Hypoxia/Temperature/pH Triple Stimuli–Responsive Block Copolymers: Synthesis, Self‐Assembly, and Controlled Drug Release

Abstract

The amphiphilic block copolymer poly(methacrylic acid-co-2-nitroimidazole acrylate)-b-poly(2-(N,N-dimethylamino)ethyl methacrylate) (P(MAA-co-NIMA)-b-PDMAEMA) with the hypoxia/temperature/pH triple responsiveness is synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT), hydrolysis, and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (EDC) reactions, and successfully self-assembled into micelles. The hypoxia response in vitro is realized, and then the sensitivity of the self-assembled micelles to the hypoxia condition is studied by controlling the grafting amount of aminated 2-nitroimidazole. Because 2-(N,N-dimethylamino) ethyl methacrylate (DMAEMA) is a typical material sensitive to temperature and pH conditions, the self-assembled micelles are also responsive to temperature and different acidic/basic conditions. In addition, the cumulative release rate of doxorubicin (DOX) at 42°C, pH = 6.0, and hypoxic conditions increases significantly, and verifies the synergistic promotion effect of the above stimulations. This intelligent polymer with triple response mechanism improves the controllability and efficiency of drug release, and is expected to be a drug carrier for cancer treatment.

Shoot the Arrow at the Target: Innovative Stimulus-Responsive Smart Nanocarriers for Cancer Therapy

“…In summary, the present study provides an innovative strategy to efficiently generate ROS and consume ROS scavenging system through a cascade reaction, and rationally design a highly efficient nanocatalator for tumor catalytic therapy. A large number of triple stimulus-responsive nanodrug delivery systems have been reported for tumor treatment in the TME, showing superior specificity, targeting, controllability and safety [33], for example, pH/redox/NIR triple-responsive ZnO quantum dots-conjugated hollow mesoporous carbon nanoplatform [110], light and dual-redox triple-responsive core-crosslinked micelles [111], hypoxia/temperature/pH triple-responsive block copolymers [112], and so forth. Recently, Wu et al reported a pH/thermal/glutathione triple-responsive smart supramolecular nanomedicine (FUS/ICG@PEDD) which was constructed by utilizing particular and kinetic hydrogen bonding interactions [112].…”

“…A large number of triple stimulus-responsive nanodrug delivery systems have been reported for tumor treatment in the TME, showing superior specificity, targeting, controllability and safety [33], for example, pH/redox/NIR triple-responsive ZnO quantum dots-conjugated hollow mesoporous carbon nanoplatform [110], light and dual-redox triple-responsive core-crosslinked micelles [111], hypoxia/temperature/pH triple-responsive block copolymers [112], and so forth. Recently, Wu et al reported a pH/thermal/glutathione triple-responsive smart supramolecular nanomedicine (FUS/ICG@PEDD) which was constructed by utilizing particular and kinetic hydrogen bonding interactions [112]. The supramolecular polymeric micelles were co-loaded with α, ω-functionalized symmetric hydrogen bonding precursor drug 5-fluorouracil acetate -SS-5-fluorouracil acetate (FUS) and dual photothermal/photodynamic agent (indocyanine green, ICG).…”

A temperature, pH, and ion sensitive block copolymer with an unusual phase transition: Monomethoxy polyethylene glycol - block-polyethyleneimine

“…Stimuli-responsive materials known as "smart" materials, have attracted great interest due to their unique properties which made them useful in many applications. [1][2][3][4][5][6].…”

Hyaluronidase-trigger nanocarriers for targeted delivery of anti-liver cancer compound

“…Stimulus-responsive drug delivery system (DDS) is a functional nanocarrier that can release drugs rapidly or at a certain rate aer entering the body by changing the structure and conguration of the carrier under the stimulation of a specic environment including light, heat, ultrasound, enzyme, and pH changes. [12][13][14][15][16][17][18] Especially, enzyme-responsive nanocarriers have been investigated extensively due to their high sensitivity, catalytic activity, and mild reaction. [19][20][21][22][23][24] As we all know, abnormal expression of enzymes is one of the markers of the occurrence and development of tumors.…”