Overcoming Mechanisms of Acquired and Innate Doxorubicin Resistance Using Nanomedicine and Tumor-Associated Macrophage Immunotherapy

Author

Rashed M. AlmuqbilFollow

DOI

https://doi.org/10.25772/1KWY-J409

Author ORCID Identifier

https://orcid.org/0000-0003-2991-620X

Defense Date

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Sandro R.P. da Rocha

Abstract

ABSTRACT

Overcoming Mechanisms of Acquired and Innate Doxorubicin Resistance Using Nanomedicine and Tumor-Associated Macrophage Immunotherapy

By Rashed M. Almuqbil, Pharm.D.

Director: Sandro R.P. da Rocha, PhD

Cancer is a leading cause of death worldwide. The available treatment for solid tumors may include surgery, radiotherapy, immunotherapy, and chemotherapy or a combination of all those regimens. Chemotherapy is widely used in the treatment of both lung cancers and breast cancer, including metastases, irrespective of type and stage. The poor rates of survival can be attributed to late diagnosis, and due to the development of acquired and innate chemoresistance. Lung tumors are intrinsically resistant to chemotherapy, thus requiring the development of predictive biomarkers to personalize chemotherapeutic agents. In breast cancer patients, continuous exposure to a single chemotherapeutic agent can lead to (acquired resistance) such as multidrug resistance.

Here, we formed a realistic in vitro model for the screening of chemotherapy, as the tumor stroma is composed of extracellular matrix, fibroblast, as well as how it is able to grow in a 3D manner. We described the formulation of a 4^th generation PAMAM dendrimer and evaluated its efficacy and penetration through a 3D model of single and coculture spheroids, as a strategy to overcome doxorubicin’s resistance. Also, the efficacy of DOX in vivo as a single and in combination with the immunotherapy PLX3397 was evaluated, to modulate the tumor microenvironment in a syngeneic orthotopic Balb/c mice model by repolarizing M2 macrophages toward more M1 like macrophages, a potential strategy to enhance the innate immunity to fight cancer cells and overcome resistance and diminish distant metastasis.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-12-2021