Rapid Self-Assembly of Polymer Nanoparticles for Synergistic Codelivery of Paclitaxel and Lapatinib via Flash NanoPrecipitation.

Shani L Levit,Hu Yang,Christina Tang

doi:10.3390/nano10030561

Abstract

Taxol, a formulation of paclitaxel (PTX), is one of the most widely used anticancer drugs, particularly for treating recurring ovarian carcinomas following surgery. Clinically, PTX is used in combination with other drugs such as lapatinib (LAP) to increase treatment efficacy. Delivering drug combinations with nanoparticles has the potential to improve chemotherapy outcomes. In this study, we use Flash NanoPrecipitation, a rapid, scalable process to encapsulate weakly hydrophobic drugs (logP < 6) PTX and LAP into polymer nanoparticles with a coordination complex of tannic acid and iron formed during the mixing process. We determine the formulation parameters required to achieve uniform nanoparticles and evaluate the drug release in vitro. The size of the resulting nanoparticles was stable at pH 7.4, facilitating sustained drug release via first-order Fickian diffusion. Encapsulating either PTX or LAP into nanoparticles increases drug potency (as indicated by the decrease in IC-50 concentration); we observe a 1500-fold increase in PTX potency and a six-fold increase in LAP potency. When PTX and LAP are co-loaded in the same nanoparticle, they have a synergistic effect that is greater than treating with two single-drug-loaded nanoparticles as the combination index is 0.23 compared to 0.40, respectively.

Highlights

Ovarian cancer remains one of the most difficult cancers to treat due to late-stage diagnosis and its highly malignant nature [1]
We extend the use of Flash NanoPrecipitation (FNP) to PTX and LAP by leveraging in situ coordination complexation of tannic acid and iron
To prepare tannic acid (TA)–Fe based nanoparticles, FNP was performed by mixing drug(s), dissolving TA and PS-b-PEG in a water-miscible (THF or dimethyl sulfoxide (DMSO)) organic solvent with iron (III) chloride dissolved in water in a confined impinging jet mixer

Summary

Introduction

Ovarian cancer remains one of the most difficult cancers to treat due to late-stage diagnosis and its highly malignant nature [1]. Chemotherapies such as Taxol, a formulation of paclitaxel (PTX), remains to be one of the most widely used cancer treatments, for recurring ovarian carcinomas following surgery [1,2,3]. The mechanism of action for PTX is binding to the β-subunit of tubulin at two sites, which stabilizes the tubulin polymers preventing cytoskeletal rearrangement for cellular function [4,5,6]. PTX is used in combination with other drugs to increase the efficacy of treatment by targeting multiple pathways [11,12,13]

Methods

Results

Conclusion