Preparation and evaluation of dabrafenib-loaded, CD47-conjugated human serum albumin-based nanoconstructs for chemoimmunomodulation
- Title
- Preparation and evaluation of dabrafenib-loaded, CD47-conjugated human serum albumin-based nanoconstructs for chemoimmunomodulation
- Author
- 최한곤
- Keywords
- Macrophage-mediated phagocytosis; Dabrafenib; CD47; Nanoparticle albumin-bound technology; Programmed death-1; Chemoimmunomodulation
- Issue Date
- 2021-11
- Publisher
- ELSEVIER
- Citation
- COLLOIDS AND SURFACES B-BIOINTERFACES, v. 208, Page. 112093-112105
- Abstract
- The transmembrane proteins, CD47 and signal-regulatory protein α are overexpressed in cancer cells and mac-
rophages, respectively, and facilitate the escape of cancer cells from macrophage-mediated phagocytosis. The
immunomodulatory and targeting properties of CD47, the chemotherapeutic effects of dabrafenib (D), and the
anti-programmed death-1 antibodies (PD-1) pave the way for effective chemoimmunomodulation-mediated
anticancer combination therapy. In this study, CD47-conjugated, D-loaded human serum albumin (HSA) nano-
systems were fabricated by modified nanoparticle albumin-bound technology. Cis-aconityl-PEG-maleimide (CA),
an acid-labile linker, was used to conjugate D@HSA and CD47; the resultant CD47-CA@D@HSA exhibited
tumor-specificity through receptor targeting, as well as preferential cleavage and drug release in the acidic tumor
microenvironment (pH 5) compared to normal physiological pH conditions (pH 6.5, 7.4). The successful prep-
aration of nanosized (~220 nm), narrowly dispersed (~0.13) CD47-CA@D@HSA was proven by physico-
chemical characterization. In vitro and in vivo internalization, accumulation, cytotoxicity, and apoptosis were
observed to be higher with CD47-conjugated nanoconstructs, than with free D or non-targeted nanoconstructs.
CD47-CA@D@HSA was found to promote the infiltration of cytotoxic T cells and tumor-associated macrophages
into tumors and improve in vivo tumor inhibition. Administration in combination with PD-1 further improved
antitumor efficacy by promoting immune responses that blocked the immune checkpoint. No signs of toxicity
were seen in mice treated with the nanoconstructs; the formulation was, therefore, thought to be biocompatible
and as having potential for clinical use. The targeted chemoimmunomodulation achieved by this combination
therapy was found to combat major immunosuppressive facets, making it a viable candidate for use in the
treatment of cancer.
- URI
- https://www.sciencedirect.com/science/article/pii/S0927776521005373https://repository.hanyang.ac.kr/handle/20.500.11754/169827
- ISSN
- 0927-7765
- DOI
- 10.1016/j.colsurfb.2021.112093
- Appears in Collections:
- COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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