Photo‐ and pH‐Responsive Polycarbonate Block Copolymer Prodrug Nanomicelles for Controlled Release of Doxorubicin

Abstract

Photo/pH dual‐responsive amphiphilic diblock copolymers with alkyne functionalized pendant o‐nitrobenzyl ester group are synthesized using poly(ethylene glycol) as a macroinitiator. The pendant alkynes are functionalized as aldehyde groups by the azide‐alkyne Huisgen cycloaddition. The anticancer drug doxorubicin (DOX) molecules are then covalently conjugated through acid‐sensitive Schiff‐base linkage. The resultant prodrug copolymers self‐assemble into nanomicelles in aqueous solution. The prodrug nanomicelles have a well‐defined morphology with an average size of 20–40 nm. The dual‐stimuli are applied individually or simultaneously to study the release behavior of DOX. Under UV light irradiation, nanomicelles are disassembled due to the ONB ester photocleavage. The light‐controlled DOX release behavior is demonstrated using fluorescence spectroscopy. Due to the pH‐sensitive imine linkage the DOX molecules are released rapidly from the nanomicelles at the acidic pH of 5.0, whereas only minimal amount of DOX molecules is released at the pH of 7.4. The DOX release rate is tunable by applying the dual‐stimuli simultaneously. In vitro studies against colon cancer cells demonstrate that the nanomicelles show the efficient cellular uptake and the intracellular DOX release, indicating that the newly designed copolymers with dual‐stimuli‐response have significant potential applications as a smart nanomedicine against cancer.

Stimuli-Responsive Aliphatic Polycarbonate Nanocarriers for Tumor-Targeted Drug Delivery

“…The use of a triple stimulus allowed control of the changes in the morphology of nanoparticles, and thus for a precise, controlled release of drugs [163]. Kalva et al [164] reported pH/photo-dual-sensitive nanocarriers. The micelles consisted of PEGylated APC bearing photo-responsive o-nitrobenzyl ester group and doxorubicin molecules conjugated via acid-sensitive Schiff-base linkage.…”

“…(B) In vitro cumulative release of DOX at pH 7.4, 6.0, 5.0, and pH 5.0 with 10 min UV light irradiation. Reprinted with permission from ref[164]. Copyright 2020 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim, Germany.…”

Backbone-Degradable (Co-)Polymers for Light-Triggered Drug Delivery

“…Recently, light as a stimulus gained tremendous attention since this trigger can be applied both remotely and accurately by adjusting the parameters of irradiation, such as wavelength, irradiation time, or intensity. , Thus, light-responsive polymers show high potential as efficient and targeted controlled release systems, which reduce side effects compared to conventional therapy. , Photocleavable moieties employed most commonly in such systems are coumarin , and ortho -nitrobenzyl − (oNB) derivatives. The combination of different stimuli-responsive units in one polymer is regarded especially useful for controlling release profiles or enhancing release rates of the drug delivery system (DDS). − For example, Kalva et al developed a photo and pH dual-responsive polycarbonate (PC) block copolymer conjugated with doxorubicin via an imine linkage to pendant groups that also contain oNB functions . Upon cleavage of the pendant groups by irradiation or pH decrease, the drug was released successfully, while the disintegration of the micelles due to hydrophilic/hydrophobic imbalance was observed.…”

“…29−31 For example, Kalva et al developed a photo and pH dual-responsive polycarbonate (PC) block copolymer conjugated with doxorubicin via an imine linkage to pendant groups that also contain oNB functions. 32 Upon cleavage of the pendant groups by irradiation or pH decrease, the drug was released successfully, while the disintegration of the micelles due to hydrophilic/ hydrophobic imbalance was observed. Polymeric nano-and microparticles are a typical platform for drug delivery systems and a promising therapeutic strategy for pharmaceutically challenging drugs.…”

Utilization of Polymer-Lipid Hybrid Nanoparticles for Targeted Anti-Cancer Therapy

“…The different chemical modifications with polymers diversify the various polymeric nano-carriers formed such as polymeric micelles, drug-polymer conjugates, and polymeric NPs. Biodegradable polymers, such as synthetic polymer poly-lactic acid (PCL), poly (lactic-co-glycolic acid) (PLGA), and the natural polymer chitosan are mostly used in cancer therapeutics [ 23 , 24 ]. However, the disadvantages of polymeric NPs include the need for organic solvents for synthesis, limited payload, and moderate circulation half-life [ 25 ].…”