Self-Assembly of pH-Labile Polymer Nanoparticles for Paclitaxel Prodrug Delivery: Formulation, Characterization, and Evaluation.

Shani L Levit,Thomas D Roper,Hu Yang,Narendar Reddy Gade,Christina Tang

doi:10.3390/ijms21239292

Shani L Levit, Thomas D Roper + Show 3 more

Open Access

https://doi.org/10.3390/ijms21239292

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Abstract

The efficacy of paclitaxel (PTX) is limited due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms. Designing paclitaxel prodrugs can improve its anticancer activity and enable formulation of nanoparticles. Overall, the aim of this work is to improve the potency of paclitaxel with prodrug synthesis, nanoparticle formation, and synergistic formulation with lapatinib. Specifically, we improve potency of paclitaxel by conjugating it to α-tocopherol (vitamin E) to produce a hydrophobic prodrug (Pro); this increase in potency is indicated by the 8-fold decrease in half maximal inhibitory concentration (IC50) concentration in ovarian cancer cell line, OVCA-432, used as a model system. The efficacy of the paclitaxel prodrug was further enhanced by encapsulation into pH-labile nanoparticles using Flash NanoPrecipitation (FNP), a rapid, polymer directed self-assembly method. There was an 1100-fold decrease in IC50 concentration upon formulating the prodrug into nanoparticles. Notably, the prodrug formulations were 5-fold more potent than paclitaxel nanoparticles. Finally, the cytotoxic effects were further enhanced by co-encapsulating the prodrug with lapatinib (LAP). Formulating the drug combination resulted in synergistic interactions as indicated by the combination index (CI) of 0.51. Overall, these results demonstrate this prodrug combined with nanoparticle formulation and combination therapy is a promising approach for enhancing paclitaxel potency.

Highlights

Taxol, a formulation of paclitaxel (PTX), is widely used for treating ovarian carcinomas
Given the drug release profiles observed, these nanoparticles may be well suited for incorporating into oral dosage formulations, which are of increasing interest as alternatives to paternal formulations to increase patient compliance [63]
The prodrug is more potent than paclitaxel as indicated by the 8-fold decrease in IC50 concentration measured in ovarian cancer cell line, OVCA-432, used as a model system

Summary

Introduction

A formulation of paclitaxel (PTX), is widely used for treating ovarian carcinomas. There are challenges associated with taxol treatment due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms that together result in low drug efficacy [1,2,3,4]. Design of paclitaxel prodrugs is a promising method to improve its anticancer activity [5,6]. Prodrug design involves conjugation via a degradable linkage to retain therapeutic activity. The conjugation chemistry [5,6] can be selected to tune release half-life and release mechanism and has been reviewed elsewhere [7]. The aim of this work is to improve the potency of paclitaxel though a combination of prodrug synthesis, nanoparticle formation, and formulation with lapatinib (LAP) with synergistic effects

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