Functionalized Block Co‐Polymer Pro‐Drug Nanoparticles with Anti‐Cancer Efficacy in 3D Spheroids and in an Orthotopic Triple Negative Breast Cancer Model

Vincenzo Taresco,Alison Ritchie,Thais F Abelha,Catherine E Vasey,Marianne B Ashford,Amanda K Pearce,Keith A Spriggs,Ruman Rahman,Cameron Alexander,Stewart Martin,Philip Clarke,Patrícia F Monteiro,Anna M Grabowska,Robert J Cavanagh,Akosua B Anane‐Adjei

doi:10.1002/adtp.202000103

Abstract

AbstractAmphiphilic block co‐polymers composed of poly(ethylene glycol)‐co‐poly(lactide)‐co‐poly(2‐((tert‐butoxycarbonyl)amino)‐3‐propyl carbonate) (PEG‐pLA‐pTBPC) are synthesized in monomer ratios and arrangements to enable assembly into nanoparticles with different sizes and architectures. These materials are based on components in clinical use, or known to be biodegradable, and retain the same fundamental chemistry across “AB” and “BAB” block architectures. In MCF7 and MDA‐MB‐231 breast cancer cells, nanoparticles of <100 nm are internalized most rapidly, by both clathrin‐ and caveolin‐mediated pathways. In THP‐1 cells, polymer architecture and length of the hydrophilic block is the most important factor in the rate of internalization. The organ distributions of systemically injected nanoparticles in healthy mice indicate highest accumulation of the BAB‐blocks in lungs and liver and the lowest accumulation in these organs of a methoxyPEG5000‐pLA‐pTBPC polymer. Conjugation of doxorubicin via a serum‐stable urea linker to the carbonate regions of PEG5000‐pLA‐pTBPC generates self‐assembling nanoparticles which are more cytotoxic in 2D, and penetrate further in 3D spheroids of triple negative breast cancer cells, than the free drug. In an aggressive orthotopic triple negative breast cancer mouse model, the methoxyPEG5000‐pLA‐pTBPC is of similar potency to free doxorubicin but with no evidence of adverse effects in terms of body weight.

Highlights

Polymer pro-drugs offer much promise for drug delivery, owing to the ability to tune the macromolecular structures for solubility and stability in biological fluids, and to encode for drug release in disease-specific environments.[1]
Previous studies[21] had shown that the doxorubicin urea linker to the polycarbonate backbone was stable at pH 7.4, but that the drug released over time at acidic pH 5.0, and we considered the chemistries to be suitable in the first instance for our investigation
The experiments reported here have shown that a range of amphiphilic polymers, derived in simple steps from accessible precursors and with components similar to those used in clinicallyapplied formulations, can be assembled into kinetically-trapped micellar-like nanoparticles

Summary

Introduction

Polymer pro-drugs offer much promise for drug delivery, owing to the ability to tune the macromolecular structures for solubility and stability in biological fluids, and to encode for drug release in disease-specific environments.[1].

Methods

Results

Conclusion