Drug resistance causes treatment failure and death in more than 90% of patients with metastatic cancer. Ovarian cancer (OvCa) is a leading cause of death from cancer in women with a projected 14,270 deaths in US in 2014, and is generally diagnosed in advanced stages when the tumor has metastasized and numerous micrometastases with intrinsic or acquired resistance have formed.
We aim to synchronize delivery of therapeutic oligonucleotides (ONs) and photodynamic therapy (PDT) agents to OvCa using nanoparticles (NPs), and thus to provide a combination therapy to overcome drug resistance in OvCa. ONs and PDT can provide mechanistically distinct therapies for resistant OvCa but both have limitations when used as monotherapy. ONs are capable of targeting any specific gene that causes drug resistance; however, their therapeutic activity had been constrained by the poor access to their intracellular sites of action because of non-productive endosomal trapping. PDT is a clinically approved anticancer procedure; however, it suffers from sub-lethal cancer cell killing due to its own resistance mechanisms and a short duration of action. We hypothesize that NP-based co-delivery enables complementation of these two modalities, leading to synergism at two levels. Firstly, when delivered together to endosomes in OvCa cells, laser-activated PDT triggers endosomal escape of ONs to their intracellular action sites. Thereafter, the functional delivery of the ONs can target specific genes and overcome drug resistance in multiple modes. Thus, when apoptosis-promoting Bcl-x splice-switching oligonucleotide (SSO) is used, it can guide PDT to an apoptotic pathway. When MDR1 siRNA is used, it can resensitize OvCa to paclitaxel, the first line chemotherapy drug to OvCa. We have prepared ultra-small OvCa-targeted NPs carrying ONs and the PDT drug Ce6. Preliminary studies indicated that laser activation of Ce6 enables functional delivery of the ONs and causes cytotoxicity to OvCa cells. In this proposal, 4 specific aims are designed to test our hypothesis and realize the goal: 1. Elucidate cellular mechanisms for synergism of ONs and PDT and then optimize the NPs for greater synergistic action. 2. Evaluate therapeutic activity of the NPs in 3-D OvCa models that recapitulate some key features of in vivo microenvironment. 3. Test photochemical delivery of Bcl-x SSO in vivo. 4. Test photochemical delivery of MDR1 siRNA. Studies proposed in this grant will thus provide distinct approaches to address the two underlying causes of drug resistance in OvCa: increased intrinsic survival ability and reduced intracellular drug concentration of OvCa cells.

Public Health Relevance

Successful implementation of this project will provide a highly specific cancer therapy due to receptor-targeted delivery, laser-guided activation, and cancer cell specific overexpression of oncogenes such as Bcl-xL, all of which will contribute to a therapy with maximum cancer killing and minimum toxicity. The targeted delivery systems can be easily changed to aim to other cancers by using different ligands, and we can target other cancer-permissive genes by choosing from various ONs including siRNAs, antisense, SSOs, microRNAs, and their antagomirs. Therefore, studies proposed in this grant will expand the physicians' menu of cancer therapies that can be customized for specific cancers, and increasingly, specific patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA194064-01A1
Application #
9029956
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Buchsbaum, Jeffrey
Project Start
2015-12-01
Project End
2016-07-31
Budget Start
2015-12-01
Budget End
2016-07-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Zhao, Yan; Li, Fang; Mao, Chengqiong et al. (2018) Multiarm Nanoconjugates for Cancer Cell-Targeted Delivery of Photosensitizers. Mol Pharm 15:2559-2569
Suo, Xubin; Eldridge, Brittany N; Zhang, Han et al. (2018) P-Glycoprotein-Targeted Photothermal Therapy of Drug-Resistant Cancer Cells Using Antibody-Conjugated Carbon Nanotubes. ACS Appl Mater Interfaces 10:33464-33473
Mao, Chengqiong; Qu, Ping; Miley, Michael J et al. (2018) P-glycoprotein targeted photodynamic therapy of chemoresistant tumors using recombinant Fab fragment conjugates. Biomater Sci 6:3063-3074
Li, Fang; Zhao, Yan; Mao, Chengqiong et al. (2017) RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer. Mol Pharm 14:2793-2804
Wang, Ling; Ariyarathna, Yamuna; Ming, Xin et al. (2017) A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides. ACS Chem Biol 12:1999-2007
Wang, Mengzhe; Mao, Chengqiong; Wang, Hui et al. (2017) Molecular Imaging of P-glycoprotein in Chemoresistant Tumors Using a Dual-Modality PET/Fluorescence Probe. Mol Pharm 14:3391-3398
Li, Fang; Zheng, Chunli; Xin, Junbo et al. (2016) Enhanced tumor delivery and antitumor response of doxorubicin-loaded albumin nanoparticles formulated based on a Schiff base. Int J Nanomedicine 11:3875-90
Wu, Lin; Mao, Chengqiong; Ming, Xin (2016) Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells. Biomed Res Int 2016:7478650