Stimuli-responsive targeted therapeutics for treatment of primary and metastatic prostate cancer

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Title Stimuli-responsive targeted therapeutics for treatment of primary and metastatic prostate cancer
Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Peng, Zheng-Hong (Joseph)
Date 2014-08
Description Prostate cancer is the most common malignant cancer and the second leading cause of cancer-related death among men in the United States. The major aim of this dissertation was to develop stimuli-responsive, targeted therapeutics for prostate cancer treatment. In the first part, 2-[3-(1,3-dicarboxypropyl)-ureido] pentanedioic acid (DUPA)- targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel (DTX) conjugates were developed for treatment of prostate cancer expressing prostate-specific membrane antigen. The in vivo results show that the spacer length between targeting moieties (DUPA) and HPMA copolymer backbone can significantly affect the treatment efficacy of DTX conjugates against C4-2 tumor bearing nu/nu mice. In the second part, a tumor-homing peptide iRGD and histone deacetylase inhibitor valproic acid conjugate (VPA-GFLG-iRGD) was developed and its activities were tested against prostate cancer cells. The conjugate VPA-­GFLG-­iRGD and a mixture of valproic acid (VPA) and GFLG-­iRGD have shown similar cytotoxicity against DU-­ 145 prostate cancer cells. However, the treatment of DU-­145 cells with conjugate VPA-­ GFLG-­iRGD resulted in a decreased percentage of cells in the G2 phase, whereas the exposure of a mixture of VPA and GFLG-­iRGD led to an increased percentage of cells in the G2 phase. iv In the third part, tumor-homing and penetrating peptide iRGD-targeted HPMA copolymer doxorubicin conjugates (P-DOX-PLGLAG-iRGD) were developed for prostate cancer treatment. iRGD was attached to HPMA backbone via a matrix metallopeptidase 2 (MMP-2) cleavable spacer (-PLGLAG-). Doxorubicin (DOX) was conjugated to HPMA copolymer via a lysosomal cleavable tetrapeptide spacer (-GFLG-). The activities of P-DOX-PLGLAG-iRGD and related controls were assessed in both monolayer and multilayer prostate cancer cells. The results demonstrated that the conjugate P-DOX-PLGAGL-iRGD has better penetration ability than P-DOX and a mixture of P-DOX and iRGD. In the fourth part, a HPMA copolymer CXCR-4 antagonist (BKT140) conjugate (P-PLGLAG-BKT140) was developed for inhibiting prostate cancer cell migration. BKT140 was attached to the HPMA backbone via a matrix metallopeptidase 2 (MMP-2) cleavable spacer (-PLGLAG-). The in vitro cell cytotoxicity results show that the conjugation of BKT140 to HPMA did not impact the functionality of BKT140. The migration results show that both HPMA copolymer BKT140 conjugate and free BKT140 inhibited the CXCL12 induced PC-3 prostate cancer cell migration. The conjugate PPLGLAG- BKT140 has greater impact than that of free BKT140.
Type Text
Publisher University of Utah
Subject Oncology
Subject MESH Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Neoplasm Metastasis; Receptors, Transferrin; Molecular Targeted Therapy; Prostate-Specific Antigen; Theranostic Nanomedicine; Tumor Microenvironment; Matrix Metalloproteinases; Antineoplastic Agents
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Stimuli-Responsive Targeted Therapeutics for Treatment of Primary and Metastatic Prostate Cancer
Rights Management Copyright © Zheng-Hong (Joseph) Peng 2014
Format application/pdf
Format Medium application/pdf
Format Extent 14,147,060 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6478qtn
Setname ir_etd
ID 1409632
Reference URL https://collections.lib.utah.edu/ark:/87278/s6478qtn
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