Acid-Responsive Adamantane-Cored Amphiphilic Block Polymers as Platforms for Drug Delivery

Abstract

Four-arm star-shaped (denoted as ‘S’) polymer adamantane-[poly(lactic-co-glycolic acid)-b-poly(N,N’-diethylaminoethyl methacrylate) poly(ethylene glycol) monomethyl ether]4 (S-PLGA-D-P) and its linear (denoted as ‘L’) counterpart (L-PLGA-D-P) were synthesized, then their self-assembled micelles were further developed to be platforms for anticancer drug delivery. Two types of polymeric micelles exhibited strong pH-responsiveness and good drug loading capacity (21.6% for S-PLGA-D-P and 22.9% for L-PLGA-D-P). Using doxorubicin (DOX) as the model drug, their DOX-loaded micelles displayed well controlled drug release behavior (18.5–19.0% of DOX release at pH 7.4 and 77.6–78.8% of DOX release at pH 5.0 within 80 h), good cytocompatibility against NIH-3T3 cells and effective anticancer efficacy against MCF-7 cells. However, the star-shaped polymeric micelles exhibited preferable stability, which was confirmed by the lower critical micelle concentration (CMC 0.0034 mg/mL) and decrease rate of particle sizes after 7 days incubation (3.5%), compared with the linear polymeric micelle L-PLGA-D-P (CMC 0.0070 mg/mL, decrease rate of particle sizes was 9.6%). Overall, these developed polymeric micelles have promising application as drug delivery system in cancer therapy.

Schiff-Linked PEGylated Doxorubicin Prodrug Forming pH-Responsive Nanoparticles With High Drug Loading and Effective Anticancer Therapy

“…Therefore, significant progress has been made towards the fabrication of ideal DOX delivery system with improved drug utilization at the action sites and reduced side effects in non-target tissues. Although the liposomal formulations of DOX have been approved for clinical use and many polymeric nanoparticles loading DOX molecules are being evaluated in clinical trials (14)(15)(16)(17)(18), these DOX-loaded nanocarriers have some inherent drawbacks like low drug loading, premature burst release and inactive carriers to patients, which may ascribe to the high polarity and hydrophilicity of DOX molecules. To overcome this unintended and undesirable leakage, chemically-linked drug carriers offer an alternative for the effective anti-tumor treatment.…”

Using Amphiphilic Polymer Micelles as the Templates of Antisolvent Crystallization to Produce Drug Nanocrystals

“…As shown in Figure A, the size of micelles does not change significantly in PBS at pH 7.4 within monitoring duration, while the sizes of micelles in PBS at pH 6.5 and 1.2 exhibit a noticeable increase, increasing from 164.0 to 295.0 nm and 255.0 to 1480.0 nm, respectively. It can be explained that the ester linkages between hydrophilic CMCS and hydrophobic PLA as well as the amide bond between CMCS and hydrophobic OA are broken in the acid environment, in turn causing the micelle disassembly. − Therefore, CPT-loaded micelles exhibit pH sensitivity, which will be conducive to the controlled release of drugs in the acidic environment.…”

“…The release ratio of CPT increased with decreasing pH, which is owing to the acidic condition leading to disassembly of the micelles. In an acidic environment, the ester bond formed between PLA and CMCS and the amide bond between CMCS and OA are broken due to protonation, leading to a dissociation of PLA-CMCS-g-OA micelles and accordingly a fast release of CPT. − Meanwhile, erosion or degradation of micelles in acidic conditions may also bring about the faster drug release than in neutral environments. − According to the literature, , the micelles constructed of biocompatible PLA, CMCS, and OA shall reduce the cytotoxicity of CPT nanocrystals on normal cells, which can be further clarified through in vitro and in vivo studies. The standard curve of CPT in DMF is shown in the Supporting Information (Figure S3).…”

PH-Sensitive Polymeric Nanoparticles for Targeted Delivery of Doxorubicin

“…DOX nanocarriers are reported to be more physically or chemically delivered in vivo to achieve better release. Although DOX liposomes have been clinically available, these nanocarriers still have some inherent disadvantages, such as low drug loading, early release and individual differences, as evaluated in clinical trials [12][13][14][15] . We speculate that these disadvantages are related to the structural properties of DOX molecule itself.…”