Background of Cancer Treatment
Currently, the common clinical treatments for malignant tumours include chemotherapy, radiotherapy and surgery. Among these, chemotherapy is the most widely used and important treatment for malignant tumours and has an irreplaceable position in the treatment of malignant tumours. In recent years, new anti-tumour drugs have been introduced and treatment options have been continuously improved. However, there are still many problems with the anti-tumour drugs used clinically: (1) poor water solubility and stability; (2) rapid metabolism and circulation in the body has a short half-life; (3) lack of selectivity, low drug utilization, and has high toxicity and side effects on normal tissues; (4) some tumour cells are prone to develop drug resistance during chemotherapy, etc.
In order to solve the above problems, a wide variety of nanocarriers, including micelles, vesicles, nanogels and nanofibers, are used to deliver anti-tumor drugs. Among them, micelles formed by self-assembly of amphiphilic copolymers have been widely studied due to their simple preparation method and controllable particle size. Polymer micelles have unique advantages as drug carriers, such as nanometer size, good thermodynamic stability and unique "core-shell" structure. Therefore, polymer micelles can improve the stability of anti-tumor drugs in water, prolong their circulation time in the blood, and increase their aggregation in tumor sites, thereby reducing toxic side effects and improving tumor inhibitory effects.
PEG-b-PLA
Among many amphiphilic copolymers, polyethylene glycol-polylactide block copolymer (PEG-b-PLA) has shown good application prospects due to its excellent biodegradability and biocompatibility, and has been It has been approved by the U.S. Food and Drug Administration (FDA) and can be used as an injectable pharmaceutical excipient. For PEG-b-PLA micelles, the hydrophilic PEG "shell" can increase the water solubility of the micelles and reduce protein adhesion, while the hydrophobic PLA "core" can load hydrophobic drugs or protect bioactive drugs, making the drug reaches the "lesion" site smoothly.
Figure 1. mPEG-PLA diblock and PLA-PEG-PLA triblock nanoparticles.(Ghasemi R, et al.; 2018)
As we all know, lactide has an enantiomeric structure. Both enantiomeric polymers have good biocompatibility, and there is a stereoscopic compound effect relationship between poly-d-lactide (PDLA) and poly-l-lactide (PLLA). Based on the above effects, the PEG-b-PLA three-dimensional composite micelles have a denser structure and stronger stability than PEG-b-PDLA and PEG-b-PLLA micelles. In addition, compared with linear copolymer micelles, star-shaped copolymer micelles exhibit special thermal properties, with lower viscosity, lower critical micelle concentration, smaller hydrodynamic diameter, and more stable structure, and has received widespread attention from the scientific community and industry.
4-arm PEG-b-PLA Construction and Characteristics
Based on the above background and previous work, the researchers synthesized two kinds of 4-arm PEG-b-PLA enantiomeric copolymers, and used nanoprecipitation method to prepare 4-arm PEG-b-PDLA micelles (PDM) and 4-arm PEG-b-PLLA micelles (PLM) and 4-arm PEG-b-PDLA/4-armed PEG-b-PLLA stereocomplex micelles (SCM) were used to examine the effect of stereocomplexation on micelle properties, and The drug loading, controlled release and cell proliferation inhibition properties of 4-arm PEG-b-PLA micelles were studied. In this study, researchers used Sn(Oct)2 as a catalyst to prepare 4-arm PEG-PLA enantiomeric copolymers through 4-arm PEG-initiated ring-opening polymerization of DLA or LLA. The synthesized copolymer can self-assemble into spherical micelles in an aqueous environment and is used to load the model anti-tumor drug DOX. Compared with single micelles, SCM has a denser structure, smaller particle size and higher drug loading efficiency. SCM/DOX is more stable, has slower DOX release, and can effectively slow down the burst release of PDM/DOX and PLM/DOX. Drug-loaded 4-arm PEG-PLA micelles, especially SCM/DOX, have good proliferation inhibitory effects on HepG2 cells and exhibit excellent long-lasting inhibition. In addition, the study found that compared with DOX, drug-loaded micelles have less toxicity to L929 cells, thus proving its possibility of reducing the toxicity of anti-tumor drugs to normal tissues and cells. In addition, the researchers shows that there is room for further development, including the introduction of active targeting groups to improve its endocytosis, the introduction of intracellular environment-responsive linking bonds between the PEG and PLA blocks to give it the function of intracellular targeted release and carry out end group modification to improve its DLC and DLE, etc. Therefore, 4-arm PEG-PLA three-dimensional composite micelles can be used as a potential in vivo drug delivery carrier for malignant tumor chemotherapy, and have great room for further optimization.
References
- Afsharzadeh M, et al.; PEG-PLA nanoparticles decorated with small-molecule PSMA ligand for targeted delivery of galbanic acid and docetaxel to prostate cancer cells. J Cell Physiol. 2020, 235(5):4618-4630.
- Xiao RZ, et al.; Recent advances in PEG-PLA block copolymer nanoparticles. Int J Nanomedicine. 2010, 5:1057-65.
- Ghasemi R, et al.; mPEG-PLA and PLA-PEG-PLA nanoparticles as new carriers for delivery of recombinant human Growth Hormone (rhGH). Sci Rep. 2018, 8(1):9854.
