A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models.

Jayanta Bhattacharyya,Isaac Weitzhandler,Jonathan R Mcdaniel,Joseph J Bellucci,Chao-Chieh Lin,Ivan Spasojevic,Jen-Tsan Ashley Chi,Xinghai Li,Ashutosh Chilkoti

doi:10.1038/ncomms8939

Abstract

Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumor specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ~60-nm diameter near-monodisperse nanoparticles that increased the systemic exposure of PTX by 7-fold compared to free drug and 2-fold compared to the FDA approved taxane nanoformulation (Abraxane®). The tumor uptake of the CP-PTX nanoparticle was 5-fold greater than free drug and 2-fold greater than Abraxane. In a murine cancer model of human triple negative breast cancer and prostate cancer, CP-PTX induced near complete tumor regression after a single dose in both tumor models, whereas at the same dose, no mice treated with Abraxane survived for more than 80 days (breast) and 60 days (prostate) respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for paclitaxel delivery.

Highlights

Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential
We have previously shown that conjugation of small molecules with an octanol–water distribution coefficient of 41.5 drives the self-assembly of the chimeric polypeptide (CP) into near-monodisperse sub-100-nm-diameter nanoparticles[5], and that doxorubicin-loaded chimeric polypeptides (CPs) nanoparticles showed good efficacy in a subcutaneous (s.c.) murine colon cancer tumour model[6]
The therapeutic efficacy of the CP–PTX nanoparticles compared with Abraxane was even more pronounced in a s.c. prostate cancer model, as mice bearing prostate cancer tumours treated with Abraxane only survived r60 days, while 100% of the CP–PTX nanoparticle-treated mice survived for 470 days

Summary

Introduction

Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential. An emerging approach is to package highly hydrophobic drugs into highly water-soluble nanoscale delivery vehicles (10–100 nm diameter), as objects within this size range accumulate within solid tumours due to the enhanced permeability and retention (EPR) effect, which results from an aberrant and leaky tumour vasculature and the lack of a poorly developed lymphatic drainage system in many solid tumours[3,4] To this end, we have previously shown that conjugation of small molecules with an octanol–water distribution coefficient (logD) of 41.5 drives the self-assembly of the chimeric polypeptide (CP) into near-monodisperse sub-100-nm-diameter nanoparticles[5], and that doxorubicin-loaded CP nanoparticles showed good efficacy in a subcutaneous (s.c.) murine colon cancer tumour model[6]. These results show that a molecularly engineered nanoparticle with precisely engineered design features can outperform Abraxane—the current gold standard for PTX delivery—across multiple tumour models, which augurs well for its clinical translation

Methods

Results

Conclusion