Abstract
The key objective of the current research was to fabricate and optimize Capecitabine (Cap)-loaded [poly(lactic-co-glycolic acid)] PLGA-based nanoparticles (NPs) by enabling quality by design (QbD) approach for enhancing antitumor activity by promising delivery of the drug at the colonic site. The current research was based on fabricating PLGA-based nanoparticles along with Eudragit S100 as enteric polymer employing solvent shifting method followed by optimization using QbD approach. This approach was found to be useful for understanding the multiple factors and their interaction influencing the product by utilizing Design of Experiment (DOE). Box-Behnken design (BBD) was adopted to achieve the required critical quality attributes (CQAs), i.e., minimizing particle size, maximizing entrapment efficiency, and minimizing PDI value. The optimized nanoparticles were lyophilized and characterized by FT-IR, DSC, TEM, DLS, MTT assay using HT-29 cell lines, and in vivo pharmacokinetic studies. The optimized PLGA-based nanoparticles were found to possess average particle size, PDI, zeta potential, and entrapment efficiency of 195 nm, 0.214, -6.65 mV, and 65%, respectively. TEM analysis revealed the spherical nature of nanoparticles. The FT-IR and DSC studies revealed no interaction. The bioavailability of Cap-loaded nanoparticles was found to be two fold increased than the pure drug, and also, it exhibited significantly more cytotoxic to tumor cells as compared to pure drug as confirmed by MTT assay. The optimized PLGA-based nanoparticles found to possess enhanced bioavailability and significantly more cytotoxic potential as compared to pure drug.
Highlights
Capecitabine is a prodrug of 5-Fluorouracil (5 FU) with antineoplastic activity
The most common method for developing PLGA nanoparticles i.e. by nanoprecipitation method may lead to low entrapment efficiency for hydrophilic drugs as reported in the literature [7], but it is not an issue for hydrophobic drugs
The formulations in Taguchi Design with their limits were portrayed in Table 8 and the pareto charts for screening factors as portrayed in Fig. 3.The final formulation was optimized by implementing Box.Behnken Design (BBD)
Summary
Capecitabine is a prodrug of 5-Fluorouracil (5 FU) with antineoplastic activity It is highly recommended for the treatment of advanced stage of colorectal cancer and metastatic breast cancer [1,2]. Its ultra-short elimination half-life may lead to increase in dosing frequency, side effect and decrease in patient compliance [4]. This prodrug is tumor-activated to cytotoxic moiety as 5 FU by the enzyme thymidine phosphorylase. Our research was concentrated to fabricate and optimize the Capecitabine loaded PLGA based nanoparticles by solvent shifting method implementing Quality by Design (QbD) platform which would boost drug availability at the target site with more cytotoxic potential to colon tumor cells. There are different methods available for synthesizing nanoparticles but nanoprecipitation method is widely accepted as it is the simplest technique of few steps [10,11]
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