Luo, Zhangyi
(2024)
Tumor-Targeting Nanoparticles for Improved Cancer Therapy.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In the past decade, advancements in nanotechnology and our growing understanding of cancer biology and nano-bio interactions have led to the development of various nanoparticles (NPs). However, the targeting efficiency of existing NPs is still too limited to be translated into clinic. Developing new tumor targeting NPs and unveiling the targeting mechanism emerges as an ideal strategy to overcome the limitations in the current paradigm of tumor-targeted delivery and improve the therapeutic effect of anticancer agents.
An ultra-small NP was first developed based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the co-delivery of AZA and BMN673. AZA conjugation significantly reduced the nanoparticle size to 12 nm, allowing efficient tumor targeting through more effective enhanced permeation and retention (EPR) effect and penetration via the in-situ formation of fibronectin-enriched protein corona in the blood, which mediated transcytosis through ITGA5 receptor on tumor cells. An RNAseq-guided mechanistic study demonstrated that PAZA carrier reduced the DNA repair induced by BMN673, sensitizing HR-proficient non-small cell lung cancer (NSCLC) to BMN673. Furthermore, BMN/PAZA enhanced both innate and adaptive antitumor immune response, which was more effective at a lower dosage.
Despite the improved tumor targeting with the ultra-small PAZA NPs, it is still somewhat subjected to the limitation of EPR effect. To target tumors through a mechanism independent of the EPR effect, we developed a biodegradable nanocarrier coated with chondroitin sulfate (PCL-CP). PCL-CP NPs were highly effective in tumor targeting and penetration through both EPR and CD44-mediated transcytosis in tumor endothelial cells and tumor cells, resulting in superior efficiency in active tumor targeting and tumor penetration. More importantly, we discovered a novel pharmacological target, iRhom1, and elucidated its role in chemo-immuno-resistance. However, there are no small molecule drugs available for inhibiting iRhom1. Better synergy could be achieved by combining chemotherapy drugs with gene therapeutics for "undruggable" targets. PCL-CP was further modified to be effective in co-delivering iRhom1 pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. Co-delivery of pre-siiRhom1 and a chemotherapy agent (DOX or CPT-SAHA) led to significantly enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
23 July 2024 |
| Date Type: |
Publication |
| Defense Date: |
25 January 2024 |
| Approval Date: |
23 July 2024 |
| Submission Date: |
16 June 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
134 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Nanoparticle; Drug delivery, Cancer |
| Date Deposited: |
23 Jul 2024 16:38 |
| Last Modified: |
23 Jul 2024 16:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46568 |
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