Reversibly Crosslinked Nanocarriers for on-demand Drug Delivery in Cancer Treatment

Abstract

Polymer micelles have proven to be one of the most versatile nanocarriers for anticancer drug delivery. However, the in vitro and in vivo stability of micelles remains a challenge due to the dynamic nature of these self-assembled systems, which leads to premature drug release and nonspecific biodistribution in vivo. Recently, reversibly crosslinked micelles have been developed to provide solutions to stabilize nanocarriers in blood circulation. Increased stability allows nanoparticles to accumulate at tumor sites efficiently via passive and/or active tumor targeting, while cleavage of the micelle crosslinkages, through internal or external stimuli, facilitates on-demand drug release. In this review, various crosslinking chemistries as well as the choices for reversible linkages in these nanocarriers will be introduced. Then, the development of reversibly crosslinked micelles for on-demand drug release in response to single or dual stimuli in the tumor microenvironment is discussed, for example, acidic pH, reducing microenvironment, enzymatic microenvironment, photoirradiation and the administration of competitive reagents postmicelle delivery.

Facile construction of dual-bioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release

“…It should be noted; however, that irreversible photo-crosslinking may induce incomplete drug release, and generate non-degradable polyacrylate components. In recent years, much attention has been given to the development of reversibly crosslinked polymeric micelles in that complete drug release can be obtained by de-crosslinking of the micelles [9,31]. In particular, crosslinking via disulfide bonds, which are prone to cleavage in the intracellular environment due to the presence of a high reduction potential in the cytoplasm as well as in the cell nucleus, is an attractive approach to construct reversibly crosslinked nanocarriers for triggered drug release [32,33].…”

Design of hybrid nanovehicles for remotely triggered drug release: an overview

“…159 These kinds of MSN-based materials, engineered with capping components and possessing responsiveness to specific stimuli, have been recently reviewed in detail by Zink and coll. Furthermore, MSNs with the mesopores capped with magnetic nanoparticles, [176][177][178] GNPs, 179 UCNPs 180 and sulfonatocalix [4]arene, 167 oligonucleotides, 173 etc., have also been used to regulate the release behaviours with remote stimuli. For intravenous administration, remote and non-invasive physical stimuli are preferable to control the therapeutic treatment.…”

“…gating systems in the mesoporous silica 2 and reversibly-cross-linked micelles or nanogels, 4 in order to obtain a good entrapment of the cargo molecules and get rid of the risk from undesired premature release. Usually, the diffusion of guest molecules from the nanovehicles into the surrounding environment is an unavoidable thermodynamic procedure under a concentration gradient.…”

Acid‐Labile Copolymer Micelles Cross‐Linked by a Twin Ortho Ester Cross‐Linking Agent: Synthesis, Characterization, and Evaluation

“…In addition, micelles concentration will decrease below the critical micelle concentration (CMC) after intravenous administration, resulting rapidly into dissociated unimers. This instability of micelles can result in earlier disintegration or aggregation, premature drug release before reaching the tumor area, opsonization, and reticuloendothelial system clearance . To overcome the instability problem, stimuli‐responsive cross‐linked micelles (SCMs) which contain environmentally sensitive cross‐linkers or assembling units have been employed for drug delivery.…”