Core-crosslinked polymeric micelles: Principles, preparation, biomedical applications and clinical translation

Abstract

Polymeric micelles (PM) are extensively used to improve the delivery of hydrophobic drugs. Many different PM have been designed and evaluated over the years, and some of them have steadily progressed through clinical trials. Increasing evidence suggests, however, that for prolonged circulation times and for efficient EPR-mediated drug targeting to tumors and to sites of inflammation, PM need to be stabilized, to prevent premature disintegration. Core-crosslinking is among the most popular methods to improve the in vivo stability of PM, and a number of corecrosslinked polymeric micelles (CCPM) have demonstrated promising efficacy in animal models. The latter is particularly true for CCPM in which (pro−) drugs are covalently entrapped. This ensures proper drug retention in the micelles during systemic circulation, efficient drug delivery to pathological sites via EPR, and tailorable drug release kinetics at the target site. We here summarize recent advances in the CCPM field, addressing the chemistry involved in preparing them, their in vitro and in vivo performance, potential biomedical applications, and guidelines for efficient clinical translation.

Folic acid-targeted disulfide-based cross-linking micelle for enhanced drug encapsulation stability and site-specific drug delivery against tumors

“…5,6 However, the nanocarrier for this drug delivery system is still confronted with a series of barriers when applied to antitumor activities in vitro and in vivo. [7][8][9] Among them, encapsulation stability is an urgent problem to be solved. First, when drug-loaded nanocarriers are exposed to the blood stream or normal tissues, the core-shell structure of nanocarriers may be dissolved and diluted to a concentration below their critical micelle concentration (CMC), which can result in a trail of side effects.…”

Facile approach to prepare pH and redox-responsive nanogels via Diels-Alder click reaction

“…In this experiment, GSH was used as a reducing agent because it is spontaneously produced at high concentration in cancer cells. Hence, the use of GSH could reflect more accurate drug release profile as compare with DTT [46,47]. A concentration of 10 mM GSH was chosen to simulate the cytoplasmic concentration of GSH in cancer cells [48,49].…”

Bioreducible cross-linked core polymer micelles enhance in vitro activity of methotrexate in breast cancer cells

“…6,7 These include low stability in vivo, poor penetration, modest accumulation in target tissues and premature payload discharge in the bloodstream due to inadequate control over drug release. [8][9][10] To overcome such limitations, stimuli-responsive or smart polymeric nanocarriers have been developed. 11,12 These materials are designed to release payloads in response to internal or external stimuli such as light, magnetic fields, temperature, enzymes, redox-potential, and reactive oxygen species.…”

“…26 . Various types of disulfide can be used to crosslink micelles internally, 27 either in the core, 9 or at the shell. 28 Although shell crosslinked micelles can offer better stability along with higher drug loading, however, a challenge in preparation of shell-crosslinked micelles is the need for highly dilute conditions to circumvent undesired inter-micellar crosslinking, therefore making this route difficult for large-scale micellar preparation.…”