Evaluating a simple nanochemistry for lineage-targeted drug delivery

University Of North Carolina Charlotte, Charlotte NC

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Abstract

ABSTRACT Many diseases are lineage-restricted in nature ? the indiscriminate action of drugs today is only because there is no practical, robust tools to selectively target drugs to a particular cell lineage. For example, traditional cancer treatments destroy normal cells along with the cancer cells systemicly, and can result in substantial toxicities to the patients. Destruction of normal cells is especially problematic when treating myeloid malignancies (e.g., acute myeloid leukemia, AML), where normal hematopoietic stem cells are needed to reverse low blood counts that can lead to morbidity and death. An obvious solution to this problem is to deliver drugs selectively to malignant cells of specific lineage and reduce unnecessary exposure of normal cells and tissues to the therapeutic agents. However, current state-of-the-art technologies, such as monoclonal antibody- drug conjugates (ADCs) and drug encapsulating liposome/polymer vehicles, have limitations. For example, poor drug loading/release in ADCs requires the use of extra-toxic agents as drugs, undermining the overall goal of improved safety; and liposome/polymer vehicles rely on leaky tumor blood vessels (enhanced retention permeability effect, EPR), an active exploitation of the vehicles? steric effect as the main mode of delivery, which is not optimal with treating myeloid malignancies. As an alternative to using EPR, we will evaluate a nanotechnology that uses ligand-exchange chemistry to release a drug payload selectively at redox-stressed cells of myeloid lineage. This approach, Au nano-linker, uses precisely-sized nanometer-scale gold (Au) as intermediaries to which drug and targeting moieties are simultaneously attached by simple, yet different chemistries. By exploiting two chemistries, the Au nano-linker irreversibly links the targeting moiety while allowing for loading and controlled release of abundant (~100) drug molecules. This nanochemistry operates at a size regime (~2 nm) comparable to the length of typical chemical linkers. These properties suggest that the Au nano-linker can be used to confer a targeted functionality onto standard, off-the-shelf conventional AML drugs, without relying on EPR, in order to make treatments less toxic, more effective and with fewer side effects. Outcomes include in vitro and in vivo proof of versatility, safety and effectiveness of this nanochemistry in conferring a targeted property onto off-the-shelf, chemically unmodified, drugs. This AREA project will expose undergraduate and graduate students to an integrative and cross-disciplinary research environment by extending biomedical training opportunities in the Department of Physics and Optical Science at the University of North Carolina Charlotte, a rapidly-growing urban institution that seeks to strengthen its biomedical research program. This project has attracted many undergraduate students through the PI?s classroom teaching, and will provide these undergraduates hands-on experience with laboratory research techniques and introduction to career in nano-medicine research. Students will participate in peer-to-peer training at all levels, including an emphasis on skills needed for professional success such as teamwork and communication.