Multifunctional nanogel engineering with redox-responsive and AIEgen features for the targeted delivery of doxorubicin hydrochloride with enhanced antitumor efficiency and real-time intracellular imaging

Abstract

Nanogels exhibit potential application values in drug delivery systems because of their tunable properties and biocompatibility. In this study, multifunctional hyaluronic-based nanogels (HNPs), all-trans retinoid acid (ATRA)/aggregation-induced emission luminogen (AIEgen) fluorophores (TPENH 2)-grafted hyaluronic acid (HA) with disulfide bonds as linkers of (HA-ss-ATRA/TPENH 2), were successfully developed for doxorubicin hydrochloride (DOX) delivery. Besides, the controls of HA-ATRA/TPENH 2 were also developed for comparison. The HNPs with nanoscale particle sizes possessed an excellent DOX-loading capacity. As expected, the DOX-loaded HNPs exhibited the higher stability in a normal physiological environment (10 mM GSH), but rapidly disintegrated in the cancer microenvironment (20 mM GSH) according to an in vitro drug release study. The intracellular observation of HNPs by the fluorescence microscopy indicated that the self-fluorescent DOX-loaded HNPs with unique AIEgen characteristic transported DOX into the cancer cells and visibly accumulated within the cytoplasm. Importantly, the accumulation of DOX-loaded HNPs was largely increased due to the targeted reorganization of CD44 or LYCE-1 receptors by HA moieties on the surface of HNPs. Based on in vitro cytotoxicity analyses, the DOX-loaded HNPs displayed dramatically enhanced virulence to cancer cells compared to the controls and free DOX. This is the first study to achieve combined functionalities of targeted delivery, controllable release and real-time intracellular imaging on HA-base nanogels with enhanced antitumor efficiency. Therefore, the multifunctional HA-ss-ATRA/TPENH 2 HNPs have good potential to develop a novel drug delivery platform for the targeted delivery and controlled release of DOX to achieve enhanced antitumor efficiency as well as real-time intracellular imaging.

CD44-Targeted Nanocarrier for Cancer Therapy

“…Higher intracellular accumulation of DOX-loaded HNPs caused significantly higher tumor cell suppression than the control and free drug. An in vitro real-time imaging biodistribution and uptake study of DOX-loaded HNPs exhibited CD44-mediated tumor accumulation and uptake in the tumor cells ( Ma et al, 2018 ). In all the above studies, HA-decorated nanogels exhibited outstanding results which was due to binding of HA specifically to the CD44 receptor which promoted cellular internalization of nanocarriers, leading to release of their cargo into the tumor microenvironment because generally at low pH bonding between HA and its cargo could be broken.…”

Research Progress Review of Preparation and Applications of Fluorescent Hydrogels

“…Ma et al [63] reported a multifunctional nanomel gel project with redox reaction and AIEgen characteristics. All-transretinoic acid (ATRA), with a disulfide bond as a linking agent and a group of aggregation induced luminescence (TPENH 2 ) grafted with hyaluronic acid (HA), forms a fluorescent gel HA-ss-ATRA/TPENH 2 HNPs delivery carrier: ATRA as the hydrophobic core of multifunctional hyaluronic acid nanomaterials (HNPs), HA as a hydrophilic agent, using disulfide bond as redox sensitive bonds between HA and ATRA, and preparing HA-ss-ATRA two affinity conjugates, which can control the release of drugs according to the intracellular environment (Figure 11).…”

“…(a) Synthesis of HA-ss-ATRA/TPENH 2 conjugate. (b) HA-ss-ATRA/TPENH 2 HNPs is formed and used for drug delivery (reprinted from[63]).…”

A Comprehensive Outlook of Synthetic Strategies and Applications of Redox‐Responsive Nanogels in Drug Delivery

“…A variety of internal and external stimuli, that is, light, magnetism, temperature, enzyme, pH, ultrasonic waves, glucose, and redox potential have been used to get desired response and coordinated drug release . Especially, nanogels releasing therapeutics in response to intracellular redox potential have received considerable interest due to their immediate response capability and applicability in cancer drug delivery . In the past decade, a majority of redox‐responsive matrices have been designed, aiming prolonged circulation time and degradation after cellular internalization.…”