Investigating the role of Pluronic-g-Cationic polyelectrolyte as functional stabilizer for nanocrystals: Impact on Paclitaxel oral bioavailability and tumor growth.
Paclitaxel (PTX) is a potent anticancer drug which suffers limitations of extremely low oral bioavailability due to low solubility, rapid metabolism and efflux by P-gp transporters. The main objective of this study was to overcome the limitation of PTX by designing delivery systems that can enhance the absorption using multiple pathways. A novel Pluronic-grafted chitosan (Pl-g-CH) copolymer was developed and employed as a functional stabilizer for nanocrystals (NCs) and hypothesized that it would improve PTX absorption by several mechanisms and pathways. Pl-g-CH was synthesized and characterized using (1)H NMR and then used as a stabilizer during nanocrystal development. To establish our proof of concept the optimized formulation having a particle size 192.7 ± 9.2 nm and zeta potential (+) 38.8 ± 3.12 mV was studied extensively on in vitro Caco-2 model. It was observed that nanocrystals rendered higher PTX accumulation inside the cell than Taxol™. P-gp inhibitory potential of Pl-g-CH was proved by flow cytometry and fluorescence microscopy where the much enhanced fluorescence intensity of Rhodamine 123 (Rho-123, P-gp substrate) was observed in the presence of Pl-g-CH. In addition, a significant decrease in Trans Epithelial Electrical Resistance (TEER) of Caco-2 cell monolayers was observed with nanocrystals as well as with Taxol™ (in the presence of free Pl-g-CH compared to only Taxol™). This supports the role of the stabilizer in reversible opening of tight junctions between cells which can allow paracellular transport of drug. The in vivo results were in complete corroboration with in vitro results. Nanocrystals resulted in much enhanced absorption with 12.6-fold improvement in relative bioavailability to that of Taxol™. Concomitantly efficacy data in B16 F10 murine melanoma model also showed a significant reduction in tumor growth with nanocrystals compared to Taxol™ and control. Based on the results it can be suggested that nanocrystals with functional stabilizers can be a promising approach for the oral delivery of anticancer drugs which are P-gp substrates


CONCLUSIONS
Nanocrystals are currently one of the most explored novel drug delivery systems especially for oral delivery of drugs because of ease in synthesis and high drug loading. But their use is still limited for oral delivery of anticancer drugs which are P-gp substrates. This particular study aims at widening the scope of nanocrystals by using a functional stabilizer which participates in enhancing the oral absorption of anticancer drugs and controlling the tumor growth.
Division of Pharmaceutics, CSIR-Central Drug Research Institute (Council of Scientific and Industrial Research), B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, U.P. 226031, India.
Shweta
S
Sharma
Division of Pharmaceutics, CSIR-Central Drug Research Institute (Council of Scientific and Industrial Research), B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, U.P. 226031, India.
Ashwni
A
Verma
Division of Pharmaceutics, CSIR-Central Drug Research Institute (Council of Scientific and Industrial Research), B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, U.P. 226031, India.
Gitu
G
Pandey
Division of Pharmaceutics, CSIR-Central Drug Research Institute (Council of Scientific and Industrial Research), B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, U.P. 226031, India.
Naresh
N
Mittapelly
Division of Pharmaceutics, CSIR-Central Drug Research Institute (Council of Scientific and Industrial Research), B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, U.P. 226031, India. Electronic address: prabhat_mishra@cdri.res.in.
Prabhat Ranjan
PR
Mishra
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003460:Crystallization / Q000379:methods; D004058:Diffusion; D004573:Electrolytes / Q000737:chemistry; D005079:Excipients / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000097:blood* / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D004573:Electrolytes; D005079:Excipients; D053769:Nanocapsules; D017239:Paclitaxel
Chitosan; Murine melanoma; P-gp efflux inhibition; Rhodamine 123; TEER; Taxol™