Adaptive micro and nanoparticles: Temporal control over carrier properties to facilitate drug delivery

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Abstract

Recent studies have led to significant advances in understanding the impact of key drug carrier properties such as size, surface chemistry and shape on their performance. Converting this knowledge into improved therapeutic outcomes, however, has proved challenging. This owes to the fact that successful drug delivery carriers have to navigate through multiple physiological hurdles including reticuloendothelial system (RES) clearance, target accumulation, intracellular uptake and endosomal escape. Each of these processes may require unique, and often conflicting, design parameters, thus making it difficult to choose a design that addresses all these hurdles. This challenge can be addressed by designing carriers whose properties can be changed in time so as to successfully navigate them through various biological hurdles. Several carriers have been reported that implement this strategy. This review will discuss the current status and future prospects of this emerging field of “adaptive micro and nanoparticles”.

Introduction

Advances in new drug delivery systems have vastly improved the pharmacokinetics and biodistribution of drugs that suffer from poor solubility, poor stability and unwanted toxicity [1], [2]. Such systems include polymeric particles, liposomes, dendrimers and micelles, among others, that collectively facilitate encapsulation, targeting and release of drugs. Various physicochemical attributes of drug carriers such as composition, size, surface chemistry, shape and mechanical flexibility influence their therapeutic function [3], [4], [5], [6]. Optimization of these parameters has yielded carriers with improved performance and some of them are currently available in the market, for example, Doxil®.

Despite many advances, drug carriers still face several challenges including immune clearance, difficulty in achieving high target selectivity and low therapeutic concentration at target subcellular compartments [7], [8], [9]. These challenges arise from the complexity of the biological hurdles that must be overcome by the carriers prior to accomplishing their therapeutic objective. From administration to pharmacological activity, several hurdles limit the efficacy of carriers, including RES and renal clearance, extravasation, target accumulation, cellular internalization and in some cases, endosomal escape. Each of these hurdles requires particles of different and often contradictory attributes. For example, surface modification with polyethelyne glycol (PEG) offers prolonged circulation of carriers via minimization of their interactions with the immune system [10]. However, the same property of PEG also compromises their ability to engage with the target and hence reduces targeted accumulation [11], [12], [13], [14]. To address these issues, efforts have been recently focused on designing carriers whose properties can be changed in real time so as to navigate them through the complex biological hurdles. Such particles, which adapt their properties either by self-evolution over time or in response to an external stimulus, are labeled as “adaptive particles” and are reviewed here.

Section snippets

Role of particle properties in key drug delivery processes

Drug delivery vehicles introduced in the blood stream undergo a complex journey prior to arriving at the target site [1], [15], [16]. The carriers circulate through the vasculature and interact extensively with the reticuloendothelial system (RES), the body's primary mechanism of clearing foreign entities [17], [18]. The RES comprises phagocytic cells, both mobile and fixed tissue macrophages [19]. Apart from macrophages, the carrier has to escape filtration that takes place in the spleen and

Triggered release

The earliest examples of temporal control over particle properties can be found in the form of triggered drug release. Such particles, often referred to as stimulus-responsive particles, have been extensively reviewed elsewhere and are not discussed in detail here. A brief overview of stimulus-responsive release is provided for comprehensiveness. The primary focus of this review is on particles whose key parameters are actively controlled in time to navigate them through the biological hurdles.

Conclusion

Effective drug delivery requires successful navigation of carriers through complex biological processes in the body. Hence, particles whose properties can be controlled in real time open new opportunities. Control over particle properties including size, surface chemistry and shape provide timely control over their interactions with cells or subcellular compartments. Benefits of achieving temporal control over properties have been demonstrated through in vitro and in vivo studies. Particles

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Hybrid Nanostructures for Diagnostics and Therapeutics”.

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