DOI
https://doi.org/10.25772/KHNF-N668
Author ORCID Identifier
0000-0003-1199-0612
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Sandro da Rocha
Second Advisor
Guizhi Zhu
Third Advisor
Adam M Hawkridge
Fourth Advisor
Masoud Manjili
Fifth Advisor
Matthew C Hartman
Abstract
Cancer is the second leading cause of death in United States causing an estimated six hundred thousand death in 2019. Among different types of cancer, lung cancer is the leading cause of cancer related death in both male and female. While targeted therapy and immunotherapy have shown promising clinical outcomes, currently there remain a significant proportion of patients who do not benefit from these strategies or who cannot tolerate them, making Pt based doublet chemotherapy still an indispensable component in almost all stages of treatment. However, partially due to the poor tumor distribution of small molecule drug, the development of drug resistance and the severe toxicity, its clinical benefits was not obvious, and the increase in survival rate of lung cancer patients in the past 5 decades was still limited. In last decades, the concept of immunotherapy was widely accepted and was considered as the next era for cancer treatment. Tumor associate macrophage (TAM), a major component of the leukocyte infiltrate that is present in almost all tumors, have a dominant role as orchestrators of cancer-related inflammation that can finally determine the effectiveness of the treatment. Clinical evidence indicates that there is a positive correlation between the survival rate and the M1/M2 ratio in the tumor of non-small cell lung cancer patient. Thus, it will be promising to enhance the treatment outcome by increasing the M1/M2 ratio.
In this work, a combination of local lung targeting (to increase the local drug concentration while minimize its systemic exposure), biodegradable nanocarriers (an upgrade for the rigid dendrimer to modulate interactions with physiological environment), chemotherapy (first line treatment for late stage lung cancer) and macrophage repolarization immunotherapy (to modulate the tumor microenvironment) are reported. We describe the development of a surface modified polyester dendrimer nanocarriers as a platform for the delivery of platinum based chemotherapeutics, the development of a highly reliable and reproducible animal model, the evaluation of the efficacy of dendrimer-platinum nanoconjugate both in vitro and in vivo, and the evaluation of a combination regimen of systemically delivery of chemotherapy with pulmonary delivery of tumor associated macrophage (TAM) targeting immunomodulator. Overall, we conclude that all these strategies described above have the potential translational capability to enhance the current standard of care for the lung cancer patients.
Rights
© Hanming Zhang
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-20-2020
Included in
Animal Experimentation and Research Commons, Immunotherapy Commons, Nanomedicine Commons, Pharmaceutics and Drug Design Commons