Folic acid conjugation improves the bioavailability and chemosensitizing efficacy of curcumin-encapsulated PLGA-PEG nanoparticles towards paclitaxel chemotherapy.

Arun Kumar T Thulasidasan,Kavya S Pillai,Vinod Vijayakurup,Shabna Anwar,Gopalakrishnapillai Sankaramangalam Vinod Kumar,Teena Jacob Chirayil,Sankar Sundaram,Mohan Shankar,Archana P Retnakumari,Vijai V Alex,Ruby John Anto,C Devika Nandan,Jisha J Pillai,Sanu Thankachan

doi:10.18632/oncotarget.22376

Abstract

Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs. Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively. Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time. Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies. Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death. In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo, in Swiss albino mice. Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe. We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice. Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts. The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials.

Highlights

Paclitaxel is one of the most potent naturally derived chemotherapeutic agents discovered till date [1]
Curcumin encapsulated in nanoparticles prepared from Poly lactic-coglycolic acid (PLGA)-poly ethylene glycol (PEG) block copolymer and conjugated to the tumor-targeting ligand folic acid showed significant chemosensitization potential towards paclitaxel compared to free curcumin [19]
The tumor reduction was supported by the results of various molecular assays and immunohistochemical analyses, which indicate that PPFcurcumin in combination with paclitaxel is exceedingly successful in down-regulating the key survival pathways responsible for the uncontrolled proliferation, apoptosis evasion and tumor progression

Summary

Introduction

Paclitaxel is one of the most potent naturally derived chemotherapeutic agents discovered till date [1]. Our in vitro studies have successfully demonstrated that, encapsulation of curcumin in PLGA nanoparticles conjugated with folic acid could increase the therapeutic potential of curcumin [17, 18]. We could successfully demonstrate that the encapsulation of curcumin in PLGA-PEG nanoparticles and further conjugation with folic acid enhanced the bioavailability and tissue retention of curcumin in vivo compared to liposomal curcumin. Since the present study aimed to evaluate whether folic acid conjugation can improve the tissue retention and bioavailability of curcumin encapsulated PLGA-PEG nanoparticles than liposomal curcumin (as used in the previous study), the same route of administration was used for both tumor reduction and safety studies. We strongly believe that the current study, illustrating the efficacy of PPF-curcumin might be a therapeutically efficient strategy for sensitizing cancer cells towards paclitaxel, which could further enhance the therapeutic outcome of paclitaxel chemotherapy

Methods

Results

Conclusion