Hyaluronic-Acid-Based pH-Sensitive Nanogels for Tumor-Targeted Drug Delivery

Abstract

A natural polysaccharide-based nanogel has been synthesized and characterized as pH-sensitive drug delivery system for poorly water-soluble anticancer drugs. In this work, methacrylated hyaluronic acid (MAHA) was used to prepared acid degradable nanogels by a surfactant-free polymerization method in water, where 2,2-dimethacroyloxy-1-ethoxypropane (DMAEP) served as a pH labile cross-linker. Nanogels of different cross-linking density were prepared and doxorubicin (DOX) was successfully encapsulated into the nanogels with drug-loading contents (DLC) ranging from 7.67 to 12.15%. An accelerated DOX release was found in acidic conditions. Cytotoxicity study showed that the DOX loaded nanogels have significantly enhanced cytotoxicity in vitro compared with the nonsensitive ones. Confocal microscopy revealed that there was more DOX in the nuclei of tumor cells when incubated with DOX-loaded pH sensitive nanogels for 3 to 12 h. The enhanced anticancer activity of DOX-loaded pH-sensitive nanogels was also verified by in vivo therapeutic study on mice, in which tumor volume evolution was measured and tumor tissues cell apoptosis and proliferation was examined.

Redox‐Responsive Self‐Assembled Nanoparticles for Cancer Therapy

“…One is to utilize acid-labile chemical bonds, such as hydrazone and acetal; the other is to use protonation of alkaline or acidic groups (amino, phosphoric, or carboxylic groups) in polymers. [23,24,25] When reaching the unique tumor acid environment, the pH-responsive selfassembled NPs undergo protonation or rapid chemical reactions, leading to related physicochemical changes, and finally realize release of drugs encapsulated in NPs in a controlled way.…”

pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

“…They observed the percentage release of DOX from hydrogel around 65% in 48 h at pH 5. Similarly, a hyaluronic‐acid‐based pH‐sensitive nanogel for tumor‐targeted drug delivery was reported by Song et al The DOX released from these nanogels was around 83% in 72 h at pH 5. However, the doxorubicin released in the solution from the PEGDA/PAMAM injectable network hydrogel system was 99 ± 1% at pH 5 in presence of 0.1 wt % DTT in 42 h. Compared to the above single stimulus responsive hydrogel/nanogel systems, the present PEGDA/PAMAM injectable network hydrogel showed faster release due to their dual‐stimuli‐responsive behavior viz both pH and reduction.…”

“…The success of delivery of such encapsulated drugs/dyes, peptides, proteins, growth factors at the targeted site could be achieved by introduction of stimuli‐responsive functional groups in these polymeric assemblies or hydrogels . Most of the natural biopolymers such as polysaccharides are biocompatible and biodegradable .…”

“…Injectable hydrogels are particularly interesting due to their spontaneous gelation at physiological conditions (pH and temperature) and being free of any requirement of additional external chemical treatment . Injectable hydrogels with single stimuli‐sensitive group such as acetal, hydrazone, oxime, disulfide, and so forth either in the hydrogel backbone or in the cross‐linker have been synthesized in past decades for targeted anticancer drug delivery and other biological applications . Hydrogel systems which respond to the combination of two or multiple stimuli would be more attractive for targeted or selective and fast/burst release of the encapsulated payloads than the single stimulus‐responsive hydrogels .…”

Redox-sensitive Polymeric Micelles With Aggregation-induced Emission for Bioimaging and Delivery of Anticancer Drugs

“…In this regard, smart polymeric micelles with stimuli-sensitive features have been explored for target site-triggered drugs release in response to appropriate environment of tumor tissues. [22][23][24][25][26] Among various stimuli-sensitive antitumor drug nanocarriers, redox-sensitive disul de linkage contained polymeric micelles have attracted more and more attention for controlled delivery and intelligent release of anticancer drugs. Disul de linkage of the polymeric micelles can be quickly cleaved by reductive substance glutathione (GSH) via thiol-disul de exchange 27 at high concentration of GSH in the intracellular environment of tumor cells (approximately 2-10 mM), while relatively stable at a low concentration of GSH in the extracellular environment (approximately 2-20 µM).…”