Chemotherapy, whether in combination therapies or as a monotherapy, is the standard treatment for most cancer subtypes. However, these regimens are administered systemically, resulting in poor pharmacokinetics and reducing the overall efficacy. Additionally, most chemotherapeutics, such as paclitaxel (PTX), are hydrophobic necessitating the use of solvents such as polyethoxylated castor oils, which are inherently toxic. Local delivery can mitigate these off-target toxicities while increasing the bioavailability of the payload. This was confirmed in studies by Dr. Paul Sugarbaker, showing that local paclitaxel, in the setting of multimodal therapy, can improve disease-free survival for peritoneal mesothelioma. However, this regimen is associated with high postoperative morbidities, due to the inherent toxicities. These studies establish the validity of local chemotherapy while also confirming the need for a novel delivery platform to allow for safe delivery of higher doses. Nanoparticles (NPs) have long been investigated to enhance chemotherapeutic delivery, increasing bioavailability, prolonging exposure durations, and mitigating off-target side effects. To address the unmet need for a local, sustained drug delivery system, this thesis discusses the formulation and validation of ultra-high loaded polymeric nanoparticles. Specifically, we use a biodegradable polymer comprised of glycerol, CO2, succinic acid, and paclitaxel building blocks, termed poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX), to form NPs. By additionally entrapping free PTX within the NP core, we create ultra-high loaded “PGC-PTX+PTX NPs”. These NPs encapsulate over 75 wt% PTX, as the mass of the drug is greater than the mass of the carrier, and generate the desired greater initial release, while simultaneously maintaining therapeutic levels long-term due to cleavage of the chemically conjugated PTX over time. These nanoparticles demonstrate efficacy both in vitro and in vivo against murine models of both mesothelioma and metastatic breast cancer. Locally delivery ablates the primary tumor, while also decreasing metastasis to the lungs. This thesis validates the ability to deliver local chemotherapies utilizing the ultra- high loaded nanoparticles safely and effectively.
Mesothelioma and breast cancer are both ideal models for local chemotherapy delivery due to their confined biology. However, more difficult biologies such as tumors in the GI tract suffer from significant fluid movement and peristalsis. Mucoadhesive materials, such as naturally occurring polysaccharides (chitosan and alginate) and positively charged synthetic polymers (poly(allylamine) hydrochloride and poly((2-dimethylamino)ethyl methacrylate) have been investigated for mucosal delivery, yet suffer from high variability and/or toxicities. Amine-functionalized poly-amido-saccharides (AmPASs) offer a unique solution, as they have exquisite control of molecular weight, high cationic charge density, are water soluble, and exhibit low toxicities due to their sugar backbone. Synthesizing an amphiphilic diblock copolymer was accomplished with AmPAS as the hydrophilic portion and poly(lactic acid) as the hydrophobic portion. When placed in aqueous conditions, this polymer forms 200nm diameter particles with a zeta potential of +25mV (mucoNPs). Utilizing a mini-emulsion technique, nanoparticles are loaded with ultra-high levels of paclitaxel, encapsulating both free drug, and drug conjugated to a hydrophobic core polymer (PGC-PTX). The mucoNPs release drug over the span of 28 days, with varying pharmacokinetics depending on encapsulation of free drug, conjugated drug, or both. These NPs rapidly enter OE19 and OE33 esophageal cancer cells, resulting in pronounced cytotoxicity when coupled with the ultra-high paclitaxel loading. Most importantly, the mucoNPs display greater adhesion to porcine gastric mucin and porcine esophageal tissue compared to non-mucoadhesive PEG nanoparticles. This work indicates the need for future in vivo studies with the mucoNPs, and ultimately enhance local mucosal delivery. / 2025-05-24T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/46240 |
| Date | 24 May 2023 |
| Creators | Sabatelle III, Robert C. |
| Contributors | Grinstaff, Mark W. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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