Publication: Thiolated Alginate- Poly(Lactic-co-glycolic Acid) Aptamer-functionalised As A Tamoxifen-curcumin Nanocarrier Against Resistant Breast Cancer Cell
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Date
2023-12
Authors
Hock Ing, Chiu
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Abstract
Breast cancer therapy often fails due to the development of multidrug resistance (MDR), which is commonly mediated by the overexpression of P glycoprotein (P-gp), a drug efflux transporter presents in the membrane. Traditional drug delivery methods for single-drug chemotherapy have limitations such as low bioavailability, fast clearance, and MDR. Combination chemotherapy has reduced MDR and side effects, but toxicity issues remain a challenge. Targeted drug delivery systems have been developed to overcome drug resistance and improve cancer therapy effectiveness and safety. These systems are safer than conventional therapies and allow for greater drug doses, which is essential for improving efficacy and reducing toxicity. The objective of this project is to create thiolated alginate nanoparticles with the surface fabrication of poly(lactic-co-glycolic acid) (PLGA) and AS1411 aptamer for targeted delivery of tamoxifen (TAM) and curcumin (CUR) to resistant breast cancer cells. The thiolated alginate nanoparticles were prepared under the self-assembly process and further coated with PLGA for biofunctionalisation and a drug protection layer. TAM and CUR were entrapped into AS1411 aptamer and PLGA fabricated thiolated alginate nanoparticles (ACDL and ATDL). ACDL and ATDL nanoparticles showed particle sizes of -16 mV, showing stable nano-sized particles with narrow size distribution. Herein, the entrapment efficiencies of TAM and CUR in ACDL and ATDL nanoparticles were ~40% and 10%, respectively, indicating that the co-entrapment of TAM and CUR in the ACDL and ATDL nanoparticles was successful. The conjugation efficiency of AS1411 aptamer was recorded as >26%, providing cancer targeting for the nanoparticles. The cumulative release of CUR (>44%) and TAM (>65%) reached a plateau at 72 h in ACDL and ATDL nanoparticles, indicating that the ACDL and ATDL nanoparticles exhibited sustained drug release. In vitro studies were performed using MCF-7, MCF-7/TAMR-1, and MCF-7/10A cells. The viability of MCF 7/TAMR-1 cells was significantly lower than MCF-7/10A cells 72 h post treatment with ACDL and ATDL nanoparticles, proving that the nanoparticles were selective against cancer cells over normal cells. ACDL and ATDL nanoparticles also induced early apoptosis and cell cycle arrest at the G0/G1 phase in MCF-7/TAMR-1 cells, showing that the nanoparticles were effectively suppressed the growth of resistant breast cancer cells. The cellular uptake of ACDL and ATDL nanoparticles showed time- and dose-dependent results, with an optimum 2 h incubation and concentration as low as 6.3 µg/mL via nucleolin receptor- and clathrin-mediated endocytosis. ACDL and ATDL nanoparticles suppressed P-gp expression and ATP activity while improving intracellular tamoxifen accumulation and retention. In conclusion, the results suggest that ACDL and ATDL nanoparticles have the potential to be effective anticancer agents for resistant breast cancer therapy by improving drug retention and reducing P-gp expression and ATP activity
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Keywords
Thiolated Alginate , Lactic-co-glycolic Acid , Tamoxifen-curcumin Nanocarrier , Against Resistant Breast Cancer Cell , Chiu Hock Ing , medical