Xiong, Guojun; (2023) Strategies for improving the effectiveness of nanomedicine in triple negative breast cancer model. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Breast cancer is the most prevalent and the second leading cause of death among women worldwide. Metastatic triple negative breast cancer (mTNBC) is the most aggressive type of breast cancer, and an effective treatment for mTNBC patients remains a high unmet medical need. Nowadays, [nab-paclitaxel (Abraxane®)] based combination therapy is recommended by the National Comprehensive Cancer Network® (NCCN®) as the first-line treatment for mTNBC. However, Abraxane® exhibited limited survival benefit as a monotherapy in cancer patients when compared with the innovator PTX formulation, Taxol®. In this work, two feasible solutions have been proposed that may further enhance the chemotherapeutic effect of PTX in the treatment of mTNBC. Firstly, by increasing the colloidal stability and payload of the nanocarrier, thereby improving the tumour deposition of PTX. The eligible nanocarrier (HSA-PLA nanoparticle) was created by the covalent binding of poly(L-lactide) to albumin cysteine residue. The PTX-loaded HSA-PLA nanomedicine has shown superior tumoricidal activity when compared to the Abraxane® in 4T1 tumour bearing mice at the same PTX dose. The final tumour weight of the mice treated with the HSAPLA (PTX) was 239.8 ± 43.0 mg (n = 5) and was statistically smaller than the group (n = 5) treated with the Abraxane®, where the tumour weight was 340.6 ± 62.8 mg (p < 0.5). Secondly, by further modifying the albumin, this nanocarrier is enabled to target the CD44 and folate receptors of the TNBC tumours. Briefly, this tumour-tropism nanocarrier (Ac-HSA-PLA nanoparticle) was fabricated by acetylating the albumin (Ac-HSA) and subsequently conjugating of the polymer PLA to the acetylated albumin. In MDA-MB-231 tumour bearing mice, the TNBC tumours (n = 5) were completely eliminated after the treatment with the Ac-HSA-PLA (PTX), whereas the injected Abraxane® and HSA-PLA (PTX) at the same PTX dose could not achieve the same results. These promising in vivo results have encouraged us to further investigate these nanomedicines.

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