京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21075号 / 工博第4439号 / 新制||工||1690(附属図書館) / 京都大学大学院工学研究科化学工学専攻 / (主査)教授 前 一廣, 教授 吉田 潤一, 教授 長谷部 伸治 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21003号 / 医博第4349号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 木村 剛, 教授 小西 靖彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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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

Two possible ways for increasing the rate of separation for magnetic bead separation has been observed. Increasing NP concentration by 2.5x gave a slight increase in rate of separation while 1.5x and 2.0x concentration increase resulted in a slight decrease in rate of separation. Synthesizing the magnetic beads under the influence of an external magnetic field also showed promising results. In a literature review, several types of magnetic beads and technologies are discussed, and how there is a great future potential for magnetic beads in the isolation of several types of biomolecules. It is concluded that the market for magnetic beads for cell isolation is expanding greatly with many different applications and expects to be worth 14.64 billion USD by 2025.

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Rate limited chemical reactions can be enhanced by improving the mass transport of the suspended analyte to the catalytic (or electrocatalytic) surface. While many attempts have been made to enhance this mass transport, these approaches are limited to utilizing only two enhancement methods – increasing available catalytic surface area, and increasing the flow of analyte in solution. Flow through high aspect ratio microstructures, however, would provide additional mass transport enhancement via boundary layer confinement. Platinum functionalized carbon nanotube microarray membranes (Pt-CNT-MMs) offer enhanced mass transport via all three methods, and were fabricated for demonstration in a H2O2 sample system, for which propulsion and chemical sensing applications were investigated. Propulsion testing of Pt-CNT-MM samples demonstrated thrust typically required for MUV propulsion, while achieving high H2O2 fuel utilization. Also, the proposed approach minimizes component exposure to the environment and is comprised of a simple, static architecture relative to other micro-propulsion systems. Moreover, it was shown that additional thrust is attainable by further enhancing the introductory rate of the H2O2 fuel to the Pt-CNT-MMs, which would effectively increase the locomotive capability of this propulsion system. Pt-CNT-MMs used for chemical sensing of H2O2 likewise demonstrated favorable performance. Initial studies revealed that the molar flux achieved for a Pt-CNT-MM sample in a through-flow environment (50 [µL s-1]) was approximately a ten-fold increase over that achieved in a stirred environment (150 [rpm]). This ten-fold increase in molar flux can be attributed to both an increase in exposed electrocatalytic surface area, as well as increase in boundary layer confinement. Furthermore, comparison of sensed molar flux to calculated molar flux for through-flow conditions revealed that Pt-CNT-MMs can achieve near-complete H2O2 oxidation within the flowrate range studied. Additionally, chronoamperometric testing of a Pt-CNT-MM sample demonstrated a sensitivity toward H2O2 of 9.18 [mA mM-1 cm-2], over one hundred times that of the GluOx/Pt-SWCNT/PAA structures referenced herein (0.0724 [mA mM-1 cm-2]).1 These findings suggest that mass transport enhancement, achieved by Pt-CNT-MMs applied in through-flow environments, heightens the performance achieved in rate-limited chemical reactions. Specifically, Pt-CNT-MMs demonstrate high fuel utilization in H2O2 based propulsion applications, as well as offer a highly sensitive preliminary structures for non-invasive glucose sensing.