Participant: PROMISE AGEP Research Symposium
Institution: University of Maryland, College Park (UMD)
Unassisted Defeat of Multidrug Resistance Using Intracellularly Actuated Nanoparticle Bioconjugates in a Model Cancer Cell Line
Fischell Department of Bioengineering
University of Maryland- College Park
Multidrug resistance (MDR) is a significant challenge in the treatment of many types of cancers as membrane-associated transporters actively pump drugs out of the cell, limiting therapeutic efficacy. While nanoparticle (NP)-based therapeutics have emerged as a mechanism for overcoming MDR, they often rely on the delivery of multiple anticancer drugs, nucleic acid hybrids, or MDR pump inhibitors. The effectiveness of these strategies, however, can be limited by their off-target toxicity or the need for genetic transfection. The goal of this project is to synthesize a nanoparticle (NP)-peptide-drug bioconjugate that achieves significant cell killing in MDR-positive cancer cells without the need for additional drugs. We do so by using a quantum dot (QD) as a central scaffold to append to species of peptide: 1) a cell uptake peptide to facilitate endocytic internalization and 2) a cleavable ester-DOX peptide to controllably release drug cargo near the nucleus in order to overcome MDR. This approach relies on spatiotemporal control over drug release, where endosomes traffic drug away from membrane-resident pumps and release it closer to the nucleus. Cellular delivery and localization studies revealed high uptake of the NP-drug complex and nuclear localization of the drug in MDR-positive cells. Additionally, cytotoxicity studies showed much higher toxicity for the bioconjugate compared to free drug, confirming the utility of this system in overcoming MDR in cancer cells.
Ajmeeta Sangtani is a fifth year PhD student in the Department of Bioengineering and is completing her graduate research at the US Naval Research Laboratory. Ajmeeta graduated from Case Western Reserve University (CWRU) in 2014 with a B.S. in Biomedical Engineering and minors in Spanish and Chemistry. At CWRU, she conducted research in the Department of Enviornmental Engineering under the direction of Dr. Banu Yildiz. Ajmeeta worked on developing household bio-sand filters and travelled to a remote community in the Dominican Republic to implement the project. She presented her findings at two conferences in Ohio. Ajmeeta also researched use of multifunctional agents for tumor targeting in the Case Center for Biomolecular Engineering under the direction of Dr. Zheng Rong Lu. Ajmeeta is interested in studying controlled drug release from the surface of hard nanoparticles. Specifically, in Dr. Delehanty’s lab, Ajmeeta is working on using quantum dots as a model scaffold to control release of appended cargo using internal and external stimuli. Ajmeeta has published first author review papers and journal articles and presented talks at national conferences including SPIE BioS and the ACS National meeting. She is passionate about generating interest in STEM within the younger generation and has been engaged in outreach during her undergraduate and graduate studies. She is currently involved in ReSET, a volunteer program that seeks to interest elementary school students in STEM by replacing one science class a week with an experiment. In her free time, Ajmeeta enjoys running, travelling, cooking and hiking.
GENERAL SUMMARY OF GRADUATE RESEARCH
Traditional, systemic delivery of drugs and imaging agents relies on repeated dosing of large concentrations of poorly targeted cargos, leading to off-target toxicity. In recent years, nanoparticle (NP)-mediated drug delivery (NMDD) has been developed as a novel method to overcome the limitations of traditional delivery. NMDD seeks to take advantage of the unique size-dependent properties of NPs for doing more, such as imaging, labeling, therapy or a combination of the three. Additionally, it has the ability to specifically target cargos while being able to augment the activity of the imaging agent or drug cargo. NPs are classified into two categories, soft or hard, based on their physicochemical makeup and the manner in which cargo is loaded into or appended onto the NP. Currently, our most advanced understanding of controlling NP-associated cargos is in the context of soft nanoparticles and passive actuation, where there is little control over cargo release. The goal of this research work is to utilize hard NPs, which can be synthesized at a smaller scale, and active actuation to achieve a high level of spatiotemporal control of drug release and therapeutic efficacy. This work will be accomplished through using (1) a NP-cell uptake peptidyl platform combined with various intracellular responsive peptide-drug linkages to modulate the toxicity of a drug (2) a version of the NP-cell uptake peptidyl platform from (1) to overcome multidrug resistance in cells and (3) a NP-photosensitizer-drug platform to control drug release externally.
SELECTED LIST OF PRESENTATIONS AND PUBLICATIONS
- Sangtani, A., Muroski, M. E., Delehanty, J.B., (2018). Actively-Triggered Drug Delivery Using Hard Nanoparticle Carriers. In ACS Symposium Series. ACS Book Publications. Just accepted.
- Sangtani, A., Petryayeva, E., Wu, M., Susumu, K., Oh, E., Huston, A.L., Lasarte-Aragonés, G., Medintz, I.L., Algar, W.R., Delehanty, J.B., (2017). Intracellularly Actuated Quantum Dot–Peptide–Doxorubicin Nanobioconjugates for Controlled Drug Delivery via the Endocytic Pathway. Bioconjugate Chemistry, 29(1), 136-148.
- Sangtani, A., Nag, O. K., Field, L. D., Breger, J. C., & Delehanty, J. B., (2017). Multifunctional nanoparticle composites: progress in the use of soft and hard nanoparticles for drug delivery and imaging. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 9(6), e1466. (Featured on journal)
- Sangtani, A., Petryayeva, E., Wu, M., Susumu, K., Oh, E., Huston, A.L., Lasarte-Aragonés, G., Medintz, I.L., Algar, W.R., Delehanty, J.B., (2017) Nanoparticle Bioconjugate for Controlled Cellular Delivery of Doxorubicin. SPIE BiOS, San Francisco, California, January 27-February 1, 2018.
- Sangtani, A., Petryayeva, E., Wu, M., Susumu, K., Oh, E., Huston, A.L., Lasarte-Aragonés, G., Medintz, I.L., Algar, W.R., Delehanty, J.B., (2017) Spatiotemporal Modulation of Doxorubicin Toxicity via Delivery as a Nanoparticle-bioconjugate Complex. ACS National Meeting, Washington, D.C., August 20-24, 2017.
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