期刊
ADVANCED THERAPEUTICS
卷 4, 期 1, 页码 -出版社
WILEY
DOI: 10.1002/adtp.202000103
关键词
drug delivery; polymer pro-drugs; polymer therapeutics; self-assembled nanoparticles; triple negative breast cancer
资金
- Engineering and Physical Sciences Research Council [EP/N006615/1, EP/N03371X/1, EP/H005625/1, EP/L013835/1, EP/R035563/1]
- Royal Society [WM150086]
- EPSRC [EP/N006615/1] Funding Source: UKRI
Amphiphilic block co-polymers can assemble into nanoparticles with different sizes and structures, affecting the internalization rate and cytotoxicity towards breast cancer cells, with the BAB blocks accumulating most in the lungs and liver. Nanoparticles generated by conjugating doxorubicin show higher cytotoxicity compared to the free drug.
Amphiphilic block co-polymers composed of poly(ethylene glycol)-co-poly(lactide)-co-poly(2-((tert-butoxycarbonyl)amino)-3-propyl carbonate) (PEG-pLA-pTBPC) are synthesized in monomer ratios and arrangements to enable assembly into nanoparticles with different sizes and architectures. These materials are based on components in clinical use, or known to be biodegradable, and retain the same fundamental chemistry across AB and BAB block architectures. In MCF7 and MDA-MB-231 breast cancer cells, nanoparticles of <100 nm are internalized most rapidly, by both clathrin- and caveolin-mediated pathways. In THP-1 cells, polymer architecture and length of the hydrophilic block is the most important factor in the rate of internalization. The organ distributions of systemically injected nanoparticles in healthy mice indicate highest accumulation of the BAB-blocks in lungs and liver and the lowest accumulation in these organs of a methoxyPEG(5000)-pLA-pTBPC polymer. Conjugation of doxorubicin via a serum-stable urea linker to the carbonate regions of PEG(5000)-pLA-pTBPC generates self-assembling nanoparticles which are more cytotoxic in 2D, and penetrate further in 3D spheroids of triple negative breast cancer cells, than the free drug. In an aggressive orthotopic triple negative breast cancer mouse model, the methoxyPEG(5000)-pLA-pTBPC is of similar potency to free doxorubicin but with no evidence of adverse effects in terms of body weight.
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