期刊
JOURNAL OF DRUG TARGETING
卷 30, 期 10, 页码 1088-1105出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/1061186X.2022.2092623
关键词
Human serum albumin; TNBC; metastasis; tumour; olaparib; nanoparticles
资金
- Department of Science and Technology-Science and Engineering Research Board (DST-SERB) [CRG/2018/001065]
- DST(FIST) grant [SR/FST/LS-II/2018/210]
A bioinspired/active-tumour targeted nanoparticles system of human serum albumin with physically entrapped olaparib showed promising therapeutic effectiveness in highly metastatic TNBC cells.
Poly(ADP-ribose) polymerase inhibitor olaparib demonstrated therapeutic effectiveness in highly metastatic triple-negative breast cancer (TNBC). However, olaparib offers a weak therapeutic response in wild-type BRCA cancers due to the drug's poor bioavailability. Here, a bioinspired/active-tumour targeted nanoparticles system of human serum albumin with physical entrapment of olaparib was prepared via a low-energy desolvation technique using the crosslinker glutaraldehyde. The developed OLA@HSA NPs were nanosize (similar to 140 nm), kinetically stable with a low polydispersity (0.3), exhibited olaparib entrapment (EE 76.01 +/- 2.53%, DL 6.76 +/- 0.22%) and sustained drug release at pH 7.4 with an enhancement of drug release in acidic pH. OLA@HSA NPs decreased the half-maximal inhibitory concentrations (IC50) of olaparib by 1.6-, 1.8-fold in 24 h and 2.2-, 2.4-fold in 48 h for human (MDA-MB 231) and mouse (4T1) TNBC cells, respectively, mediated by their enhanced time-dependent cellular uptake than free olaparib. The OLA@HSA NPs induced concentration-dependent phosphatidylserine (apoptotic marker) externalisation and arrested the cell population in the G2/M phase in both the tested cell lines at a higher level than free olaparib. The NPs formulation increased DNA fragmentation, mitochondrial membrane depolarisation and ROS generation than the free olaparib. The in vivo study conducted using 4T1-Luc tumour-bearing mice demonstrated strong tumour growth inhibitory potential of OLA@HSA NPs by elevating apoptosis ROS generation and reducing the level of the antiproliferative marker, Ki-67. OLA@HSA NPs reduced the occurrence of lung metastasis (formation of metastasis nodules decreased by similar to 10-fold). OLA@HSA NPs could be a promising nanomedicine for the TNBC treatment.
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