Nano Aerosolized Chemotherapy (NAC) – a technology for generating nanoparticle aerosolized chemotherapy for intraperitoneal application

Nano Aerosolized Chemotherapy (NAC) – a technology for generating nanoparticle aerosolized chemotherapy for intraperitoneal application | 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 Nano Aerosolized Chemotherapy (NAC) – a technology for generating nanoparticle aerosolized chemotherapy for intraperitoneal application Sanket Mehta, Praveen Kammar, Palkesh Agrawal, Niharika Garach, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4158412/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Ultrasonic technology could be used for aerosol generation for intraperitoneal aerosolized chemotherapy. Current devices or systems for generation of aerosolized chemotherapy generate a polydisperse aerosol with the average droplet size measuring in micrometres. In this manuscript, we describe the functioning of a new device designed to generate nanoparticle-aerosolized chemotherapy for intraperitoneal application. The results of an experimental study looking at the particle size in the aerosol generated using this technology and another experiment evaluating its safety are presented and discussed. Methods A drug delivery system called nano-aerosolized chemotherapy (NAC) system was developed indigenously and has two components, a controller unit- Nanosol® and a nozzle – Nanowand®. The system has an accessory for aerosol evacuation, a nano-particle (NP) filter. In an experimental setting, doxorubicin, cisplatin and oxaliplatin were aerosolised using the NAC system. The aerosol that was deposited on a copper grid was studied using a transmission electron microscope (TEM). The experiment was repeated 3 times for each of the drugs. For the safety testing, cisplatin and doxorubicin were aerosolised in an experimental set up. Wipes from the operating table, the floor near it, the surgeon’s gloves and the air duct as well as two air samples were collected and tested for the presence of drug using inductively coupled plasma mass spectrometry (ICP-MS). The samples were collected with and without laminar air flow. Additional testing was performed to check the performance of the NP filter using a second inline filter. Results Nanoparticle aerosol was successfully generated using the NAC system. The average particle size was <65nm for doxorubicin in all three experiments, <66 nm for cisplatin and <63 nm for oxaliplatin. No micrometer sized particles were observed in any of the nine experiments. In all 8 wipe samples, the platinum levels were below detectable limits of 0.1ppb. In the 4 air samples and two samples from air filters, the platinum levels were also below detectable limits. Conclusions Doxorubicin, cisplatin and oxaliplatin were successfully aerosolized using the NAC system producing a nanoparticle aerosol. Future studies looking at spatial distribution, depth of penetration and tissue concentration will determine the suitability for clinical application. aerosolized chemotherapy NAC Ultrasonic aerosol generator intraperitoneal chemotherapy nanoparticle aerosol peritoneal metastases peritoneal carcinomatosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The discovery of the plasma peritoneal barrier led to the use of the peritoneal cavity as a route of drug delivery in patients with peritoneal malignancies.[ 1 ] To date, the most common mode of intraperitoneal chemotherapy (IPC) using liquid chemotherapy solutions is hyperthermic intraperitoneal chemotherapy (HIPEC) that involves circulation of a heated chemotherapy solution in the peritoneal cavity for 60–90 mins using a roller pump.[ 2 ] HIPEC is now performed by the minimally invasive route as well but has the problem of uneven drug distribution leading to under treatment of some peritoneal surfaces, variable tumour nodule uptake and a multitude of methodological, pharmacokinetic and pharmacodynamic variables that affect its efficacy.[ 3 , 4 ] Pressurized intraperitoneal aerosolised chemotherapy (PIPAC) is a technique of intraperitoneal drug delivery that overcomes some of the limitations of IPC using liquid solutions. [ 5 ] In PIPAC, the abdomen is accessed with two trocars and insufflated with CO2 under standard pressure conditions (12 mm Hg).[ 5 ] The chemotherapy solution is then aerosolized using a Capnopen (Capnopen®, Capnopharm, Villingendorf, Germany) that is available commercially around the world and the therapeutic capnoperitoneum maintained for 30 minutes. PIPAC in the experimental setting has shown a better drug distribution in the peritoneal cavity and deeper penetration in normal peritoneum compared to other modalities of IPC.[ 6 ] This technology has opened the opportunity for aerosolizing not just chemotherapy solutions but a lot of other drugs/solutions for intraperitoneal application.[ 7 ] The use of PIPAC is increasing world-wide thought its benefit over systemic chemotherapy alone has not been demonstrated in any well-designed randomized trial.[ 8 ] There are several limitations of PIPAC, the two main ones being the size of the droplets or the particle size which measures in micrometres and the depth of penetration being similar to other modalities of IPC except in the region directly under the nozzle.[ 9 ] One important factor that is known to influence the efficacy of IPC is the particle size. While large particles (100-1000nm in size) or microparticles are known to be retained in the peritoneal cavity for a longer period, nanoparticles have a greater diffusion in the cavity and a greater likelihood of being internalized by the cancer cells and releasing the drug therein.[ 10 ] Nanoparticles have been developed as carriers to deliver chemotherapeutic agents directly to the peritoneal cavity.[ 11 ] The clinical applications of numerous nanoparticle based drug delivery systems that have been developed are currently limited. Liposomal doxorubicin in which doxorubicin is delivered to the tumour tissue through nanometre- sized pegylated liposomes has proven to be both efficacious and less toxic than conventional doxorubicin in several malignancies.[ 12 ] However, it’s intraperitoneal use is limited. Similarly, nanoparticle albumin-bound paclitaxel has been used systemically with a marked reduction in the toxicity compared to the formulation in which an ethanol vehicle was used.[ 13 ] Ultrasonic nozzles have been used to generate aerosols in the chemical, biomedical, and pharmaceutical industry. [ 14 , 15 ] These nozzles convert high frequency sound waves into mechanical energy that aerosolizes the liquid passing through the nozzle. The main advantage is that the droplet size can be controlled. In this manuscript, we discuss the principle of ultrasonic aerosol generation and the functioning of a new device designed to generate aerosolized chemotherapy for intraperitoneal application. The results of an experimental study looking at the particle size in the aerosol generated using this technology and another experiment evaluating its safety are presented and discussed. Methods We developed a new system for intraperitoneal drug delivery called the nano-aerosolized chemotherapy (NAC) system based on the ultrasonic principle to generate a nano-particle aerosol. The principle of aerosol generation, the device that we have developed and the experimental study to determine the particle size and safety of the system in the preclinical setting are described herewith. Ultrasonic Atomization /aerosol generation Ultrasonic nozzles contain piezoelectric transducers that act on the tip and create capillary waves in a liquid film passing through the nozzle. Once the amplitude of these capillary waves reaches a critical height, they become too tall to support themselves and tiny droplets fall off the tip of each wave resulting in atomization. The size of the droplets generated depends on the frequency of vibration, the surface tension and viscosity of the liquid and the flow rate of the liquid.[ 16 ] The higher the frequency of vibration, the smaller the droplet size. Frequencies are commonly in the range of 20–180 kHz, beyond the range of human hearing. Unlike pressure nozzles, ultrasonic nozzles do not force liquids through a small orifice using high pressure in order to produce a spray. Liquid is fed through the centre of a nozzle, without pressure, and is atomized due to ultrasonic vibrations in the nozzle. Mechanism of Droplet Formation Atomization occurs owing to the competition between destructive and cohesive forces on the liquid surface, leading to fluctuations and disturbances in the liquid. [ 15 ] The cohesive effect of surface tension of the liquid keeps it in a state that has the lowest surface energy. The viscosity of the liquid has a stabilizing effect that counteracts any variation in the liquid geometry. Contrary to this, external forces that can be aerodynamic, centrifugal or electrostatic, act on the surface of the liquid and promote its disintegration. [ 16 ] An equation to calculate the size of droplets was developed based on multiple parameters by Robert Lang and this is described in detail in Supplement 1. [ 17 , 18 , 19 , 20 ] By changing the wavelength of the ultrasound waves, the droplet size can be altered and thus, the size of the drug particles in the droplets.[ 21 ] More details are provided in supplement 1 . Description of the ultrasonic device for generating nanoparticles: The drug delivery system is called NAC System (Fig. 1 ) and has two components and one additional accessory: A Controller unit – Nanosol® A Nozzle – Nanowand® Accessory: An evacuation system – NP Filter (Nano-particle Filter) The entire system was developed indigenously by Curotherm Techno Solutions LLP, Mumbai. The device was developed following the regulations laid down by CDSCO (Central drug standard control organization, Government of India) and is registered as a medical device under CDSCO in July 2021. The controller unit (Nanosol®) provides power to the probe, Nanowand® that has a hollow titanium tube 10 inches long with a circular hub at one end. The piezoelectric crystals are housed in the hub. These crystals receive energy from the controller and generate the ultrasonic waves. The hub also receives an external channel for fluid inflow from the infusion unit. Fluid is fed into the device under the effect of gravity. Fluid is fed at the rate of 0.5ml/second. The flow rate could be controlled independently. No pressure application is needed. This system was developed as an alternative for performing PIPAC. The Nanowand® is suitable for use through laparoscopic trocars. The whole procedure is termed ‘nano-aerosolised chemotherapy’ (NAC) as it is developed to generate a nanoparticle aerosol. The evacuation system – NP Filter is a specially designed filter system consisting of an inline filter and flexible tubes attached to it on either side. Its function is to filter out residual aerosolized drug particle from the peritoneal cavity. The filter has an ester membrane with nanometre-sized pores. Experimental study A. Particle Size Testing The size of the drug particles generated by aerosolizing different chemotherapy solutions using Nanosol® was studied. This study is performed at the SAIF (Sophisticated analytical instrument facility) laboratory at the All India Institute of Medical Sciences (AIIMS), New Delhi, India, which is a government certified laboratory for performing such experiments. The experimental set up was similar to what has been described for PIPAC. The setup mimics the intraabdominal milieu during laparoscopic surgery. A rectangular box made of high-density polyethylene (HDPE) box measuring 20 cm x 15 cm x 18 cm (height x width x length) and with volume of 5.4 litres was used. A copper grid with an outer diameter of 3.05 mm was placed at the bottom of the box. The grid had a mesh which had 300 squares and each side of each square measured 63 micrometres. The box was hermatically sealed to prevent leakage of aerosol from it. A 12mm trocar was inserted as shown in the figure. The distance between the end of the trocar and the copper grid was 10 cm. The box was insufflated with carbon-dioxide and the pressure set at 12mm of Hg using the equipment used during laparoscopic surgery. The Nanowand® was connected to the infusion system (burette set). Doxorubicin (4mg diluted in 50 ml NS) solution was then filled in the infusion bag and allowed to flow into the Nanowand® at a flow rate of 30ml/min (0.5ml/sec) under the effect of gravity. The control unit was turned on simultaneously and the drug is aerosolized and released in the box. Our goal was to achieve a particle size of around 60nm that is around the minimum particle size of 71nm obtained in PIPAC and a frequency of 60KHz is required to attain that. This particle size is independent of the flow rate. After aerosolizing 2ml of doxorubicin, the aerosolization is stopped and the copper grid was removed and loaded on a transmission electron microscope (HR-TEM, Make: FEI Tecnai G2, F30) chamber. The full quantity was not aerosolised as the goal was to study the particle size and aerosolising more liquid could lead to droplets coalescing and the particles overlapping each other thus making it difficult to measure their sizes. A 40-300kV electron beam was focused on it. The transmitted electrons were converted to visible light and images acquired through a high resolution digital CCD (Charged Coupled Device) camera, in conjunction with image processing software (iTEM of Olympus Soft Imaging System, Germany). Each square on the mesh had multiple droplets. The lens was than zoomed to “49000 x” on one droplet and an image captured along with the scale size on it. Similarly, multiple images from different square of the mesh of the copper grid were captured. The experiment was repeated with 3 times, using a different copper grid for each experiment. For each grid, 5 images were captured in ordered to cover the whole area of the grid, leading to a total of 15 images for each drug. Each droplet contained numerous particles and their sizes were measured using the ‘ImageJ’ software. Depending on the number of particles in each image, the number of particles measured varied. More than 50% of the particles were measured on each image. The smallest are largest particles were also measured. Thus, a total of 75–85 particle size measurements were performed for all three grids put together for each drug. In the same manner, oxaliplatin and cisplatin were aerosolized and the particle sized measured. B. Environmental and Operator Safety Testing This part of the study was carried out in the sterile environment of an operation theatre of Specialty Surgical Oncology Hospital and Research Centre (SSOHRC) with laminar air flow. The entrance of the operating room (OR) bore the sign of ‘chemotherapy in progress’. Personnel present in the OR had been trained for the procedure and wore personal protective equipment as described necessary for such chemotherapy administration (including waterproof surgical overall clothing, protective boot covers, double layer of sterile surgical gloves, N92 Mask, transparent face shield to minimize the risk for cutaneous exposure). Air sampling was performed with a custom device having air suction flow rate of 2 m 3 /h was used. A mixed cellulose ester nitrate filter (MF-Millipore) of diameter 47mm was installed in this custom device. Air samples are collected from this filter. The device was turned on an hour before the NAC was generated and kept turned on during the application time and the hold-up time of 30 mins both. For wipes from surfaces, mixed cellulose polyester non-woven wipes were used. A rectangular high-density polyethylene (HDPE) specially sealed box measuring 20cm x 15cm x 18cm (height x width x length) with a volume of 5.4 litres was placed at the centre of the OR table ( Fig. 1 ) . The height at which the box was placed was 100cm. A 12mm trocar was inserted in the box and a pressure of 12mmHg generated and maintained as described before. The Nanowand® was placed in the trocar and connected to drug delivery bag (burette set) and controller unit Nanosol®. Doxorubicin (4mg diluted in 50ml NS) was aerosolized first followed by Cisplatin (5mg diluted in 50ml NS). The hold-up time for aerosolized drug was 30 minutes. Air samples and wipes were taken from the following locations after the application time of 30 mins. Wipe sample 1: OR Table Wipe sample 2: OR floor near OR table Wipe sample 3: Surgeon’s gloves Wipe sample 4: Return air duct Air Sample 1: Near the OR table Air Sample 2: Near the return air duct The whole experiment was carried out twice with and without laminar air flow. Scenario 1: OR with laminar air flow Samples were stored in bottles tagged with the location and ‘laminar air flow condition’. Air filters were taken and stored in sample bottles tagged with location and details of the laminar air flow conditions. The 4 wipes and 2 air samples collected in this manner twice were then sent to Spectro analytical laboratories limited, Mumbai (An independent NABL certified laboratory) for further processing & testing. Scenario 2: OR with no laminar air flow. The same procedure was repeated with the laminar air flow system turned off. Analysis technique: Inductively coupled plasma mass spectrometry (ICP-MS) is an elemental analysis technology capable of detecting most of the periodic table of elements at milligram to nanogram levels per litre. The instrument used in this test was made by Agilent technologies (model 7700e). For microwave digestion, the MARS-1 apparatus by CEM corporation, NC, USA was used. Sample were prepared by the microwave digestion and analysis were performed on ICPMS. The details of the test are provided in Supplement 2. The test could detect platinum particles at a concentration as low as 0.1ppb. These values are less than allowable exposure limits of 2.5 ppb .[ 22 ] Evacuation System Testing This test was performed to check the efficacy of evacuation system - NP filter. The evacuation system was connected to the trocar as shown in Fig. 2 . The valve of the trocar was opened to let fresh air flow in which pushes the intraperitoneal gas into the filtering system. The other end of the evacuation system was connected to NP filter 2. The other end of NP filter 2 was connected to the regular suction system ( Fig. 2 ; supplement 2) . 15 minutes after opening the valve, the two filters were collected in sampling bottles labelled with ‘Evacuation filter 1 (NP Filter 1)’ and ‘Evacuation filter 2 (NP Filter 2)’ and sent to Spectro analytical laboratories limited, Mumbai (NABL certified laboratory) for further processing & testing. Two filters were used for this experiment alone and in the clinical setting only one filter will be used. The purpose of the second filter is to check if there are any particles that are not filtered by the first filter. Results Nanoparticle aerosol was successfully generated using the Nanosol® system. With the controller system turned on, drug was aerolized and sprayed in the box on all surfaces as well as the copper grid, placed at the bottom of the box. The aerosolization did not alter the color of the drug and the deposition of the aerosol was visible on all the inner surfaces of the box. A. Particle size measurement The goal was to achieve an average particle size of 60nm as this is the lowest particle size achieved with PIPAC. Doxorubicin Each square on the copper grid with each side measuring 63 micrometres had multiple droplets measuring 10–12 micrometres each. The particles in these droplets ranged from 27.4nm to 129.5nm ( Table 1 ) . Table 1 Mean particle size in each of the 9 grids on which the aerosol was sprayed Drug Grid Mean particle size in nanometres [range] Doxorubicin 1 63.0 [28.9-115.6] Doxorubicin 2 64.6 [34.2-117.6] Doxorubicin 3 57.1 [27.4- 129.5] Cisplatin 1 65.5 [31.5-142.6] Cisplatin 2 65.1 [36.8-118.1] Cisplatin 3 61.8 [37.2-134.3] Oxaliplatin 1 62.0 [28.6-135.6] Oxaliplatin 2 62.6 [30.6-128.9] Oxaliplatin 3 59.7 [35.2-101.7] In the 3 experiments, particles measuring more than 100nm were only seen 4 times. No micrometre- sized particles were observed. Figure 3 shows one image in which 9 measurements were performed. Cisplatin Each square with 63 micrometres in length had multiple droplets measuring 10–12 micrometres each. The particles in these droplets ranged from 31.5nm to 142.6nm. In the 3 experiments, particles measuring more than 100nm were only seen 7 times. No micrometre- sized particles were observed. Oxaliplatin Each square with 63 micrometres in length had multiple droplets measuring 10–12 micrometres each. The particles in these droplets ranged from 28.6nm to 135.6nm. In the 3 experiments, particles measuring more than 100nm were only seen 7 times. No micrometre sized particles were observed. Table 1 and Fig. 4 summarise the average particle size for the 9 experiments conducted on the 3 drugs. The detailed results are available in tabular form supplement 3 . Experimental and operator safety testing In all 8 wipe samples, the platinum levels were below detectable limits ( Table 2 ) . Table 2 Platinum levels in 8 wipe samples collected from different areas in the operating set up Sample no Sample description Test name Result Method detection limit Test method Wipe sample 1 OR table; laminar air flow on Platinum content, ppb BDL 0.1 Samples were prepared by microwave digestion and analysis performed on ICPMS Wipe sample 2 Floor near the operating table; laminar air flow on Platinum content, ppb BDL 0.1 Wipe sample 3 Surgeon’s gloves; laminar air flow on Platinum content, ppb BDL 0.1 Wipe sample 4 Return air duct; laminar air flow on Platinum content, ppb BDL 0.1 Wipe sample 5 OR table; laminar air flow off Platinum content, ppb BDL 0.1 Wipe sample 6 Floor near the operating table; laminar air flow off Platinum content, ppb BDL 0.1 Wipe sample 7 Surgeon’s gloves; laminar air flow off Platinum content, ppb BDL 0.1 Wipe sample 8 Return air duct; laminar air flow off Platinum content, ppb BDL 0.1 Air sample 1 Near the operating table; laminar air flow on Platinum content, ppb BDL 0.1 Air sample 2 Near the return air duct; laminar air flow on Platinum content, ppb BDL 0.1 Air sample 3 Near the operating table; laminar air flow off Platinum content, ppb BDL 0.1 Air sample 4 Near the return air duct; laminar air flow off Platinum content, ppb BDL 0.1 Air sample 5 Evacuation filter 1 Platinum content, ppb BDL 0.1 Air sample 6 Evacualtion filter 2 Platinum content, ppb BDL 0.1 Abbreviations: ppb- parts per billion; BDL- below detectable levels In the 4 air samples taken from the operating room and two samples taken from the air filters, the platinum levels were also below detectable limits. Efficacy of the evacuation system The platinum concentration was used as a marker for defining efficacy of filtration done by evacuation system. The platinum concentrations were below the detectable limit (Method detection limit is 0.1 ppb) in both the filters. This shows our evacuation system is effective. Discussion Using the NAC system, a nanoparticle aerosol was successfully generated. For all the three drugs that are most commonly used for aerosolised chemotherapy, nanoparticle aerosol was successfully generated. This is the first study to measure the drug particle size for all three drugs. Previous studies have focussed on the doxorubicin alone. The safety study duplicated the results achieved with what has been previously described in literature using the Capnopen. This was necessary as the quality of the aerosol generated with the two systems is different and could have different properties. More elaborate safety studies will be conducted during phase 1 studies in humans. Our experiment differs from all other conducted so far because we have focused not on the droplet size but the particle size of the drugs. During the atomisation, the drug is also broken down into smaller particles and this was what we aimed to measure. Hence, instead of using a granulometric analysis, TEM was used.[ 23 ] To measure the particle size with TEM, a copper grid is needed. It is not possible to perform this experiment on a patch of peritoneum. The experiment was repeated thrice for each drug to ensure reproducibility. Khosrawipour et al have challenged the concept that aerosol particles exhibit a gas-like behaviour in the abdomen creating a therapeutic capnoperitoneum. [ 24 ] PIPAC was performed on peritoneum samples via microcatheter (MC) at a pressure of 12 mmHg C0 2 at 27°C in an established ex-vivo model. Solutions of doxycycline, liposomal doxorubicin and macrophage cells were aerosolized. The surface structure of the particles generated and in contact with the peritoneum was studied using electron microscopy. When doxycycline aerosol came in contact with the peritoneum, a nanofilm, of ~ 200 nm height was created on the peritoneal surface. The height was independent on the particle size hitting that spot. However, coated particles such as liposomal doxorubicin and macrophages remained intact following contact with the peritoneal surface. They concluded that the interaction of the aerosol with the peritoneum is closer to the distribution of liquid film than that of a gas and further investigation was needed in this direction. The diffusion of drug particles into the peritoneum follows Fick’s law and is influenced by drug concentration and the actual size of the drug particles.[ 10 ] Thus, smaller the size of the drug particle better is the diffusion. However, the drug particle size has never been studied with respect to efficacy of PIPAC. For the NAC system, we are currently studying the depth of penetration and spatial distribution of the aerosol which will provide further proof of its efficacy in the experimental setting. We used the principle of ultrasonic atomisation for NAC system as it is considered most suitable for generation of nanoparticles.[ 25 ] The size of the particles can be controlled by adjusting the fluid velocity which is not possible using pressure injectors currently used to generate aIPC. Our aim was to generate nano-particle aerosol as the smaller the particle size, the better the diffusion into tumour tissues. The initial efforts to use aerosolized chemotherapy intraperitoneally comprised of a micropump using piezoelectric crystals.[ 26 ] The aerosol was produced by piezoelectric crystals stimulating three micro- perforated silicon chips. This pump was developed for multiple applications using the benefit of pneumoperitoneum created during laparoscopy and was able to aerosolize not just chemotherapy solutions but also other aqueous and ethanol-based solutions like bacteriostatic drugs and adhesion modulating agents, in vitro. In-vivo, since the chips were exposed to the intraperitoneal milieu, when the humidity reached 100%, water condensation occurred on them and aerosol generation stopped. Thus, gas had to be continuously removed from the peritoneal cavity, which is not done in routine laparoscopic surgery and would not be conducive to a procedure like PIPAC. In Nanosol®, the piezoelectric crystals are not exposed to the intraperitoneal milieu and this problem is avoided. In one study, the performance of a nebulizer using the ultrasonic principle was compared to the standard PIPAC device (Capnopen).[ 27 ] The spray pattern, granulometry and drug concentration in the tissue were similar for both devices but the depth of penetration was significantly lower for the ultrasound device, leading the authors to conclude that the former technology in its current form was inferior to the standard PIPAC technology.[ 27 ] Our system differs from the ultrasound technology described in this study- a pressure injector is not used for aerosol generation and the aerosol is a nanoparticle aerosol, thus these results cannot be extrapolated to the performance of the NAC system. The particle size generated by the NACT system falls within a narrow range. This is in contrast to the other aIPC devices that generate a polydisperse aerosol with a broader range of particles/droplets.[ 28 ] Some other advantages of Nanosol® are that a pressure injector is not required and thus a larger amount of solution can be aerosolised. The chamber of the pressure injector has a capacity of 150 ml thus limiting the quantity of liquid that is aerosolised. Since there is no leakage of the aerosol from the experimental set up, in future manipulation of the device during the aerosolization to distribute the aerosol more evenly is possible. There are multiple physical and biological barriers between nanoparticles and their targets once they are released in the peritoneal cavity. When they are directly instilled in the peritoneal cavity, the presence of organs, fluid, mucous, gravity and micro-obstacles such as phagocytosis that remove by macrophages and clearance through lymphatics all hinder their even distribution and delivery to the target tissues. Breaking down chemotherapy drugs into nanoparticle and delivering it an aerosolized form could overcome many of this barriers. Nanoparticles are ideal for uniform spatial distribution of the aerosol. [ 7 ] Nanoparticles are also produced using the capnopen but there is no way to control the proportion of small and large particles leading to an inhomogeneous aerosol. [ 27 ] The application time, drug doses and regimens, possibility of using other drugs like NAB paclitaxel and docetaxel will all have to be considered. The piezoelectric crystals and other electronics are embedded along with the nozzle and cannot be re-sterilized. Hence the device has to be of single use nature and thus avoiding any cross contamination between two patients. Conclusions Doxorubicin, cisplatin and oxaliplatin were successfully aerosolized using the NAC system producing a nanoparticle aerosol. 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ScientificWorldJournal. 2013 Dec 31;2013:482910. doi: 10.1155/2013/482910. PMID: 24501580; PMCID: PMC3899708. R.L. Peskin, R.J. Raco, J. Acoust. Soc. Am. 35 (9) (1963) 1378 L. Rayleigh, Proc. London Math. Soc. 10, 4 (1878) Rajan R 1 , Pandit AB. Correlations to predict droplet size in ultrasonic atomisation. Ultrasonics. 2001 Jun;39(4):235-55. R.J. Lang, Ultrasonic atomization of liquids, J. Acoust. Soc. Am. 34 (1962) 6. Delhorme JB, Klipfel A, D'Antonio F, Greget MC, Diemunsch P, Rohr S, Romain B, Brigand C. Occupational safety of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in an operating room without laminar airflow. J Visc Surg. 2019 Dec;156(6):485-488. doi: 10.1016/j.jviscsurg.2019.06.010. Onoyama K, Matsui S, Kikuchi M, Sato D, Fukamachi H, Kadena M, Funatsu T, Maruoka Y, Baba K, Maki K, Kuwata H. Particle Size Analysis in Aerosol-Generating Dental Procedures Using Laser Diffraction Technique. Front Oral Health. 2022 Feb 11;3:804314. doi: 10.3389/froh.2022.804314. PMID: 35224541; PMCID: PMC8873144. Khosrawipour V, Khosrawipour T, Kern AJ, Osma A, Kabakci B, Diaz-Carballo D, Förster E, Zieren J, Fakhrian K. Distribution pattern and penetration depth of doxorubicin after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a postmortem swine model. J Cancer Res Clin Oncol. 2016 Nov;142(11):2275-80. doi: 10.1007/s00432-016-2234-0. Epub 2016 Sep 2. PMID: 27590613. Nii, S. (2016). Ultrasonic Atomization. In: Handbook of Ultrasonics and Sonochemistry. Springer, Singapore. https://doi.org/10.1007/978-981-287-278-4_7 Reymond M.A., Hu B., Garcia A., Reck T., Kockerling F., Hess J., Morel P. Feasibility of therapeutic pneumoperitoneum in a large animal model using a microvaporisator. Surg. Endosc. 2000;14:51–55. doi: 10.1007/s004649900010 Höltzcke P, Sautkin I, Clere S, Castagna A, Königsrainer A, Pott PP, Reymond MA. Feasibility of pressurized intra peritoneal aerosol chemotherapy using an ultrasound aerosol generator (usPIPAC). Surg Endosc. 2022 Oct;36(10):7848-7858. doi: 10.1007/s00464-022-09525-y. Epub 2022 Aug 29. Gohler D., Khosrawipour V., Khosrawipour T., Diaz-Carballo D., Falkenstein T.A., Zieren J., Stintz M., Giger-Pabst U. Technical description of the microinjection pump (MIP((R))) and granulometric characterization of the aerosol applied for pressurized intraperitoneal aerosol chemotherapy (PIPAC) Surg. Endosc. 2017;31:1778–1784. doi: 10.1007/s00464-016-5174-5. Additional Declarations Competing interest reported. The study was funded by Curotherm Techno Solutions LLP and two of the authors belong to the organization. Supplementary Files Supplement1mechanismofdropletformation.docx Supplement2.xlsx Supplement3.docx Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-4158412","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":283818947,"identity":"49d58177-cee3-4e55-bf97-46e2f7e58b9d","order_by":0,"name":"Sanket Mehta","email":"","orcid":"","institution":"Specialty Surgical Oncology Hospital and Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Sanket","middleName":"","lastName":"Mehta","suffix":""},{"id":283818948,"identity":"ad2322a2-9c68-44a6-bb2b-a5020071feb9","order_by":1,"name":"Praveen Kammar","email":"","orcid":"","institution":"Specialty Surgical Oncology Hospital and Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Praveen","middleName":"","lastName":"Kammar","suffix":""},{"id":283818950,"identity":"4331f448-43b0-4feb-b317-baa3dd4b39e1","order_by":2,"name":"Palkesh Agrawal","email":"","orcid":"","institution":"Curotherm Techno Solutions LLP","correspondingAuthor":false,"prefix":"","firstName":"Palkesh","middleName":"","lastName":"Agrawal","suffix":""},{"id":283818952,"identity":"aec8645a-baa5-4ed1-9a4e-c720b6dc2a2f","order_by":3,"name":"Niharika Garach","email":"","orcid":"","institution":"Specialty Surgical Oncology Hospital and Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Niharika","middleName":"","lastName":"Garach","suffix":""},{"id":283818954,"identity":"b304b8af-be7b-46d6-88d2-66e9b3240a5a","order_by":4,"name":"Vivek Sukumar","email":"","orcid":"","institution":"Specialty Surgical Oncology Hospital and Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Vivek","middleName":"","lastName":"Sukumar","suffix":""},{"id":283818956,"identity":"15892962-6ad0-46c2-832d-5ba705ad1186","order_by":5,"name":"Nirav Mehta","email":"","orcid":"","institution":"Curotherm Techno Solutions LLP","correspondingAuthor":false,"prefix":"","firstName":"Nirav","middleName":"","lastName":"Mehta","suffix":""},{"id":283818958,"identity":"618fbb70-1e5e-458e-8c27-e4e31b336e8e","order_by":6,"name":"Aditi Bhatt","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYFCCxAaGBAYGxjb+xsYHQC4PHxFaGhvAWiQONxuAtLAR1pLA2AAkgUR6mwSIT1ALf3ty+4OHOTayfQwH2yq/5tjJsDEwP3x0A48WiTMPGxsSt6UZtzE3tt2W3ZYMdBibsXEOPmtuJIK0HE5sA9pyW3IbM1ALD5s0Pi3yCC2JbcWS2+oJazFA1sL4cdthwloMgX6ZAfaLxMFmacZtx3nYmAn4Re54+oOPP7fZyM7vb38IZFTb87M3P3yM1/vIgJkHTBKrHAQYf5CiehSMglEwCkYMAAD8KlAFHRV/BwAAAABJRU5ErkJggg==","orcid":"","institution":"KD hospital","correspondingAuthor":true,"prefix":"","firstName":"Aditi","middleName":"","lastName":"Bhatt","suffix":""}],"badges":[],"createdAt":"2024-03-24 14:29:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4158412/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4158412/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53530342,"identity":"bae88e27-814a-44d4-812b-1a4c25e9b8c3","added_by":"auto","created_at":"2024-03-27 06:13:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1173078,"visible":true,"origin":"","legend":"\u003cp\u003eThe experimental set-up for testing environmental and operator safety\u003c/p\u003e\n\u003cp\u003eThe custom air sampling devices are circled in blue. Each has an air suction flow rate of 2 m3/h. A filter is attached at suction point of this device. This filter is a cellulose ester nitrate filter (MF-Millipore) of diameter 47mm. It is used for air sampling during environmental and Operator safety testing only.The nozzle Nanowand® is circled yellow\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/c46c0e19b9123f19abbf9a11.jpg"},{"id":53530106,"identity":"e6f0a473-8483-4ad5-a134-15d8aa9315f5","added_by":"auto","created_at":"2024-03-27 06:05:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":63985,"visible":true,"origin":"","legend":"\u003cp\u003eDiagrammatic representation of the evacuation system test\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/c5cef2bc12a8cc7fdf184782.png"},{"id":53530111,"identity":"547efbfa-814f-4160-b843-1906c0f7b7ce","added_by":"auto","created_at":"2024-03-27 06:05:02","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":335860,"visible":true,"origin":"","legend":"\u003cp\u003eDoxorubicin particles as they appear on TEM with the corresponding measurements (image 4 of grid 1)\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/4247a83d43712e1161c81735.jpg"},{"id":53530113,"identity":"0dcd38a3-9a90-4bab-9cf0-d35d77040355","added_by":"auto","created_at":"2024-03-27 06:05:02","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1387889,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical representation of the number and size of particles in each of the 9 copper grids\u003c/p\u003e\n\u003cp\u003eX-axis: image number and the individual size of the particles\u003c/p\u003e\n\u003cp\u003eY-axis: diameter of the individual particles\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/c07bd157ed800d771f1af0f6.jpg"},{"id":55448195,"identity":"b0bbe9fe-9e7e-4987-8344-3b970da03397","added_by":"auto","created_at":"2024-04-28 05:05:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1198916,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/add1ef4e-6564-49df-a56e-79c7ab0302e1.pdf"},{"id":53530107,"identity":"bd9f19f7-0288-4e77-b922-46c8d05c28ac","added_by":"auto","created_at":"2024-03-27 06:05:02","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":44707,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement1mechanismofdropletformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/62ed0b2d26625a730678f119.docx"},{"id":53530108,"identity":"904f49fb-0118-49ea-b537-dfde111e4828","added_by":"auto","created_at":"2024-03-27 06:05:02","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":124526,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/82d72e783ea44b9a64f435ab.xlsx"},{"id":53530343,"identity":"b93317f4-ca9c-4f15-ac05-78d3821486be","added_by":"auto","created_at":"2024-03-27 06:13:02","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":410803,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4158412/v1/633bdb18c727a08b5bba71e0.docx"}],"financialInterests":"Competing interest reported. The study was funded by Curotherm Techno Solutions LLP and two of the authors belong to the organization.","formattedTitle":"Nano Aerosolized Chemotherapy (NAC) – a technology for generating nanoparticle aerosolized chemotherapy for intraperitoneal application","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe discovery of the plasma peritoneal barrier led to the use of the peritoneal cavity as a route of drug delivery in patients with peritoneal malignancies.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] To date, the most common mode of intraperitoneal chemotherapy (IPC) using liquid chemotherapy solutions is hyperthermic intraperitoneal chemotherapy (HIPEC) that involves circulation of a heated chemotherapy solution in the peritoneal cavity for 60\u0026ndash;90 mins using a roller pump.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] HIPEC is now performed by the minimally invasive route as well but has the problem of uneven drug distribution leading to under treatment of some peritoneal surfaces, variable tumour nodule uptake and a multitude of methodological, pharmacokinetic and pharmacodynamic variables that affect its efficacy.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Pressurized intraperitoneal aerosolised chemotherapy (PIPAC) is a technique of intraperitoneal drug delivery that overcomes some of the limitations of IPC using liquid solutions. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] In PIPAC, the abdomen is accessed with two trocars and insufflated with CO2 under standard pressure conditions (12 mm Hg).[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] The chemotherapy solution is then aerosolized using a Capnopen (Capnopen\u0026reg;, Capnopharm, Villingendorf, Germany) that is available commercially around the world and the therapeutic capnoperitoneum maintained for 30 minutes. PIPAC in the experimental setting has shown a better drug distribution in the peritoneal cavity and deeper penetration in normal peritoneum compared to other modalities of IPC.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] This technology has opened the opportunity for aerosolizing not just chemotherapy solutions but a lot of other drugs/solutions for intraperitoneal application.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] The use of PIPAC is increasing world-wide thought its benefit over systemic chemotherapy alone has not been demonstrated in any well-designed randomized trial.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] There are several limitations of PIPAC, the two main ones being the size of the droplets or the particle size which measures in micrometres and the depth of penetration being similar to other modalities of IPC except in the region directly under the nozzle.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOne important factor that is known to influence the efficacy of IPC is the particle size. While large particles (100-1000nm in size) or microparticles are known to be retained in the peritoneal cavity for a longer period, nanoparticles have a greater diffusion in the cavity and a greater likelihood of being internalized by the cancer cells and releasing the drug therein.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Nanoparticles have been developed as carriers to deliver chemotherapeutic agents directly to the peritoneal cavity.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] The clinical applications of numerous nanoparticle based drug delivery systems that have been developed are currently limited.\u003c/p\u003e \u003cp\u003eLiposomal doxorubicin in which doxorubicin is delivered to the tumour tissue through nanometre- sized pegylated liposomes has proven to be both efficacious and less toxic than conventional doxorubicin in several malignancies.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] However, it\u0026rsquo;s intraperitoneal use is limited. Similarly, nanoparticle albumin-bound paclitaxel has been used systemically with a marked reduction in the toxicity compared to the formulation in which an ethanol vehicle was used.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eUltrasonic nozzles have been used to generate aerosols in the chemical, biomedical, and pharmaceutical industry. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] These nozzles convert high frequency sound waves into mechanical energy that aerosolizes the liquid passing through the nozzle. The main advantage is that the droplet size can be controlled. In this manuscript, we discuss the principle of ultrasonic aerosol generation and the functioning of a new device designed to generate aerosolized chemotherapy for intraperitoneal application. The results of an experimental study looking at the particle size in the aerosol generated using this technology and another experiment evaluating its safety are presented and discussed.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe developed a new system for intraperitoneal drug delivery called the nano-aerosolized chemotherapy (NAC) system based on the ultrasonic principle to generate a nano-particle aerosol. The principle of aerosol generation, the device that we have developed and the experimental study to determine the particle size and safety of the system in the preclinical setting are described herewith.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eUltrasonic Atomization /aerosol generation\u003c/h2\u003e\n\u003cp\u003eUltrasonic nozzles contain piezoelectric transducers that act on the tip and create capillary waves in a liquid film passing through the nozzle. Once the amplitude of these capillary waves reaches a critical height, they become too tall to support themselves and tiny droplets fall off the tip of each wave resulting in atomization. The size of the droplets generated depends on the frequency of vibration, the surface tension and viscosity of the liquid and the flow rate of the liquid.[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e] The higher the frequency of vibration, the smaller the droplet size. Frequencies are commonly in the range of 20\u0026ndash;180 kHz, beyond the range of human hearing. Unlike pressure nozzles, ultrasonic nozzles do not force liquids through a small orifice using high pressure in order to produce a spray. Liquid is fed through the centre of a nozzle, without pressure, and is atomized due to ultrasonic vibrations in the nozzle.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eMechanism of Droplet Formation\u003c/h2\u003e\n\u003cp\u003eAtomization occurs owing to the competition between destructive and cohesive forces on the liquid surface, leading to fluctuations and disturbances in the liquid. [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e] The cohesive effect of surface tension of the liquid keeps it in a state that has the lowest surface energy. The viscosity of the liquid has a stabilizing effect that counteracts any variation in the liquid geometry. Contrary to this, external forces that can be aerodynamic, centrifugal or electrostatic, act on the surface of the liquid and promote its disintegration. [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eAn equation to calculate the size of droplets was developed based on multiple parameters by Robert Lang and this is described in detail in Supplement 1. [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e] By changing the wavelength of the ultrasound waves, the droplet size can be altered and thus, the size of the drug particles in the droplets.[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e] More details are provided in \u003cstrong\u003esupplement 1\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eDescription of the ultrasonic device for generating nanoparticles:\u003c/h2\u003e\n\u003cp\u003eThe drug delivery system is called NAC System (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) and has two components and one additional accessory:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eA Controller unit \u0026ndash; Nanosol\u0026reg;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eA Nozzle \u0026ndash; Nanowand\u0026reg;\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eAccessory:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eAn evacuation system \u0026ndash; NP Filter (Nano-particle Filter)\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe entire system was developed indigenously by Curotherm Techno Solutions LLP, Mumbai. The device was developed following the regulations laid down by CDSCO (Central drug standard control organization, Government of India) and is registered as a medical device under CDSCO in July 2021.\u003c/p\u003e\n\u003cp\u003eThe controller unit (Nanosol\u0026reg;) provides power to the probe, Nanowand\u0026reg; that has a hollow titanium tube 10 inches long with a circular hub at one end. The piezoelectric crystals are housed in the hub. These crystals receive energy from the controller and generate the ultrasonic waves. The hub also receives an external channel for fluid inflow from the infusion unit. Fluid is fed into the device under the effect of gravity. Fluid is fed at the rate of 0.5ml/second. The flow rate could be controlled independently. No pressure application is needed. This system was developed as an alternative for performing PIPAC. The Nanowand\u0026reg; is suitable for use through laparoscopic trocars. The whole procedure is termed \u0026lsquo;nano-aerosolised chemotherapy\u0026rsquo; (NAC) as it is developed to generate a nanoparticle aerosol.\u003c/p\u003e\n\u003cp\u003eThe evacuation system \u0026ndash; NP Filter is a specially designed filter system consisting of an inline filter and flexible tubes attached to it on either side. Its function is to filter out residual aerosolized drug particle from the peritoneal cavity. The filter has an ester membrane with nanometre-sized pores.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperimental study\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eA. Particle Size Testing\u003c/h2\u003e\n\u003cp\u003eThe size of the drug particles generated by aerosolizing different chemotherapy solutions using Nanosol\u0026reg; was studied. This study is performed at the SAIF (Sophisticated analytical instrument facility) laboratory at the All India Institute of Medical Sciences (AIIMS), New Delhi, India, which is a government certified laboratory for performing such experiments. The experimental set up was similar to what has been described for PIPAC. The setup mimics the intraabdominal milieu during laparoscopic surgery.\u003c/p\u003e\n\u003cp\u003eA rectangular box made of high-density polyethylene (HDPE) box measuring 20 cm x 15 cm x 18 cm (height x width x length) and with volume of 5.4 litres was used. A copper grid with an outer diameter of 3.05 mm was placed at the bottom of the box. The grid had a mesh which had 300 squares and each side of each square measured 63 micrometres. The box was hermatically sealed to prevent leakage of aerosol from it. A 12mm trocar was inserted as shown in the figure. The distance between the end of the trocar and the copper grid was 10 cm. The box was insufflated with carbon-dioxide and the pressure set at 12mm of Hg using the equipment used during laparoscopic surgery. The Nanowand\u0026reg; was connected to the infusion system (burette set). Doxorubicin (4mg diluted in 50 ml NS) solution was then filled in the infusion bag and allowed to flow into the Nanowand\u0026reg; at a flow rate of 30ml/min (0.5ml/sec) under the effect of gravity. The control unit was turned on simultaneously and the drug is aerosolized and released in the box. Our goal was to achieve a particle size of around 60nm that is around the minimum particle size of 71nm obtained in PIPAC and a frequency of 60KHz is required to attain that. This particle size is independent of the flow rate.\u003c/p\u003e\n\u003cp\u003eAfter aerosolizing 2ml of doxorubicin, the aerosolization is stopped and the copper grid was removed and loaded on a transmission electron microscope (HR-TEM, Make: FEI Tecnai G2, F30) chamber. The full quantity was not aerosolised as the goal was to study the particle size and aerosolising more liquid could lead to droplets coalescing and the particles overlapping each other thus making it difficult to measure their sizes. A 40-300kV electron beam was focused on it. The transmitted electrons were converted to visible light and images acquired through a high resolution digital CCD (Charged Coupled Device) camera, in conjunction with image processing software (iTEM of Olympus Soft Imaging System, Germany). Each square on the mesh had multiple droplets. The lens was than zoomed to \u0026ldquo;49000 x\u0026rdquo; on one droplet and an image captured along with the scale size on it. Similarly, multiple images from different square of the mesh of the copper grid were captured. The experiment was repeated with 3 times, using a different copper grid for each experiment. For each grid, 5 images were captured in ordered to cover the whole area of the grid, leading to a total of 15 images for each drug. Each droplet contained numerous particles and their sizes were measured using the \u0026lsquo;ImageJ\u0026rsquo; software. Depending on the number of particles in each image, the number of particles measured varied. More than 50% of the particles were measured on each image. The smallest are largest particles were also measured. Thus, a total of 75\u0026ndash;85 particle size measurements were performed for all three grids put together for each drug.\u003c/p\u003e\n\u003cp\u003eIn the same manner, oxaliplatin and cisplatin were aerosolized and the particle sized measured.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eB. Environmental and Operator Safety Testing\u003c/h2\u003e\n\u003cp\u003eThis part of the study was carried out in the sterile environment of an operation theatre of Specialty Surgical Oncology Hospital and Research Centre (SSOHRC) with laminar air flow. The entrance of the operating room (OR) bore the sign of \u0026lsquo;chemotherapy in progress\u0026rsquo;. Personnel present in the OR had been trained for the procedure and wore personal protective equipment as described necessary for such chemotherapy administration (including waterproof surgical overall clothing, protective boot covers, double layer of sterile surgical gloves, N92 Mask, transparent face shield to minimize the risk for cutaneous exposure).\u003c/p\u003e\n\u003cp\u003eAir sampling was performed with a custom device having air suction flow rate of 2 m\u003csup\u003e3\u003c/sup\u003e/h was used. A mixed cellulose ester nitrate filter (MF-Millipore) of diameter 47mm was installed in this custom device. Air samples are collected from this filter. The device was turned on an hour before the NAC was generated and kept turned on during the application time and the hold-up time of 30 mins both. For wipes from surfaces, mixed cellulose polyester non-woven wipes were used.\u003c/p\u003e\n\u003cp\u003eA rectangular high-density polyethylene (HDPE) specially sealed box measuring 20cm x 15cm x 18cm (height x width x length) with a volume of 5.4 litres was placed at the centre of the OR table \u003cstrong\u003e(\u003c/strong\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe height at which the box was placed was 100cm. A 12mm trocar was inserted in the box and a pressure of 12mmHg generated and maintained as described before. The Nanowand\u0026reg; was placed in the trocar and connected to drug delivery bag (burette set) and controller unit Nanosol\u0026reg;. Doxorubicin (4mg diluted in 50ml NS) was aerosolized first followed by Cisplatin (5mg diluted in 50ml NS). The hold-up time for aerosolized drug was 30 minutes. Air samples and wipes were taken from the following locations after the application time of 30 mins.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eWipe sample 1: OR Table\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eWipe sample 2: OR floor near OR table\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eWipe sample 3: Surgeon\u0026rsquo;s gloves\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eWipe sample 4: Return air duct\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAir Sample 1: Near the OR table\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eAir Sample 2: Near the return air duct\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe whole experiment was carried out twice with and without laminar air flow.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eScenario 1: OR with laminar air flow\u003c/h2\u003e\n\u003cp\u003eSamples were stored in bottles tagged with the location and \u0026lsquo;laminar air flow condition\u0026rsquo;. Air filters were taken and stored in sample bottles tagged with location and details of the laminar air flow conditions. The 4 wipes and 2 air samples collected in this manner twice were then sent to Spectro analytical laboratories limited, Mumbai (An independent NABL certified laboratory) for further processing \u0026amp; testing.\u003c/p\u003e\n\u003cp\u003eScenario 2: OR with no laminar air flow. The same procedure was repeated with the laminar air flow system turned off.\u003c/p\u003e\n\u003cp\u003eAnalysis technique:\u003c/p\u003e\n\u003cp\u003eInductively coupled plasma mass spectrometry (ICP-MS) is an elemental analysis technology capable of detecting most of the periodic table of elements at milligram to nanogram levels per litre. The instrument used in this test was made by Agilent technologies (model 7700e).\u003c/p\u003e\n\u003cp\u003eFor microwave digestion, the MARS-1 apparatus by CEM corporation, NC, USA was used.\u003c/p\u003e\n\u003cp\u003eSample were prepared by the microwave digestion and analysis were performed on ICPMS. The details of the test are provided in Supplement 2.\u003c/p\u003e\n\u003cp\u003eThe test could detect platinum particles at a concentration as low as 0.1ppb.\u003c/p\u003e\n\u003cp\u003eThese values are less than allowable exposure limits of \u003cstrong\u003e2.5 ppb\u003c/strong\u003e.[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eEvacuation System Testing\u003c/h2\u003e\n\u003cp\u003eThis test was performed to check the efficacy of evacuation system - NP filter. The evacuation system was connected to the trocar as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eThe valve of the trocar was opened to let fresh air flow in which pushes the intraperitoneal gas into the filtering system. The other end of the evacuation system was connected to NP filter 2. The other end of NP filter 2 was connected to the regular suction system \u003cstrong\u003e(\u003c/strong\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e; \u003cstrong\u003esupplement 2)\u003c/strong\u003e. 15 minutes after opening the valve, the two filters were collected in sampling bottles labelled with \u0026lsquo;Evacuation filter 1 (NP Filter 1)\u0026rsquo; and \u0026lsquo;Evacuation filter 2 (NP Filter 2)\u0026rsquo; and sent to Spectro analytical laboratories limited, Mumbai (NABL certified laboratory) for further processing \u0026amp; testing. Two filters were used for this experiment alone and in the clinical setting only one filter will be used. The purpose of the second filter is to check if there are any particles that are not filtered by the first filter.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eNanoparticle aerosol was successfully generated using the Nanosol\u0026reg; system. With the controller system turned on, drug was aerolized and sprayed in the box on all surfaces as well as the copper grid, placed at the bottom of the box. The aerosolization did not alter the color of the drug and the deposition of the aerosol was visible on all the inner surfaces of the box.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eA. Particle size measurement\u003c/h2\u003e\n \u003cp\u003eThe goal was to achieve an average particle size of 60nm as this is the lowest particle size achieved with PIPAC.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eDoxorubicin\u003c/h2\u003e\n \u003cp\u003eEach square on the copper grid with each side measuring 63 micrometres had multiple droplets measuring 10\u0026ndash;12 micrometres each. The particles in these droplets ranged from 27.4nm to 129.5nm \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMean particle size in each of the 9 grids on which the aerosol was sprayed\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDrug\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGrid\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean particle size in nanometres [range]\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoxorubicin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63.0 [28.9-115.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoxorubicin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e64.6 [34.2-117.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoxorubicin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57.1 [27.4- 129.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCisplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65.5 [31.5-142.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCisplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65.1 [36.8-118.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCisplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61.8 [37.2-134.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62.0 [28.6-135.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62.6 [30.6-128.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59.7 [35.2-101.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eIn the 3 experiments, particles measuring more than 100nm were only seen 4 times. No micrometre- sized particles were observed. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e shows one image in which 9 measurements were performed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eCisplatin\u003c/h2\u003e\n \u003cp\u003eEach square with 63 micrometres in length had multiple droplets measuring 10\u0026ndash;12 micrometres each. The particles in these droplets ranged from 31.5nm to 142.6nm. In the 3 experiments, particles measuring more than 100nm were only seen 7 times. No micrometre- sized particles were observed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eOxaliplatin\u003c/h2\u003e\n \u003cp\u003eEach square with 63 micrometres in length had multiple droplets measuring 10\u0026ndash;12 micrometres each. The particles in these droplets ranged from 28.6nm to 135.6nm. In the 3 experiments, particles measuring more than 100nm were only seen 7 times. No micrometre sized particles were observed.\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e summarise the average particle size for the 9 experiments conducted on the 3 drugs. The detailed results are available in tabular form \u003cstrong\u003esupplement 3\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eExperimental and operator safety testing\u003c/h2\u003e\n \u003cp\u003eIn all 8 wipe samples, the platinum levels were below detectable limits \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePlatinum levels in 8 wipe samples collected from different areas in the operating set up\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample no\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample description\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTest name\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eResult\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMethod detection limit\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTest method\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR table; laminar air flow on\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"14\" align=\"left\"\u003e\n \u003cp\u003eSamples were prepared by microwave digestion and analysis performed on ICPMS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFloor near the operating table; laminar air flow on\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurgeon\u0026rsquo;s gloves; laminar air flow on\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReturn air duct; laminar air flow on\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR table; laminar air flow off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFloor near the operating table; laminar air flow off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurgeon\u0026rsquo;s gloves; laminar air flow off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWipe sample 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReturn air duct; laminar air flow off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAir sample 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNear the operating table; laminar air flow on\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAir sample 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNear the return air duct; laminar air flow on\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAir sample 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNear the operating table; laminar air flow off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAir sample 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNear the return air duct; laminar air flow off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAir sample 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEvacuation filter 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAir sample 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEvacualtion filter 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum content, ppb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eAbbreviations: ppb- parts per billion; BDL- below detectable levels\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eIn the 4 air samples taken from the operating room and two samples taken from the air filters, the platinum levels were also below detectable limits.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEfficacy of the evacuation system\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe platinum concentration was used as a marker for defining efficacy of filtration done by evacuation system. The platinum concentrations were below the detectable limit (Method detection limit is 0.1 ppb) in both the filters.\u003c/p\u003e\n \u003cp\u003eThis shows our evacuation system is effective.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion ","content":"\u003cp\u003eUsing the NAC system, a nanoparticle aerosol was successfully generated.\u003c/p\u003e\n\u003cp\u003eFor all the three drugs that are most commonly used for aerosolised chemotherapy, nanoparticle aerosol was successfully generated. This is the first study to measure the drug particle size for all three drugs. Previous studies have focussed on the doxorubicin alone. The safety study duplicated the results achieved with what has been previously described in literature using the Capnopen. This was necessary as the quality of the aerosol generated with the two systems is different and could have different properties. More elaborate safety studies will be conducted during phase 1 studies in humans.\u003c/p\u003e\n\u003cp\u003eOur experiment differs from all other conducted so far because we have focused not on the droplet size but the particle size of the drugs. During the atomisation, the drug is also broken down into smaller particles and this was what we aimed to measure. Hence, instead of using a granulometric analysis, TEM was used.[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e] To measure the particle size with TEM, a copper grid is needed. It is not possible to perform this experiment on a patch of peritoneum. The experiment was repeated thrice for each drug to ensure reproducibility.\u003c/p\u003e\n\u003cp\u003eKhosrawipour et al have challenged the concept that aerosol particles exhibit a gas-like behaviour in the abdomen creating a therapeutic capnoperitoneum. [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e] PIPAC was performed on peritoneum samples via microcatheter (MC) at a pressure of 12 mmHg C0\u003csub\u003e2\u003c/sub\u003e at 27\u0026deg;C in an established ex-vivo model. Solutions of doxycycline, liposomal doxorubicin and macrophage cells were aerosolized. The surface structure of the particles generated and in contact with the peritoneum was studied using electron microscopy. When doxycycline aerosol came in contact with the peritoneum, a nanofilm, of ~\u0026thinsp;200 nm height was created on the peritoneal surface. The height was independent on the particle size hitting that spot. However, coated particles such as liposomal doxorubicin and macrophages remained intact following contact with the peritoneal surface. They concluded that the interaction of the aerosol with the peritoneum is closer to the distribution of liquid film than that of a gas and further investigation was needed in this direction. The diffusion of drug particles into the peritoneum follows Fick\u0026rsquo;s law and is influenced by drug concentration and the actual size of the drug particles.[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e] Thus, smaller the size of the drug particle better is the diffusion. However, the drug particle size has never been studied with respect to efficacy of PIPAC. For the NAC system, we are currently studying the depth of penetration and spatial distribution of the aerosol which will provide further proof of its efficacy in the experimental setting.\u003c/p\u003e\n\u003cp\u003eWe used the principle of ultrasonic atomisation for NAC system as it is considered most suitable for generation of nanoparticles.[\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e] The size of the particles can be controlled by adjusting the fluid velocity which is not possible using pressure injectors currently used to generate aIPC. Our aim was to generate nano-particle aerosol as the smaller the particle size, the better the diffusion into tumour tissues.\u003c/p\u003e\n\u003cp\u003eThe initial efforts to use aerosolized chemotherapy intraperitoneally comprised of a micropump using piezoelectric crystals.[\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e] The aerosol was produced by piezoelectric crystals stimulating three micro- perforated silicon chips. This pump was developed for multiple applications using the benefit of pneumoperitoneum created during laparoscopy and was able to aerosolize not just chemotherapy solutions but also other aqueous and ethanol-based solutions like bacteriostatic drugs and adhesion modulating agents, in vitro. In-vivo, since the chips were exposed to the intraperitoneal milieu, when the humidity reached 100%, water condensation occurred on them and aerosol generation stopped. Thus, gas had to be continuously removed from the peritoneal cavity, which is not done in routine laparoscopic surgery and would not be conducive to a procedure like PIPAC. In Nanosol\u0026reg;, the piezoelectric crystals are not exposed to the intraperitoneal milieu and this problem is avoided. In one study, the performance of a nebulizer using the ultrasonic principle was compared to the standard PIPAC device (Capnopen).[\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] The spray pattern, granulometry and drug concentration in the tissue were similar for both devices but the depth of penetration was significantly lower for the ultrasound device, leading the authors to conclude that the former technology in its current form was inferior to the standard PIPAC technology.[\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] Our system differs from the ultrasound technology described in this study- a pressure injector is not used for aerosol generation and the aerosol is a nanoparticle aerosol, thus these results cannot be extrapolated to the performance of the NAC system.\u003c/p\u003e\n\u003cp\u003eThe particle size generated by the NACT system falls within a narrow range. This is in contrast to the other aIPC devices that generate a polydisperse aerosol with a broader range of particles/droplets.[\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eSome other advantages of Nanosol\u0026reg; are that a pressure injector is not required and thus a larger amount of solution can be aerosolised. The chamber of the pressure injector has a capacity of 150 ml thus limiting the quantity of liquid that is aerosolised. Since there is no leakage of the aerosol from the experimental set up, in future manipulation of the device during the aerosolization to distribute the aerosol more evenly is possible.\u003c/p\u003e\n\u003cp\u003eThere are multiple physical and biological barriers between nanoparticles and their targets once they are released in the peritoneal cavity. When they are directly instilled in the peritoneal cavity, the presence of organs, fluid, mucous, gravity and micro-obstacles such as phagocytosis that remove by macrophages and clearance through lymphatics all hinder their even distribution and delivery to the target tissues. Breaking down chemotherapy drugs into nanoparticle and delivering it an aerosolized form could overcome many of this barriers. Nanoparticles are ideal for uniform spatial distribution of the aerosol. [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e] Nanoparticles are also produced using the capnopen but there is no way to control the proportion of small and large particles leading to an inhomogeneous aerosol. [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eThe application time, drug doses and regimens, possibility of using other drugs like NAB paclitaxel and docetaxel will all have to be considered. The piezoelectric crystals and other electronics are embedded along with the nozzle and cannot be re-sterilized. Hence the device has to be of single use nature and thus avoiding any cross contamination between two patients.\u003c/p\u003e"},{"header":"Conclusions ","content":"\u003cp\u003eDoxorubicin, cisplatin and oxaliplatin were successfully aerosolized using the NAC system producing a nanoparticle aerosol. There was no leakage of aerosol from the experimental set up with or without laminar air flow and the evacuation system was efficacious is absorbing any residual aerosol. Future studies looking at spatial distribution, depth of penetration and tissue concentration will determine the suitability for clinical application.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding-\u003c/strong\u003e The study was funded by Curotherm Techno Solutions, LLP.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJacquet P, Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res. 1996;82:53-63. doi: 10.1007/978-1-4613-1247-5_4. PMID: 8849943.\u003c/li\u003e\n\u003cli\u003eSugarbaker PH, Van der Speeten K. Surgical technology and pharmacology of hyperthermic perioperative chemotherapy. J Gastrointest Oncol. 2016 Feb;7(1):29-44. doi: 10.3978/j.issn.2078-6891.2015.105. PMID: 26941982; PMCID: PMC4754302.\u003c/li\u003e\n\u003cli\u003eWhite MG, Badgwell BD. Laparoscopic Heated Intraperitoneal Chemotherapy in the Treatment of Carcinomatosis of Gastric Adenocarcinoma Origin. J Clin Med. 2021 Oct 17;10(20):4757. doi: 10.3390/jcm10204757. PMID: 34682880; PMCID: PMC8539356.\u003c/li\u003e\n\u003cli\u003eBhatt A, de Hingh I, Van Der Speeten K, Hubner M, Deraco M, Bakrin N, Villeneuve L, Kusamura S, Glehen O. HIPEC Methodology and Regimens: The Need for an Expert Consensus. Ann Surg Oncol. 2021 Dec;28(13):9098-9113. doi: 10.1245/s10434-021-10193-w. Epub 2021 Jun 17. PMID: 34142293.\u003c/li\u003e\n\u003cli\u003eSolass W, Kerb R, Murdter T, et al. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy.\u2028\u003cem\u003eAnn Surg Oncol \u003c/em\u003e2014; \u003cstrong\u003e21: \u003c/strong\u003e553\u0026ndash;59 \u2028\u003c/li\u003e\n\u003cli\u003eSolass W., Hetzel A., Nadiradze G., Sagynaliev E., Reymond M.A. Description of a novel approach for intraperitoneal drug delivery and the related device. \u003cem\u003eSurg. 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PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment. Pharmaceutics. 2020 May 9;12(5):439. doi: 10.3390/pharmaceutics12050439. PMID: 32397428; PMCID: PMC7285054.\u003c/li\u003e\n\u003cli\u003eFranco YL, Vaidya TR, Ait-Oudhia S. Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. Breast Cancer (Dove Med Press). 2018 Sep 11;10:131-141. doi: 10.2147/BCTT.S170239. PMID: 30237735; PMCID: PMC6138971.\u003c/li\u003e\n\u003cli\u003ePetrelli F, Borgonovo K, Barni S. Targeted delivery for breast cancer therapy: the history of nanoparticle-albumin-bound paclitaxel. Expert Opin Pharmacother. 2010 Jun;11(8):1413-32. doi: 10.1517/14656561003796562. PMID: 20446855.\u003c/li\u003e\n\u003cli\u003eHongxu Duan, Francisco J. Romay, Cheng Li, Amir Naqwi, Weiwei Deng \u0026amp; Benjamin Y. H. Liu (2016) Generation of monodisperse aerosols by combining aerodynamic flow-focusing and mechanical perturbation, Aerosol Science and Technology, 50:1, 17-25, DOI: 10.1080/02786826.2015.1123213\u003c/li\u003e\n\u003cli\u003eReymond MA, Hu B, Garcia A, Reck T, K\u0026ouml;ckerling F, Hess J et al (2000) Feasibility of therapeutic pneumoperitoneum in a large animal model using a microvaporisator. Surg Endosc 14(1):51\u0026ndash;55\u003c/li\u003e\n\u003cli\u003eDalmoro A, Barba AA, Lamberti G, D\u0026rsquo;Amore M. Intensifying the microencapsulation process: ultrasonic atomization as an innovative approach. \u003cem\u003eEuropean Journal of Pharmaceutics and Biopharmaceutics\u003c/em\u003e. 2012;80(3):471\u0026ndash;477.\u003c/li\u003e\n\u003cli\u003eDalmoro A, Barba AA, d\u0026apos;Amore M. Analysis of size correlations for microdroplets produced by ultrasonic atomization. ScientificWorldJournal. 2013 Dec 31;2013:482910. doi: 10.1155/2013/482910. PMID: 24501580; PMCID: PMC3899708.\u003c/li\u003e\n\u003cli\u003eR.L. Peskin, R.J. Raco, J. Acoust. Soc. Am. 35 (9) (1963) 1378\u003c/li\u003e\n\u003cli\u003eL. Rayleigh, Proc. London Math. Soc. 10, 4 (1878)\u003c/li\u003e\n\u003cli\u003eRajan R\u003csup\u003e1\u003c/sup\u003e, Pandit AB. Correlations to predict droplet size in ultrasonic atomisation. Ultrasonics. 2001 Jun;39(4):235-55.\u003c/li\u003e\n\u003cli\u003eR.J. Lang, Ultrasonic atomization of liquids, J. Acoust. Soc. Am. \u202834 (1962) 6. \u2028\u003c/li\u003e\n\u003cli\u003eDelhorme JB, Klipfel A, D\u0026apos;Antonio F, Greget MC, Diemunsch P, Rohr S, Romain B, Brigand C. Occupational safety of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in an operating room without laminar airflow. J Visc Surg. 2019 Dec;156(6):485-488. doi: 10.1016/j.jviscsurg.2019.06.010. \u003c/li\u003e\n\u003cli\u003eOnoyama K, Matsui S, Kikuchi M, Sato D, Fukamachi H, Kadena M, Funatsu T, Maruoka Y, Baba K, Maki K, Kuwata H. Particle Size Analysis in Aerosol-Generating Dental Procedures Using Laser Diffraction Technique. Front Oral Health. 2022 Feb 11;3:804314. doi: 10.3389/froh.2022.804314. PMID: 35224541; PMCID: PMC8873144.\u003c/li\u003e\n\u003cli\u003eKhosrawipour V, Khosrawipour T, Kern AJ, Osma A, Kabakci B, Diaz-Carballo D, F\u0026ouml;rster E, Zieren J, Fakhrian K. Distribution pattern and penetration depth of doxorubicin after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a postmortem swine model. J Cancer Res Clin Oncol. 2016 Nov;142(11):2275-80. doi: 10.1007/s00432-016-2234-0. Epub 2016 Sep 2. PMID: 27590613.\u003c/li\u003e\n\u003cli\u003eNii, S. (2016). Ultrasonic Atomization. In: Handbook of Ultrasonics and Sonochemistry. Springer, Singapore. https://doi.org/10.1007/978-981-287-278-4_7\u003c/li\u003e\n\u003cli\u003eReymond M.A., Hu B., Garcia A., Reck T., Kockerling F., Hess J., Morel P. Feasibility of therapeutic pneumoperitoneum in a large animal model using a microvaporisator. Surg. Endosc. 2000;14:51\u0026ndash;55. doi: 10.1007/s004649900010\u003c/li\u003e\n\u003cli\u003eH\u0026ouml;ltzcke P, Sautkin I, Clere S, Castagna A, K\u0026ouml;nigsrainer A, Pott PP, Reymond MA. Feasibility of pressurized intra peritoneal aerosol chemotherapy using an ultrasound aerosol generator (usPIPAC). Surg Endosc. 2022 Oct;36(10):7848-7858. doi: 10.1007/s00464-022-09525-y. Epub 2022 Aug 29. \u003c/li\u003e\n\u003cli\u003eGohler D., Khosrawipour V., Khosrawipour T., Diaz-Carballo D., Falkenstein T.A., Zieren J., Stintz M., Giger-Pabst U. Technical description of the microinjection pump (MIP((R))) and granulometric characterization of the aerosol applied for pressurized intraperitoneal aerosol chemotherapy (PIPAC) Surg. Endosc. 2017;31:1778\u0026ndash;1784. doi: 10.1007/s00464-016-5174-5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"aerosolized chemotherapy, NAC, Ultrasonic aerosol generator, intraperitoneal chemotherapy, nanoparticle aerosol, peritoneal metastases, peritoneal carcinomatosis","lastPublishedDoi":"10.21203/rs.3.rs-4158412/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4158412/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUltrasonic technology could be used for aerosol generation for intraperitoneal aerosolized chemotherapy. Current devices or systems for generation of aerosolized chemotherapy generate a polydisperse aerosol with the average droplet size measuring in micrometres. In this manuscript, we describe the functioning of a new device designed to generate nanoparticle-aerosolized chemotherapy for intraperitoneal application. The results of an experimental study looking at the particle size in the aerosol generated using this technology and another experiment evaluating its safety are presented and discussed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA drug delivery system called nano-aerosolized chemotherapy (NAC) system was developed indigenously and has two components, a controller unit- Nanosol® and a nozzle – Nanowand®. The system has an accessory for aerosol evacuation, a nano-particle (NP) filter. In an experimental setting, doxorubicin, cisplatin and oxaliplatin were aerosolised using the NAC system. The aerosol that was deposited on a copper grid was studied using a transmission electron microscope (TEM). The experiment was repeated 3 times for each of the drugs.\u003c/p\u003e\n\u003cp\u003eFor the safety testing, cisplatin and doxorubicin were aerosolised in an experimental set up. Wipes from the operating table, the floor near it, the surgeon’s gloves and the air duct as well as two air samples were collected and tested for the presence of drug using inductively coupled plasma mass spectrometry (ICP-MS). The samples were collected with and without laminar air flow. Additional testing was performed to check the performance of the NP filter using a second inline filter.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNanoparticle aerosol was successfully generated using the NAC system. The average particle size was \u0026lt;65nm for doxorubicin in all three experiments, \u0026lt;66 nm for cisplatin and \u0026lt;63 nm for oxaliplatin. No micrometer sized particles were observed in any of the nine experiments.\u003c/p\u003e\n\u003cp\u003eIn all 8 wipe samples, the platinum levels were below detectable limits of 0.1ppb.\u003c/p\u003e\n\u003cp\u003eIn the 4 air samples and two samples from air filters, the platinum levels were also below detectable limits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDoxorubicin, cisplatin and oxaliplatin were successfully aerosolized using the NAC system producing a nanoparticle aerosol. Future studies looking at spatial distribution, depth of penetration and tissue concentration will determine the suitability for clinical application.\u003c/p\u003e","manuscriptTitle":"Nano Aerosolized Chemotherapy (NAC) – a technology for generating nanoparticle aerosolized chemotherapy for intraperitoneal application","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-27 06:04:57","doi":"10.21203/rs.3.rs-4158412/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68481ff4-4e39-4d10-a749-d3dcebef13a2","owner":[],"postedDate":"March 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-28T04:57:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-27 06:04:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4158412","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4158412","identity":"rs-4158412","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}