Abstract
In this study, a novel poly (lactic-co-glycolic acid) (PLGA)-based micelle was synthesized, which could improve the therapeutic effect of the antitumor drug doxorubicin hydrochloride (DOX) and reduce its toxic and side effects. The efficient delivery of DOX was achieved by active targeting mediated by double receptors and stimulating the reduction potential in tumor cells. FA-HA-SS-PLGA polymer was synthesized by amidation reaction, and then DOX-loaded micelles were prepared by dialysis method. The corresponding surface method was used to optimize the experimental design. DOX/FA-HA-SS-PLGA micelles with high drug loading rate and encapsulation efficiency were prepared. The results of hydrophilic experiment, critical micelle concentration determination, and hemolysis test all showed that DOX/FA-HA-SS-PLGA micelles had good physicochemical properties and biocompatibility. In addition, both in vitro reduction stimulus response experiment and in vitro release experiment showed that DOX/FA-HA-SS-PLGA micelles had reduction sensitivity. Molecular docking experiments showed that it can bind to the target protein. More importantly, in vitro cytology studies, human breast cancer cells (MCF-7), human non-small cell lung cancer cells (A549), and mouse colon cancer cells (CT26) were used to demonstrate that the dual receptor-mediated endocytosis pathway resulted in stronger cytotoxicity to tumor cells and more significant apoptosis. In and in vivo antitumor experiment, tumor-bearing nude mice were used to further confirm that the micelles with double targeting ligands had better antitumor effect and lower toxicity. These experimental results showed that DOX/FA-HA-SS-PLGA micelles have the potential to be used as chemotherapeutic drugs for precise tumor treatment.
Highlights
Cancer is a common and frequently occurring disease threatening human health
The results showed that the CMC values of folic acid (FA)-Hyaluronic acid (HA)-SS-PLGA and doxorubicin hydrochloride (DOX)/FAHA-SS-PLGA were low, indicating that the drug-loading system could maintain its stability in the process of reaching the target through blood circulation (Kang et al, 2019)
A total apoptotic rate of MCF-7 cells incubated with DOX/FA-HA-SS-PLGA micelles was 32.27%, which was much higher than the 15.83% of DOX/HA-SSPLGA micelles and 16.31% of DOX/FA-SS-PLGA micelles. These results indicated that DOX/FA-HA-SS-PLGA drugloaded micelles would effectively promote the apoptosis of tumor cells and improve the antitumor efficacy of DOX
Summary
Cancer is a common and frequently occurring disease threatening human health. At present, the traditional treatment of cancer mainly includes surgical resection, chemotherapy, radiotherapy, and immunotherapy. Due to the advantages that traditional delivery systems do not have, nano-drug delivery systems have been widely studied as drug carriers, and many nano-drug delivery systems have been developed, such as magnetic nanoparticles (Hosseinpour Moghadam et al, 2019), microemulsion (Lv et al, 2018; Wang et al, 2019), liposomes (Antimisiaris et al, 2021), gold nanoparticles (Lochbaum et al, 2021), platinum nanoparticles (Kawawaki et al, 2021), polymer micelles (Yang et al, 2021), etc In these drug delivery systems, polymeric micelles are considered to be effective nanocarriers because they can encapsulate hydrophobic agents into their “core-shell” structures and deliver them to tumor regions through enhanced permeability and retention (EPR) effect. The researchers used cancer cell-specific ligands as targets to make the delivery system have active targeting to improve the limitations of EPR effect, for example, folic acid (Scaranti et al, 2020), hyaluronic acid (Xiong et al, 2020), peptide (Cooper et al, 2021), transferrin (Yu et al, 2020), etc. This method significantly enhances the antitumor effect and reduces the toxicity of the delivery system
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