Abstract
The particle size (PS) and encapsulation efficiency (EE%) of drug-loaded nanoparticles (NPs) may inhibit their cellular uptake and lead to possible leakage of the drug into the systemic circulation at the tumor site. In this work, ultra-high paclitaxel-loaded poly(lactide-co-glycolide) NPs (PTX-PLGA-NPs) with ultra-small sizes were prepared and optimized by adopting the principles of quality by design (QbD) approach. The optimized PTX-PLGA-NPs showed ultra-small spherical particles of about 53 nm with EE% exceeding 90%, a relatively low polydispersity index (PDI) of 0.221, an effective surface charge of −10.1 mV, and a 10-fold increase in the in vitro drug release over 72 h relative to free drug. The cellular viability of pharynx carcinoma cells decreased by almost 50% in 24 h following treatment with optimized PTX-PLGA-NPs, compared to only 20% from the free drug. The intracellular uptake of PTX-PLGA-NPs was highly favored, and the antitumor activity of PTX was remarkably improved with a reduction in its half maximal inhibitory concentration (IC50), by almost 50% relative to free drug solution. These results suggest that the optimal critical formulation parameters, guided by QbD principles, could produce PLGA-NPs with remarkably high EE% and ultra-small PS, resulting in enhanced cellular uptake and efficacy of PTX.
Highlights
Head and neck squamous cell carcinomas (HNSCC) are considered among the most common malignancies, and a leading cause of cancer death worldwide [1]
These results suggest that the optimal critical formulation parameters, guided by quality by design (QbD) principles, could produce PLGA-NPs with remarkably high EE% and ultra-small particle size (PS), resulting in enhanced cellular uptake and efficacy of PTX
The aim of the present study is to fabricate and optimize ultra-high paclitaxel-loaded poly(lactide-co-glycolide) nanoparticles (PTX-PLGA-NPs) with ultra-small size, using the principles of QbD, to enhance the cellular uptake of PTX, and to form an extended-release drug depot in the form of PTX-PLGA-NPs at the tumor site, as a novel approach to increase the efficacy of PTX in the treatment of HNSCC, when injected in the form of an intratumoral injection (IT)
Summary
Head and neck squamous cell carcinomas (HNSCC) are considered among the most common malignancies, and a leading cause of cancer death worldwide [1]. Its chemotherapeutic effect is associated with its ability to bind to tubulin promoting microtubule assembly, stabilizing the existing microtubules and enhancing the action of tubulin dimers, inhibiting their disassembly. This interferes with the late G2 mitotic phase of the cell cycle, and inhibits cellular replication suppressing the metastasis of cancer cells [7,8]. The currently approved PTX formulation Taxol® (Bristol-Myers Squibb Company, Princeton, NJ, USA) is a solution of the drug in polyoxyethylated castor oil and ethanol (Cr/Et) administered as IV infusion, over three hours every three weeks It has been associated with serious hypersensitivity reactions, catheter-related infections, neutropenia, extravasation and prolonged peripheral neuropathy [12]. Abraxane® (Abraxis BioScience, LLC, Los Angeles, CA, USA) is a solvent-free albumin-bound PTX nanoparticles (NPs) suspension, with lower risks of hypersensitivity reactions and shorter period of administration; it is limited by elevated neurotoxicity side effects [14]
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