Date of Degree

9-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Aneta Mieszawska

Committee Members

Maria Contel

John A Martignetti

Rein V. Ulijn

Subject Categories

Materials Chemistry | Medicinal-Pharmaceutical Chemistry | Nanomedicine | Organic Chemistry | Other Chemistry | Polymer Chemistry

Keywords

nanoparticles, PLGA, Platinum Therapy, Aptamers

Abstract

Over the years, anti-cancer therapies have improved the overall survival rate of patients. Nevertheless, the traditional free drug therapies still suffer from side effects and systemic toxicity, resulting in low drug dosages in the clinic. This often leads to suboptimal drug concentrations reaching cancer cells, contributing to treatment failure and drug resistance. Among available anti-cancer therapies, metallodrugs are of great interest. Platinum (II)-based agents are highly potent and are used to treat many cancers, including ovarian cancer (OC). Cisplatin (cis-diaminedichloroplatinum (II)) is the first Food and Drug Administration (FDA)-approved metallodrug for treatment of solid tumors, and its mechanism of action is based on inhibition of cancer cell replication via binding to nuclear DNA. However, circulating cisplatin binds to glutathione and other proteins in the blood compartment, diminishing the concentration of the free drug available for therapy. Also, highly potent cisplatin is associated with severe side effects, limiting the dosage of Pt(II) that can be administered in the clinic. The next generation Pt(II) drugs aim at sustaining the same effectiveness while improving systemic toxicity. Carboplatin is a second-generation Pt-based agent approved by the Food and Drug Administration (FDA). Slower hydrolysis times for carboxylate ligands in carboplatin, compared to rather fast times for chlorine ligands in cisplatin, lead to longer blood circulation times and lesser side effects. The therapeutic effect of carboplatin is comparable with cisplatin in some tumors, but it requires higher drug dosages, and the survival rate did not improve.

The problems above associated with free Pt(II)-based therapy created a need for the development of more efficient drug delivery systems. These include targeted drug delivery such as an antibody or protein conjugates or nanoparticle (NP)-mediated drug delivery, e.g., by using liposomes, polymeric or oil-based NPs, among other approaches. This dissertation presents two alternative drug delivery systems for Pt(II)-based agents: peptide conjugate and a NP. These systems are tested in OC models, where Pt (II) therapy is a golden standard.

Chapter II focuses on a peptide-drug conjugate of nuclear localization sequence (NLS) peptide-carboplatin-like complex. Nuclear localization sequence peptides target nuclear transport protein, delivering the therapeutic payload into a cancer cell's nucleus. NLS-Pt(II) conjugate demonstrated enhanced therapeutic effect in vitro in OC cell lines when compared to carboplatin. Conjugation of carboplatin-like complexes with NLS peptide also drastically increased the solubility of Pt(II) drug in an aqueous media.

Chapter III focuses on targeted and pH-sensitive polymeric NP to deliver Pt(II). Poly lactic-co-glycolic acid (PLGA)-based NPs are explored, as the PLGA is biodegradable, biocompatible, and, most importantly, approved by the FDA. The NP's corona contains phospholipids and custom-synthesized pH-sensitive polyethylene glycol (PEG)-phospholipid coating. A DNA-aptamer against mucin 1 (MUC1), which is overexpressed in OC cells, is added as an active targeting ligand. The NP design takes advantage of a slightly acidic environment around cancer cells (pH~6.8) to disintegrate PEG-based NP's coating and to expose the aptamer targeting ligands facilitating a fast NP uptake through receptor-mediated endocytosis. Slow intracellular degradation of the NP leads to sustained release of Pt(II). The NPs showed higher cytotoxicity in vitro when compared to free carboplatin, and the NPs effectively accumulated in the tumor tissue in vivo. Importantly, the NP platform can be easily modified. The ease of functionalization of PLGA with other drugs, as well as the choice of different targeting aptamers, can extend the applications of the proposed NP platform to other disease types.

CP70(after 5 min) (for 10 min) ph6.8 Fifure 25.(1).avi (49128 kB)
Figure 25 Nanoparticle uptake

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