM histogram image\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6623006/v1/b8b3330385d3dd694565a048.jpeg"},{"id":91889967,"identity":"9c9ff216-2f1a-4c7a-869c-e76af71e3a54","added_by":"auto","created_at":"2025-09-22 16:03:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2233419,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6623006/v1/92d98b71-5e46-46b9-b325-4e1e820e8ef4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Lipid-Polymer Hybrid Nanoparticles for Solubility Enhancement of Tetrahydrocurcumin in a Noval Discriminative Dissolution Medium","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOral delivery of drugs is the simplest and easiest way for administering the drug [1]. However, promising experimental findings acquired \u003cem\u003ein vitro\u003c/em\u003e sometimes provide unsatisfactory outcomes \u003cem\u003ein vivo\u003c/em\u003e due to inadequate solubility, absorption, fast metabolism, elimination, and increased fluctuations in plasma levels [2,3]. Developing newer avenues in drug delivery systems is the need of the hour to tackle the challenges arising due to the above-mentioned factors [4,5]. In the current scenario, oral delivery of drugs is continually seeking newer avenues to tackle the challenges arising due to the above-mentioned factors [6,7]. The major problem associated with the oral administration of an active pharmacological agent is bioavailability, which mainly depends on the aqueous solubility of the agent [8]. Generally, dissolution is an important factor for the poor water-soluble compounds because these molecules are absorption rate limited [9]. The therapeutic effectiveness of a drug molecule depends upon bioavailability and mainly on its solubility [10]. Drug\u0026rsquo;s bioavailability and solubility mainly determines the therapeutics effectiveness of a drug molecule [11].\u003c/p\u003e \u003cp\u003eThe critical area of research in pharmaceutical development was solubility improvement of poorly water-soluble drugs. Various formulation strategies, such as the use of surfactants [12], solid dispersions [13,14] and nanotechnology [15], have been explored to enhance dissolution rates and consequently bioavailability. Particularly in tetrahydrocurcumin (THC) absorption, dissolution is a crucial rate-limiting step [16,17]. THC is an active metabolite of curcumin, which is categorized under BCS Class II [18]. THC has been reported to be responsible for several of the pharmacological activities of curcumin [19]. Similar to curcumin, THC processes several significant pharmacological activities as an antioxidant, anti-cancerogenic, and anti-angiogenic characteristic and prevents type II diabetes [20]. However, THC was also demonstrated to be more efficient than curcumin in alleviating diabetes, hypertension, and hepatotoxicity in rat models [21]. Hence, developing an appropriate dissolution medium is essential to forecasting variations in THC formulation\u0026rsquo;s bioavailability; we have recently proposed a dissolution method for a quality control analysis of THC in table formulations [22,23]. Developing suitable drug carrier systems is an effective means to address these problems. Depending on the specific needs of the therapy, which determines the drug's in vivo fate, these carriers ought to facilitate a controlled and localized release of the drug [24]. The carrier system's size varies from a few nanometers to a micrometer and is determined by its desired administration route [25].\u003c/p\u003e \u003cp\u003eIn the last decade, nanoparticles (NPs) have garnered significant interest due to their ability to deliver drugs to therapeutic sites at appropriate times and doses [26,27]. Of all the common nanoparticulate systems, lipid nanoparticles (L-NPs) and biodegradable polymeric nanoparticles (P-NPs) have emerged as the two leading classes of nanocarriers for drugs, which is evidenced by increasing numbers of clinical trials, research publications, and authorized and approved drug products [28,29]. Both classes have advantages and constraints in terms of their physicochemical and biological characteristics. Historically, lipids have been employed for several decades in different drug delivery systems, including liposomes, solid lipid NPs, nanostructured lipid carriers, and lipid-drug conjugates [30,31]. In case most of the liposomes' lipid components are from natural sources, they are biocompatible, biodegradable, nontoxic or mildly toxic, flexible, and non-immunogenic for systemic and non-systemic administration [32]. However, according to various perspectives, a few drawbacks of liposomal drug products include their chemical and physical stability, repeatability from batch to batch, sterilization, drug entrapment, and manufacturing scale-up [33].\u003c/p\u003e \u003cp\u003eSmaller particle size, tissue penetration, a wider range manufacturing methods, the availability of different polymers, enhanced stability in biological fluids, versatile drug loading, and release behaviours are all generally advantages of P-NPs [34]. The usage of toxic organic solvents during the manufacturing process, poor drug encapsulation for hydrophilic drugs, drug leakage prior to reaching target tissues, polymer cytotoxicity, polymer degradation, and problems with scale-up are some of P-NPs' drawbacks [35].\u003c/p\u003e \u003cp\u003eTo address some of the drawbacks of L-NPs and P-NPs, a novel, integrated system called lipid-polymer hybrid nanoparticles (LPH-NPs) has been developed [36]. To put it briefly, LPH-NPs provide a theoretically more efficient delivery mechanism by combining the biomimetic properties of lipids with the architectural benefit of the polymer core [37]. In light of the promising activity profile of THC, there is a stressing need to improve the solubility and absorption for capitalizing the full potential of THC for various therapies [38]. The present investigation was focused on developing novel LPH-NPs loaded with THC for improved oral delivery system to enhance the solubility followed by bioavailability of THC [39]. To our knowledge, this is the first study proposed to develop a novel LPH-NPs system for THC to enhance its physicochemical properties. Hence this study was aimed to prepare a stable and convenient delivery system. LPH-NPs system with maximum drug loading has been developed to study the \u003cem\u003ein-vitro\u003c/em\u003e drug release behaviour in a developed dissolution medium to optimize the solubility enhancement.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Materials\u003c/h2\u003e \u003cp\u003eTHC was obtained as a gift sample from Sami Labs, Bangalore, India. Poly lactic-co-glycolic acid (PLGA), PLGA 50:50 and lecithin were purchased from Sigma-Aldrich, Mumbai, India. Egg-L-α-phosphatidylcholine (Egg-PC) and 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-poly (ethylene glycol) (DSPE-PEG) 2000 were purchased from Avanti Polar Lipids, Alabama, USA. Sodium lauryl sulphate (SLS) was purchased from Sangrose Laboratories Pvt. Ltd., Kerala, India.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Preparation of lipid polymer hybrid nanoparticles\u003c/h2\u003e \u003cp\u003eThe LPH-NPs were prepared by the High-speed homogenization technique. The stock solutions of PLGA with the drug (THC) in acetonitrile were prepared (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The stock solutions of Egg-PC (1 mg/mL) and DSPE-PEG (1 mg/mL) were prepared with 4% ethanol. Egg-PC and DSPE-PEG solutions were added together, and the volume was brought up to 4 mL with water. To produce the NPs, 400 \u0026micro;L of PLGA solution was added to the aqueous solution, the volume was brought up to 7 mL with water, and the resultant mixture was then sonicated for 5 mins in a bath sonicator and homogenized using high speed homogenization for 10 mins at 20,000 rpm. The developed NPs were further centrifuged (Eppendorf 5415, Germany). The supernant solution was removed and the sediments were re-suspended in water [40,41].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBatch specification of THC-loaded LPH-NPs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTHC (mg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDSPE-PEG (mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEgg-PC (mL)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Characterizations of LPH-NPs\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1 Particle size analysis\u003c/h2\u003e \u003cp\u003eThe samples of the prepared LPH-NPs were analysed for particle size and its poly dispersive index (PDI) by photon correlation spectroscopy technique using Zetasizer Nano ZS90, Malvern, United Kingdom [42].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2 Zeta potential measurement\u003c/h2\u003e \u003cp\u003eThe zeta potential of the prepared LPH-NPs which is loaded with THC was analyzed using Malvern Zeta sizer. Suitable dilutions of the dispersions were prepared using water and the zeta potential was measured. Typically, 1 ml of LPH-NPs was diluted in 10 ml of water to achieve a 1 mg/ml final concentration of THC. The 1 ml of diluted formulations was placed in zetasizer to determine the zeta potential [43].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.3.3 Determination of encapsulation efficiency\u003c/h2\u003e \u003cp\u003eTypically, the prepared formulation(s) 2 ml was taken and centrifuged at 14,000 rpm for 45 min at 4\u0026deg;C. The supernatant was collected, diluted and the absorbance was measured using UV-visible spectrophotometer (UV-1601 PC Shimadzu Spectrophotometer, Japan) [44].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.3.4 Transmission electron microscopic analysis (TEM)\u003c/h2\u003e \u003cp\u003eA drop of lipid dispersion was placed onto 300-mesh, carbon-coated copper grids and allowed to adsorb. Excess dispersion was removed using blotting paper. The sample was then stained with 1% phosphotungstic acid for 30\u0026ndash;60 seconds. After staining, the nanoparticles were allowed to dry under ambient conditions and the dried NPs being examined using transmission electron microscopy (TEM; JEM-1230, JEOL, Tokyo, Japan) at an acceleration voltage of 120 kV.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.3.5 Atomic force microscopic analysis (AFM)\u003c/h2\u003e \u003cp\u003eThe shape and surface of the produced LPH-NPs were examined using atomic force microscopy (AFM). The dispersions were diluted with purified water and placed on a cover slip, dried under desiccator for 24 h. The sample was analyzed by AFM (SPM-9700, Shimadzu, Tokyo, Japan) at room temperature with 1 Hz scanning.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e\u003cem\u003e2.4 In-vitro\u003c/em\u003e drug release profiles\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e2.4.1 Development of dissolution medium\u003c/h2\u003e \u003cp\u003eIn our previous study, a UV-visible spectroscopy-based dissolution method for THC was developed and successfully validated; the developed method was used in this study to evaluate the release of THC from LPH-NPs [22].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e2.4.2 In-vitro drug release studies\u003c/h2\u003e \u003cp\u003eThe \u003cem\u003ein vitro\u003c/em\u003e drug release was evaluated by placing 2 ml of the formulation inside a semi-permeable dialysis membrane, which was then set in a beaker with 60 ml of 1% SLS in buffer solution (pH 7.4) as the release medium. This setup was maintained on a magnetic stirrer, rotating at 100 rpm at a temperature of 37\u0026deg;C. At specific time intervals, namely 0.5, 1, 2, 4, 8, 24, 48, 72, and 96 hours, 3 ml of samples were taken and replaced with buffer solution to maintain the sink conditions. The cumulative concentrations of the drug in the samples were determined by measuring absorbance through UV-visible spectrophotometry and then interpolating the results based on the calibration curves [45].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e2.4.3 In-vitro drug release kinetics\u003c/h2\u003e \u003cp\u003eKinetic models representing the drug release profile were generated using DD Solver software. The release data of the formulations were analyzed using different kinetic models, and the model that established the best fit-based on the regression coefficient and release exponent (n)-was selected to characterize the drug (THC) release pattern from the nanoparticles.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Lyophilisation\u003c/h2\u003e \u003cp\u003eThe prepared NPs were made to undergo lyophilisation in the LYODEL freeze dryer. The free-flowing powder was prepared by incorporating the cryoprotectant, mannitol to the liquid formulation and made to undergo freeze drying for 24 h.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Stability studies\u003c/h2\u003e \u003cp\u003eTo evaluate the stability of the formulations, the particle size analysis and entrapment efficiency studies were conducted for 3 months. The stability studies were conducted out accordance to ICH guidelines. The SLN formulations were stored at two distinct conditions, i.e., 5\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026deg;C (refrigeration conditions) and 25\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C (room temperature).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Statistical analyses\u003c/h2\u003e \u003cp\u003eTwo-way ANOVA was used to analyse the level of statistical significance between groups. A significance level (P) of less than 0.05 was deemed statistically significant. The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of at least of three samples was used to represent all data. Using GraphPad Prism version 5, significant differences across groups were determined.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and discussion","content":"\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Preparation of LPH-NPs formulations\u003c/h2\u003e \u003cp\u003eThe polymer DSPE-PEG was chosen to prepare the core-shell NPs [46]. The nanoformulation was prepared using DSPE-PEG in order to achieve optimum drug encapsulation efficiency, improved stability, and prolonged blood circulation (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Lecithin was used to prepare the lipid monolayer and outer shell of the polymeric core NPs. The different ratios of polymers and the drug were chosen and optimized the suitable ratio to prepare a reliable LPH-NPs formulation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Characterization of LPH-NPs formulations\u003c/h2\u003e \u003cp\u003eIn this study, we have prepared 27 LPH-NPs formulations and optimized the formulations with a suitable range of particle size, PDI, and zeta potential with maximum drug loading. The physicochemical properties were further characterized for the prepared LPH-NPs. Overall, the particle sizes of all the prepared 27 LPH-NPs formulations were found to be in the range of 98.06 to 158 nm (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Noticeably, the particle sizes for formulations F1 to F9 ranged from 124.4 to 138.4 nm. Formulations F10 to F18 exhibited sizes between 98.6 and 158 nm, whereas formulations F19 to F27 showed sizes from 129.5 to 153.9 nm. The changes observed in the particle size were due to the selection of varying concentrations of the core and coating materials. Particularly, in this study, we observed increasing concentration of THC increased the particle size of LPH-NPs formulations. The PDI of all the prepared formulations was found to be mono dispersed and within the acceptable range (PDI less than 0.5) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This shows that the developed formulations were stable.\u003c/p\u003e \u003cp\u003eEvery formulation had an anionic charge in its zeta potential. The zeta potential of formulations F10 through F18 was determined to be stable and within an acceptable range. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). On the other hand, formulations F1 to F9 and F19 to F27 were found to be less stable when compared to formulations F10 to F18. According to the study that was already published, a steady nanoformulation should have a zeta potential that is either higher or lower than to \u0026plusmn;\u0026thinsp;30 mV [47]. The encapsulation efficiency of the prepared nanoformulations F1 to F9 was found to be 67.2 to 79.6% and formulations F10 to F18 was found to be 68.4 to 80.3%. The encapsulation efficiency of formulations F19 to F27 was found to be 55.6 to 62.5%. Among the prepared formulations, F10 to F18 has shown the maximum encapsulation efficiency. Noticeably, formulation F14 has shown the maximum encapsulation efficiency (80.3%) with less particle size (129.8 nm) and PDI (0.085) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The stability of the formulation is confirmed by the obtained zeta potential value (-36.4) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Hence, formulation F14 was chosen as the best formulation among the 27 formulations and was used for further characterizations and \u003cem\u003ein-vitro\u003c/em\u003e drug release studies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe TEM image of formulation F14 showed spherical, smooth-surfaced, and uniform nanosized particles against a light background (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The image confirmed that NPs were free from drug crystals and monodispersed without the formation of any aggregates. The TEM image also evident that the size of drug-loaded NPs was in agreement with the obtained DLS results. The AFM report reveals that the THC-loaded LPH-NPs formulation was found to be uniform and spherical shaped with slightly smooth surfaces (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The average height of the NPs was found to be 99.02 nm which in agreement with the values obtained in the case of TEM and DLS methods (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). The histogram of size distribution of THC-loaded LPH-NPs shows particle size ranging from 40\u0026ndash;170 nm (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacterization of physicochemical properties of THC-loaded LPH-NPs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParticle size (nm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePDI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZeta potential (mV)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e% Encapsulation Efficiency\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e138.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-30.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e69.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e135.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-25.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e67.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e132.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-26.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e70.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e133.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-28.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e79.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e132.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-25.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e78.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e135.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-25.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e77.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e124.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-17.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e72.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e128.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-18.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e74.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e126.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-18.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e74.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-31.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e68.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e98.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-25.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e72.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e104.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-24.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e74.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e127.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-36.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e79.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e129.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-36.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e80.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e129.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-33.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e79.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e130.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-30.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e75.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e158.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-24.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e77.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e141.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-27.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e76.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e129.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-19.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e56.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e136.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-22.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e57.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e140.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-19.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e56.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e137.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-13.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e61.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e143.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e131.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-23.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e62.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e153.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-26.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e57.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e143.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-31.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e55.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e145.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-24.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e58.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e3.3 In-vitro drug release studies\u003c/h2\u003e \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e \u003ch2\u003e3.3.1 Method development\u003c/h2\u003e \u003cp\u003eBased on our previously reported study, by using a surfactant to increase its solubility and maintain the sink conditions, we attempted to develop an appropriate dissolution medium for the in-vitro release of THC. The presence of the anionic surfactant SLS and the solubility of THC in various pH media were explored, and the effect of different media on the drug's solubility was evaluated [22].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e3.3.2 Drug release\u003c/h2\u003e \u003cp\u003eAmong all the prepared LPH-NPs, formulations F13, F14, F15, F16, F17, and F18 were chosen for \u003cem\u003ein-vitro\u003c/em\u003e drug release studies based on the formulation which has maximum drug encapsulation efficiency. The drug release study was conducted for 8 hours for all formulations and pure drug THC. The formulations F13, F14, F15, F16, F17 and F18 showed maximum drug release of 93.1, 95.1, 91.6, 86.2, 89.7 and 87.3%, respectively when compared to pure drug THC (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The extent of THC release was found to be higher in formulation F14. However, all of the selected formulations showed a sustained release pattern of the drug THC [48].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section3\"\u003e \u003ch2\u003e3.3.3 In-vitro release kinetic models\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe dissolution data of the formulation F14 were subjected to release kinetic models of zero-order, first-order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas to predict the release mechanism of LPH-NPs formulation. The dissolution kinetics suggested that the release profile follows Quasi-Fickian diffusion mechanism explained by Korsmeyer-Peppas model (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The results indicates that the drug release was controlled by drug diffusion and the mechanism of polymer matrix relaxation or swelling [49].\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelease kinetics of formulation F14\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFormulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003e(R\u003csup\u003e2\u003c/sup\u003e) Correlation coefficient\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eZero order\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFirst order\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eHiguchi\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eHixson-Crowell\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eKorsmeyer-Peppas\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.9735\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.8768\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7724\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.9111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.9869\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Stability studies\u003c/h2\u003e \u003cp\u003eThe stability testing of the best formulation selected, F14, were conducted for three months in accordance with ICH guidelines [50]. Particle size, PDI, zetapotential, entrapment efficiency, and morphology were evaluated over three months after the freeze-dried formulations were kept at room temperature (24\u0026deg;C). The freeze-dried formulation was distributed in distilled water and sonicated for 2 min prior to the measurement. The findings from the stability studies revealed that there were no significant changes in the particle size, PDI, zeta potential, and entrapment efficiency of the formulation (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) [51]. The TEM (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA) and AFM (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB) images also showed the same spherical, smooth-surfaced, and uniform nanosized particles upon storage for 3 months. The AFM histogram result showed that the average height (105.46 nm) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC) and distribution (60\u0026ndash;170 nm) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD) of the NPs was found to be in close with the distribution and height values of the NPs before start the storage. The storage stability studies revealed that the formulation was stable upon storage for 3 months with no changes in morphology and are free from aggregations. Based on the obtained results, it is evident that formulation F14 containing 250 \u0026micro;l of DSPE-PEG, 12.5 \u0026micro;l of lecithin, and 10 mg of THC did not undergo any significant physicochemical changes during the time of storage at room temperature.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStability profile of THC-loaded LPH-NPs F14 formulation\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFormulation F14\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eInitial day of preparation\u003c/p\u003e \u003cp\u003e(Liquid NPs)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eAfter 3 months of storage\u003c/p\u003e \u003cp\u003e(Freeze-dried powder NPs)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePS (nm)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ePDI\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eZP (mV)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e% EE\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003ePS (nm)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003ePDI\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eZP (mV)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e% EE\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRoom Temperature\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(24\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026deg;\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eC)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e129.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-36.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e80.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e129.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.090\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-36.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e80.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eA proto-type LPH-NPs formulation for THC was successfully developed, and their physicochemical properties have been characterized. The drug release from the formulation was clearly indicative of sustained release of THC. The dissolution medium of 1% SLS in pH 7.4 showed that the developed medium was discriminative for THC. Considering this, it can be finalized that the developed dissolution method is simple, cost effective, and appropriate for the routine quality control analysis of THC although there is no official monograph and validated method available. The developed formulation showed good stability during storage. The dissolution kinetics suggested that the release profile follows Quasi-Fickian diffusion mechanism explained by the Korsmeyer-Peppas model. The obtained drug release results evident that the solubility of THC is improved with LPH-NPs. Hence the developed formulation might enable the increased oral bioavailability of THC. Further studies are needed in the future to determine the pharmacokinetics of the THC-loaded LPH-NPs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHabibur Rahman: Conceptualization, Supervision, Writing- Review and Editing,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLakshman Prathap: Writing- Original draft, Review and Editing,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDinesh Babu: Writing- Review and Editing,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRanganathan Hariprasad: Writing- Review and Editing,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSivaselvakumar Muthusamy: Review and Editing,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTelny Thomas: Review and Editing,\u003c/p\u003e\n\u003cp\u003eArjunan Karuppaiah: Supervision, Writing- Review and Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data of current research study is available with corresponding author on reasonable request it may be provided.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary data is not available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no animal experiment was performed in the study\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data of current research study is available with corresponding author on reasonable request it may be provided.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank PSG College of Pharmacy for providing all the necessary amenities to carry out this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePark H, Barbier J, Hammond RP (2003) Crystal structure and polymorphism of PbAlBO4. Solid State Sci 5:565\u0026ndash;571\u003c/li\u003e\n\u003cli\u003eKim J, De Jesus O. (2025) Medication Routes of Administration. In StatPearls. http://www.ncbi.nlm.nih.gov/pubmed/19499570\u003c/li\u003e\n\u003cli\u003eSharma M, Sharma R, Jain D. K. (2016) Nanotechnology Based Approaches for Enhancing Oral Bioavailability of Poorly Water Soluble Antihypertensive Drugs. Scientifica:1\u0026ndash;11. https://doi.org/10.1155/2016/8525679\u003c/li\u003e\n\u003cli\u003eFink C, Sun D, Wagner K, Schneider M, Bauer H, Dolgos H, M\u0026auml;der K, Peters S (2020) Evaluating the Role of Solubility in Oral Absorption of Poorly Water‐Soluble Drugs Using Physiologically‐Based Pharmacokinetic Modeling. 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Inorganic and Nano-Metal Chemistry 51(1): 27\u0026ndash;37. https://doi.org/10.1080/24701556.2020.1750428\u003c/li\u003e\n\u003cli\u003eKaruppaiah A, Babu D, Selvaraj D, Natrajan T, Rajan R, Gautam M, Ranganathan H, Siram K, Nesamony J, Sankar V (2021) Building and behavior of a pH-stimuli responsive chitosan nanoparticles loaded with folic acid conjugated gemcitabine silver colloids in MDA-MB-453 metastatic breast cancer cell line and pharmacokinetics in rats. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences 165:105938. https://doi.org/10.1016/j.ejps.2021.105938\u003c/li\u003e\n\u003cli\u003eAwadeen R H, Boughdady M F, Zaghloul R A, Elsaed W M, Abu Hashim I I, Meshali M M (2023) Formulation of lipid polymer hybrid nanoparticles of the phytochemical Fisetin and its in vivo assessment against severe acute pancreatitis. Scientific Reports 13(1):19110. https://doi.org/10.1038/s41598-023-46215-8\u003c/li\u003e\n\u003cli\u003eSoomherun N, Kreua-ongarjnukool N, Niyomthai S T, Chumnanvej S (2024) Lipid-Polymer Hybrid Nanoparticles Synthesized via Lipid-Based Surface Engineering for a robust drug delivery platform. Colloids and Surfaces B: Biointerfaces 237: 113858. https://doi.org/10.1016/j.colsurfb.2024.113858\u003c/li\u003e\n\u003cli\u003eKaruppaiah A, Siram K, Selvaraj D, Ramasamy M, Babu D, Sankar V (2020) Synergistic and enhanced anticancer effect of a facile surface modified non-cytotoxic silver nanoparticle conjugated with gemcitabine in metastatic breast cancer cells. Materials Today Communications, 23:100884. https://doi.org/10.1016/j.mtcomm.2019.100884\u003c/li\u003e\n\u003cli\u003eWilhelm Romero K, Quir\u0026oacute;s M I, Vargas Huertas F, Vega-Baudrit J R, Navarro-Hoyos M, Araya-Sibaja A. 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Pharmaceutics, 14(11): 2324. https://doi.org/10.3390/pharmaceutics14112324\u003c/li\u003e\n\u003cli\u003eSelvaraj K, Lee S.-J, Song K.-B, Yoo B.-K, Karuppaiah A (2025) Fabrication of Mastic Gum Resin Tethered Phospholipid Nanocarriers for the Evaluation and Enhancement of Anti-inflammatory and Anti-bacterial Effects. Current Pharmaceutical Design: 31. https://doi.org/10.2174/0113816128353794241225083428\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bionanoscience","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnsc","sideBox":"Learn more about [BioNanoScience](http://link.springer.com/journal/12668)","snPcode":"12668","submissionUrl":"https://submission.nature.com/new-submission/12668/3","title":"BioNanoScience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Curcumin, hybrid nanoparticles, lipid nanoparticles, polymeric nanoparticles, tetrahydrocurcumin","lastPublishedDoi":"10.21203/rs.3.rs-6623006/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6623006/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA promising strategy to overcome the problems in treatment with pharmaceutical active ingredients involves the development of suitable drug carrier systems using nanoparticles (NPs). Tetrahydrocurcumin (THC) is an active metabolite of curcumin, which comes under BCS Class II due to its less solubility. A novel, integrated system known as lipid-polymer hybrid nanoparticles (LPH-NPs) has been introduced in an effort to mitigate limitations associated with unpredictable physicochemical properties. The particle size, zeta potential, encapsulation efficiency and morphology were characterized for the prepared formulation. \u003cem\u003eIn-vitro\u003c/em\u003e drug release, release kinetics and stability of the prepared LPH-NPs were evaluated. The particle sizes of all the prepared 27 LPH-NPs formulations were found to be in the range of 98.06 to 158 nm. The formulation F14 has shown the maximum encapsulation efficiency (80.3%) with less particle size (129.8 nm) and PDI (0.085). Also the zeta potential was found to be -36.4 and it confirms the stability of the formulation. The TEM and AFM morphological images of formulation F14 showed spherical, smooth-surfaced, and uniform sized particles. The formulations F13, F14, F15, F16, F17 and F18 showed maximum drug release of 93.1, 95.1, 91.6, 86.2, 89.7 and 87.3%, respectively when compared to pure drug THC. The drug release from the formulation and kinetic results was clearly indicative of sustained release of THC. The obtained drug release results evident that the solubility of THC is improved with LPH-NPs. Hence the developed formulation would enable the increased oral bioavailability of THC.\u003c/p\u003e","manuscriptTitle":"Lipid-Polymer Hybrid Nanoparticles for Solubility Enhancement of Tetrahydrocurcumin in a Noval Discriminative Dissolution Medium","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-16 12:01:23","doi":"10.21203/rs.3.rs-6623006/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-12T11:04:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-10T14:02:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"263712723358361948363375093509102590353","date":"2025-06-02T13:55:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-19T13:01:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"207527908466376799275612718612131396151","date":"2025-05-13T17:58:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-13T08:44:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-13T08:13:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-13T06:52:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"BioNanoScience","date":"2025-05-08T18:29:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bionanoscience","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnsc","sideBox":"Learn more about [BioNanoScience](http://link.springer.com/journal/12668)","snPcode":"12668","submissionUrl":"https://submission.nature.com/new-submission/12668/3","title":"BioNanoScience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dbfa74c0-a0ca-48f6-b75f-c87990cc22e3","owner":[],"postedDate":"May 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T16:02:23+00:00","versionOfRecord":{"articleIdentity":"rs-6623006","link":"https://doi.org/10.1007/s12668-025-02145-5","journal":{"identity":"bionanoscience","isVorOnly":false,"title":"BioNanoScience"},"publishedOn":"2025-09-15 15:57:38","publishedOnDateReadable":"September 15th, 2025"},"versionCreatedAt":"2025-05-16 12:01:23","video":"","vorDoi":"10.1007/s12668-025-02145-5","vorDoiUrl":"https://doi.org/10.1007/s12668-025-02145-5","workflowStages":[]},"version":"v1","identity":"rs-6623006","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6623006","identity":"rs-6623006","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}