Date of Award
Open Access Dissertation
College of Pharmacy
Cancer is one of the leading modality diseases. The number of cancer patients has increased in the last decades due to radiation, aging, stress condition, and other reasons. There are three traditional cancer therapies (radiation therapy, chemotherapy, and surgery). Even though these treatments improve the life span of cancer patients, many cancer patients still lost their lives due to the development of tolerance. Thus, it is urgent to develop new kinds of treatments to extend the life span of patients. In recent decades, nanomedicine, which utilizes nanotechnology to deliver chemotherapy agents into tumor sites and improve the anticancer effect and reduce the side effects of treatment, has been extensively explored.
Recently, our group developed the polymer poly [(2-(pyridin-2-yldisulfanyl) ethyl acrylate)-co- [poly (ethylene glycol)]] (PDA-PEG) as a carrier for cancer therapy. Our previous study found that PDA-PEG combined with copper ions could selectively kill cancer cells while sparing normal cells. However, the mechanism of the selective cytotoxicity of PDA-PEG/copper (Poly/Cu) on cancer cells is unknown. In this study, we investigated the cell killing mechanism of PDA-PEG/copper (Poly/Cu) for breast cancer and found that PDA-PEG/copper (Poly/Cu) nanocomplexes facilitate copper ion uptake in the cancer cells. Poly/Cu killed 4T1 cells depending on the lysosome cell death pathway. Furthermore, Poly/Cu suppresses both 20S proteasome function and autophagy pathway and triggers immunogenic cell death (ICD) in 4T1 cells. The Poly/Cu induced ICD coupled with the checkpoint blockade effect of anti-PD-L1 antibody (aPD-L1) synergistically helps immune cells penetrate the tumor mass. Benefiting from the tumor-targeting effect and cancer cell-selective killing effect of Poly/Cu complexes, the combinatory treatment of aPD-L1 and Poly/Cu effectively inhibits the progression of triple-negative breast cancer without inducing systemic toxicity. Furthermore, we also explored the synergetic effect of VER155008, an HSP70 inhibitor, and Poly/Cu nanoparticle for ovarian cancer therapy. VER155008 was encapsulated into the PDA-PEG nanoparticle and conjugated the nanoparticle with Arg-Gly-Asp (RGD) peptides to further improve the antitumor effect of PDA-PEG nanoparticles and yielded RGD-VER NP. In vitro study demonstrated that RGD-VER NP could significantly facilitate the nanoparticles entering SKOV-3 and NCI-ADR/RES cells and boost their cytotoxicity. RGD-VER NP exhibited an excellent tumor-targeting effect in an advanced ovarian cancer mouse model and achieved an excellent inhibitory effect on tumor progression while not inducing systemic toxicity.
Hu, X.(2023). The Mechanism of PDA-PEG/Copper Selectively Killing Cancer Cells and Its Application in Treating Triple-Negative Breast Cancer and Advanced Ovarian Cancer. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/7380
Available for download on Sunday, August 31, 2025