Targeted drug delivery is a critical goal for effective cancer therapy. While nanoparticles (NPs) have shown promise for targeting drugs to tumors, several major challenges remain for controlling the biodistribution of NPs. In general, NPs predominantly accumulate in the liver and spleen and have difficulty penetrating poorly vascularized regions like hypoxic tumor regions. Neural Stem Cells (NSCs) are appealing for use as carriers for NPs in order to overcome these biodistribution challenges. NSCs have demonstrated inherent tumor tropic properties in pre- clinical invasive and metastatic tumor models, migrating selectively to tumors and penetrating hypoxic tumor regions. NSCs must be modified in some way to exploit their tumor targeting abilities. We have been pioneers in genetically altering NSCs to express an enzyme that converts a prodrug into active drug; recently showing safety in a first in-human clinical trial. As NSC-based therapy moves into the clinic, there is a need for complementary techniques to enable NSCs to destroy tumors that cannot be addressed with the enzyme-prodrug strategy. We have shown that NSCs maintain their tumor tropism when transporting either surface-bound or internalized NPs. The combination of NSCs and NPs offers the potential to realize a modular and general drug targeting system. We have recently published several papers showing surface-bound NPs can slowly release chemotherapy drugs, while internalized NPs can be used for thermal ablation of tumors. Here we will further develop the surface conjugated NP system and apply it to the treatment of stage III ovarian cancer (metastasized only in the abdominal cavity). Intraperitoneal (IP) as compared to intravenous (IV) chemo improved survival rates for stage III ovarian cancer. While this demonstrates that concentrating chemotherapy at the tumors has therapeutic benefit, IP therapy was also accompanied by increased toxic side effects. We hypothesize that NSC/NP hybrids can be used to target chemotherapy to abdominal ovarian cancer, improving outcomes and decreasing side effects. Conjugation of the NPs to the NSCs will be optimized and potential immunogenicity will be evaluated in vitro. Novel NPs with the desired drug release kinetics will be prepared. Once the most promising NP formulation and conjugation is identified, the efficacy of NSC/NP-targeted chemotherapy will be evaluated in vivo. The results from these studies will not only significantly impact the treatment of ovarian cancer, but should also enable improved therapy for other cancers. The NSC/NP constructs could also be used for treating other conditions that have proved amenable to NSC-therapy, such as neurodegenerative diseases.

Public Health Relevance

Our goal is to develop stem cell/nanoparticle constructs that can be used for targeted therapy. Our approach will enable not only new treatments for ovarian cancer, but also other cancers and potentially numerous other diseases like stroke that stem cells have been used to treat.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA197359-03
Application #
9303321
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Tandon, Pushpa
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Tiet, Pamela; Berlin, Jacob M (2017) Exploiting homing abilities of cell carriers: Targeted delivery of nanoparticles for cancer therapy. Biochem Pharmacol 145:18-26
Cao, Pengpeng; Mooney, Rachael; Tirughana, Revathiswari et al. (2017) Intraperitoneal Administration of Neural Stem Cell-Nanoparticle Conjugates Targets Chemotherapy to Ovarian Tumors. Bioconjug Chem 28:1767-1776
Mooney, Rachael; Weng, Yiming; Tirughana-Sambandan, Revathiswari et al. (2014) Neural stem cells improve intracranial nanoparticle retention and tumor-selective distribution. Future Oncol 10:401-15