Enhanced Antitumor Efficacy and Reduced Toxicity of Docetaxel Loaded Estradiol Functionalized Stealth Polymeric Nanoparticles.

Sanyog Jain, Gollapalli Spandana, Ashish Kumar Agrawal, Varun Kushwah, Kaushik Thanki

Index: Mol. Pharm. 12 , 3871-84, (2015)

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Abstract

In spite of extensive research over the decades, breast cancer treatment is still a major challenge due to nonspecific distribution of the chemotherapeutics. This void can be filled by restricting the distribution of chemotherapeutics toward the cancerous cells. In the present report estradiol (E2) functionalization of docetaxel (DTX) loaded PLGA nanoparticles was supposed to have specific distribution of DTX to cancerous cells simultaneously avoiding the nonspecific distribution toward the normal cells. In line, E2-PEG-PLGA conjugate was synthesized and characterized by FTIR and NMR spectroscopy. Extensive optimization of different process variables resulted in the formation of spherical E2-PEG-PLGA NPs in the size range of 228.5 ± 11.8 nm and entrapment efficiency of 94.25 ± 2.49. Trehalose (5% w/v) resulted in the formation of a fluffy, easy to redisperse freeze-dried cake of nanoparticles. PXRD analysis revealed the amorphous nature of DTX encapsulated within the nanoparticles. X-ray photoelectron spectroscopy confirmed the presence of E2 over the surface of nanoparticles. In line with our hypothesis, cellular uptake studies on ER positive MCF-7 cells revealed relatively higher uptake and efficient localization into the nuclear region of E2-PEG-PLGA NPs in comparison with plain counterparts, while in the case of ER negative HeLa cells E2-PEG-PLGA NPs showed no difference in fluorescence pattern as compared to MCF-7 cells incubated with unmodified nanoformulation, indicating nonspecific delivery of DTX. Moreover, MTT assay revealed relatively higher cytotoxicity of E2-PEG-PLGA NPs in comparison with free DTX. Furthermore, in vivo pharmacokinetic studies revealed 9.36- and 4.79-fold enhancement in circulation half-life and AUC(0-∞), respectively, of E2-PEG-PLGA NPs in comparison with Taxotere. In vivo antitumor efficacy in DMBA induced rat model demonstrated significant reduction in tumor volume in comparison with the plain counterpart (PLGA-NPs) and a marketed formulation, Taxotere. Moreover, the safety of the estradiol functionalized PLGA NPs was confirmed by hepato- and nephrotoxicity studies.