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UM E-Theses Collection (澳門大學電子學位論文庫)

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Title

Smart nano-scaled drug delivery systems with pH-responsive drug release, tumor-targeting and synergistic drugs co-delivery in hepatocellular carcinoma treatment

English Abstract

Due to the currently poor outcome of chemotherapy in advanced hepatocellular carcinoma (HCC) patients, rational design of nano-scaled therapeutics would provide a potential to enhance anti-HCC effect. Moreover, co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers another effective strategy. This study was firstly to identify the synergistic anti-HCC efficacy of pHresponsive nanocarrier constituted with D-α-tocopheryl polyethylene glycol succinatepoly(β-amino ester) copolymer and doxorubicin (Dox) and curcumin (Cur) co-delivery in the combination of pro-apoptotic and anti-angiogenesis pathway. Based on the enhanced cellular internalization and rapid drug release in tumor microenvironment, the Dox and Cur co-loaded pH-responsive NPs exhibited considerable pro-apoptosis and anti-angiogenic effects in vitro in a synergistic manner. Additionally, the enhanced anti-tumor activity of co-loaded NPs in SMMC 7721 tumor-bearing mice was consistent with its high tumor accumulation. The present study demonstrated that the synergistic effect of simultaneous delivery of Dox and Cur in a pH-sensitive nanocarrier for HCC treatment. Compared with Dox monotherapy, treatment with sorafenib (Sor) plus Dox exhibited greater median time to progression, overall survival, and progression-free survival in randomized trials. However, the out-of-step pharmacokinetic profiles of multiple free drugs greatly limit its application. The second investigation in this thesis was on the co-delivery of Dox with Sor by iRGD decorated lipid-polymer hybrid NPs to enhance the specific tumor tissue accumulation and anti-HCC efficiency. With the optimal drug ratio screened, the stabilized iRGD-decorated co-loading NPs were iii prepared, shown synergistic cytotoxicity, pro-apoptotic ability and enhanced cellular internalization by iRGD-integrin recognition. In vivo pharmacokinetic results demonstrated that an extended circulation and bioavailability of drugs in Dox+Sor/iRGD NPs than that of free drugs. More importantly, Dox+Sor/iRGD NPs significantly enhanced antitumor efficiency in HCC xenograft mouse models. Overall, this study described a promising drug delivery strategy to synergistically take advantage of tumor-targeting nanocarriers and clinical drugs combination. Moreover, to overcome the common drawbacks of NPs such as poor cancer penetration, inefficient cellular uptake and slow intracellular drug release, we designed a multifunctional mixed micellar system mediated by glycyrrhetinic acid (GA) for specific liver-targeting, TAT peptide for cell penetration, and poly (β-amino ester) core for rapid drug release in endo/lysosome. With Dox loaded in as a model drug, we evaluated the step-by-step responses of this mixed micellar system in vitro and in vivo, i.e. specific tumor distribution by GA receptor recognition, enhanced cellular uptake by TAT peptide exposure in weakly acidic tumor microenvironment (pH≈6.4), and fast Dox release in endo/lysosome (pH≈5). More importantly, it showed excellent tumor-targeting capability and remarkably increased inhibition on tumor growth in HepG2 tumor-bearing mice. Taken together, this thesis provided three types of smart functional nano-DDSs for HCC treatment. As a proof of concept, results validated these nano-therapeutic design and suggested these novel nanomedicines would be promising candidates to fight against HCC

Issue date

2016.

Author

Zhang, Jin Ming

Faculty

Institute of Chinese Medical Sciences

Degree

Ph.D.

Subject

Drug delivery systems

Liver -- Diseases -- Treatment

Cancer -- Treatment

Supervisor

王一濤

陳美婉

Files In This Item

Full-text (Internet)

Location
1/F Zone C
Library URL
991001818769706306