Controlled Release of Doxorubicin from pH-responsive Cockle Shell-derived Nanoparticle and its Pharmacokinetics in Dogs

Stimuli-responsive cockleshell derived nanocarrier (CSNP) have huge potential in drug targeted delivery. They can be employed for targeted site-specific drug delivery due to its responsive nature to stimuli such as change in pH which minimizing its systemic off-targeted effect to due to excessive releases of doxorubicin. We use a simple top-down method to synthesis CSNP carrier from biological waste of cockleshell, which were negatively charged with higher loading capacity when conjugated with DOX. This study is aimed at demonstrating the in vitro release mechanism of DOX from CSNP under the influence of change in pH and to develop a bioanalytical method for pharmacokinetics of the synthesized CSNP-DOX in dogs. Apart from drug release kinetic of CSNP evaluation, a high-performance liquid chromatography bioanalytical method was developed and validated for the pharmacokinetics of CSNP-DOX determination. Six dogs were divided into two groups to receive CSNP-DOX and free DOX 30 mg/m 2 i.v respectively. At predetermined time interval, blood was sampled and processed for DOX concentration. The CSNP-DOX with high encapsulation efficiency and a mean diameter of 34.0 ± 3.4 nm was used. The in vitro release profiles demonstrated by DOX release from CSNP-DOX-loaded were pH dependent in nature which follows a Higuchi mathematical model equation. Pharmacokinetic parameters were determined with an excellent bioanalytical method having high extraction yield and linearity of 89.87% and 0.997. CSNP-DOX increases the t 1/2 and AUC 0-t of DOX as compared to dogs given free DOX. Our data further reveal a sustained release of DOX from CSNP under the influence of change in pH. However, we developed a rapid bioanalytical method for cumula al model. Based on these novel results, CSNP reveal to have promising ability to prolong release of DOX in circulation which tends to reduce cytotoxic DOX release quantification which was further expressed on kinetic mathematic