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Chen, YC (2017) MULTIFUNCTIONAL MICELLAR NANOMEDICINE FOR TARGETED CANCER THERAPY. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Chemotherapy is frequently used in the treatment of cancer. However, their therapeutic outcome is compromised by the short circulation time and systemic toxicity. Nanomaterials have emerged as ideal platforms to circumvent these limitations and improve the therapeutic effect of anticancer agents.
We first developed a dual function carrier that is based on PEG-derivatized S-trans, trans-farnesylthiosalicylic acid (FTS) for delivery of curcumin. FTS is a potent nontoxic Ras antagonist and curcumin is a chemopreventive agent for cancers. Both curcumin and FTS have poor water solubility and limited bioavailability. The PEG5K-FTS2 led to a synergistic antitumor activity by co-delivery of curcumin. Next, we demonstrated that introduction of an Fmoc motif to PEG5k-FTS2 led to a significant improvement in the drug loading capacity and antitumor effect in vitro and in vivo.
Unfortunately, delivery of cytotoxic agents is often limited by various negative feedback mechanisms during cancer treatment. Immunochemotherapy represents a promising strategy to improve anti-cancer effect. Here we developed an immunostimulatory PEG-NLG nanomicellar carrier for delivery of paclitaxel (PTX). NLG is an indoleamine 2,3-dioxygenase (IDO) inhibitor, which can block tumor immune escape. In vivo delivery of PTX using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumor response in multiple mouse tumor models.
Although the PEG-NLG-based immunochemotherapy system achieved considerable antitumor effect, its efficacy was compromised by the accumulation of myeloid-derived suppressor cells (MDSCs). In order to solve this problem, an improved polymeric micelle system (PEG5k-Fmoc-NLG2) was developed to codeliver a multi-target receptor tyrosine kinase inhibitor, sunitinib (SUN) and PTX. SUN+PTX/PEG5k-Fmoc-NLG2 micelles could not only enhance in vivo antitumor activity but also decrease the recruitment and maturation of MDSCs in the tumor, too.
Tumoral expression of immune stimulating cytokines has been show to be an effective strategy to boost immunotherapy of cancer. This inspired us to develop a carrier system, which could codeliver both gene therapy and small molecule drug. We designed two polymeric conjugates POEG-st-Pmor and POEG-st-Ppipe for codelivery of IL-36γ plasmid DNA and Doxorubicin (Dox). Both carriers could achieve efficient Dox and pDNA co-delivery in vitro and in vivo and achieved lung-specific accumulation for treatment of lung cancer.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Chen, YCyic62@pitt.eduyic62
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorLi, Ssol4@pitt.edusol4
Committee MemberMa, XCMXIAOCHA@pitt.eduMXIAOCHA
Committee MemberYang, Ddyang@pitt.edudyang
Committee MemberVenkataramanan, Rrv@pitt.edurv
Committee MemberLu, BFbinfeng@pitt.edubinfeng
Date: 7 December 2017
Date Type: Publication
Defense Date: 20 November 2017
Approval Date: 7 December 2017
Submission Date: 5 December 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 241
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Date Deposited: 07 Dec 2017 19:40
Last Modified: 07 Dec 2017 19:40

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