Effects of Polymer 3D Architecture, Size, and Chemistry on Biological Transport and Drug Delivery In Vitro and in Orthotopic Triple Negative Breast Cancer Models.

Amanda K Pearce,Cameron Alexander,Thomas M Bennett,Akosua B Anane‐Adjei,Anna M Grabowska,Robert J Cavanagh,Patricia F Monteiro,Vincenzo Taresco,Phil A Clarke,Morgan R Alexander,Alison A Ritchie

doi:10.1002/adhm.202000892

Abstract

The size, shape, and underlying chemistries of drug delivery particles are key parameters which govern their ultimate performance in vivo. Responsive particles are desirable for triggered drug delivery, achievable through architecture change and biodegradation to control in vivo fate. Here, polymeric materials are synthesized with linear, hyperbranched, star, and micellar-like architectures based on 2-hydroxypropyl methacrylamide (HPMA), and the effects of 3D architecture and redox-responsive biodegradation on biological transport are investigated. Variations in "stealth" behavior between the materials are quantified in vitro and in vivo, whereby reduction-responsive hyperbranched polymers most successfully avoid accumulation within the liver, and none of the materials target the spleen or lungs. Functionalization of selected architectures with doxorubicin (DOX) demonstrates enhanced efficacy over the free drug in 2D and 3D in vitro models, and enhanced efficacy in vivo in a highly aggressive orthotopic breast cancer model when dosed over schedules accounting for the biodistribution of the carriers. These data show it is possible to direct materials of the same chemistries into different cellular and physiological regions via modulation of their 3D architectures, and thus the work overall provides valuable new insight into how nanoparticle architecture and programmed degradation can be tailored to elicit specific biological responses for drug delivery.

Highlights

Effects of Polymer 3D Architecture, Size, and Chemistry on Biological Transport and Drug Delivery In Vitro and in Orthotopic Triple Negative Breast Cancer Models
Based on the potential of pHPMA-based polymeric drug delivery polymers, we aimed to exploit the range of architectures and monomer compatibility provided by reversible addition fragmentation chain transfer (RAFT) polymerization to thoroughly investigate if materials of the same chemistries can be directed into different cellular and physiological regions via modulation of their 3D architectures and size, providing crucial new insight into tailoring of nanomaterials to elicit specific biological responses for drug delivery
Through aqueous RAFT polymerization, we successfully produced a small set of polymer materials spanning a size range from 5 to 60 nm, with linear, hyperbranched, star, and self-assembling micellar architectures, allowing for investigation of the contribution of architecture, size and degradability on in vivo particle distribution by maintaining the same materials chemistry throughout

Summary

Introduction

Effects of Polymer 3D Architecture, Size, and Chemistry on Biological Transport and Drug Delivery In Vitro and in Orthotopic Triple Negative Breast Cancer Models. Functionalization of selected architectures with doxorubicin (DOX) demonstrates enhanced enhanced uptake in disease sites and increased specificity of delivery.[5,6,7] in order to obtain selective tumor uptake of nanoparticle drug carriers, the delivery systems must meet several criteria, such as an appropriate size range for diffusion efficacy over the free drug in 2D and 3D in vitro models, and enhanced out of the vasculature, prolonged circulaefficacy in vivo in a highly aggressive orthotopic breast cancer model when dosed over schedules accounting for the biodistribution of the carriers These data show it is possible to direct materials of the same chemistries into different cellular and physiological regions via modulation of their 3D tion time in the bloodstream to allow for efficient uptake, reduced clearance from the bloodstream by avoidance of recognition by macrophages, and stability of the carrier during circulation.[8,9] Previous literature architectures, and the work overall provides valuable new insight into suggests that while larger nanocarriers have how nanoparticle architecture and programmed degradation can be tailored prolonged circulation times in the blood, to elicit specific biological responses for drug delivery. For disease targets such as cancer, polymeric nanocarriers have erties, the blood circulation times are often decreased been shown to be effective for achieving site-specific drug de- due to the smaller size.[11,12] In addition, it has been observed livery while minimizing off-target toxicity.[1,2,3] Typically, small that nanoparticle properties such as chemistry, size, shape, and

Objectives

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Conclusion