Date of Award

2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Xinyuan Chen

Second Advisor

Jie Shen

Abstract

Difficult-to-treat human diseases and disorders such as brain cancer and posterior segment eye diseases greatly threaten human health and quality of life. However, the presence of physiological barriers such as the blood-brain barrier (BBB), cornea, and the blood-retinal barrier, renders these organs highly impervious to most therapeutics. As a result, most therapeutics administered systemically have low therapeutic efficacy even with high doses and are often associated with systemic side effects and/or toxicity. Localized drug delivery strategies such as injectables/implants, or locally-acting dosage forms, can circumvent physiological barriers and directly introduce therapeutics to the site of action to improve bioavailability, and as such, systemic side effects and toxicity as well as therapeutic doses can be reduced. Localized drug delivery strategies have been successfully utilized for both small molecules and biologics such as ranibizumab, an antibody inhibiting vascular endothelial growth factor against age-related macular degeneration with a six-month dosing frequency. Augmented with suitable bio-adhesion, sustained drug release and/or permeation enhancement technologies, local drug delivery can enhance patient compliance and adherence to medications, improve patient quality of life, and potentially decrease the healthcare cost.

In this dissertation, we first systematically evaluated local administration technologies (such as intracerebroventricular and intraparenchymal convection-enhanced) and advanced formulation technologies (such as nanoparticles, long-acting implants, and injectables) as well as combinations of these for enhanced therapeutic effects against central nervous system (CNS) diseases. We then developed and investigated several localized drug delivery strategies for a few difficult-to-treat human diseases with highly unmet medical needs, including: 1) uveal melanoma, an eye cancer in the posterior eye segment; 2) brain cancer; and 3) bacterial vaginosis, an infection resulted from an overgrowth of harmful bacteria in the vagina.

Localized treatments based on solid implants (such as OZURDEX® and Gliadel® wafer) have been used clinically for the treatment of eye and brain diseases. These solid implants are typically administered via either an injector/applicator with a large size needle (e.g., 22-gauge) or surgical procedures and hence poor patient compliance. Over the past decade, in situ gelling hydrogels that can be injected as solutions via fine needles (i.e., 30-gauge or smaller) and transform to gels/depots at the injection site, have attracted increasing interests due to excellent injectability and less invasiveness and hence improved patient compliance. Inspired by the natural components of the human organs (such as the vitreous body and brain), we developed an in situ gelling hydrogel delivery platform composed of naturally occurring biopolymers hyaluronic acid (HA) and collagen type II (CO). This hydrogel delivery platform has fast gelling (within a couple of minutes at 37°C) and low swelling properties and can sustained release various payloads for localized cancer therapy.

Uveal melanoma (UM) is considered a rare disease yet the most common primary intraocular tumor with high metastasis and lethality in adults. Early detection and intervention are considered critical to prevent or minimize hematogenous metastases, the main cause for poor prognosis and high mortality of UM. The hypoxia-inducible factors-1α (HIF-1α) pathway is one of the main molecular mechanisms that activate UM cell mobility and invasion. We have chosen curcumin, an inhibitor of HIF-1α pathway with good ocular safety as the model therapeutic. We developed a biodegradable curcumin-loaded polymeric nanoparticle with a hydrophilic coating layer to facilitate its vitreous transport and cellular uptake in UM cells. The curcumin-loaded polymeric nanoparticles were incorporated in the developed CO-HA Gel matrix. We have demonstrated that the curcumin nanoparticle/in situ hydrogel composite was capable of sustained releasing the payload over four weeks and had excellent anti-UM effect in a short-term anti-UM efficacy study.

Glioblastoma (GBM), the most common and malignant primary brain tumor in adults. Despite the aggressive treatments involving surgical resection of the accessible tumor followed by radiation and chemotherapy, GBM recurrence is inevitable with a bleak prognosis with a median life expectancy of less than two years. The poor treatment outcome is mainly due to the presence of glioma stem cells that are resistant to chemotherapy and radiation and can form recurrent tumors, as well as the immunosuppressive nature of the GBM microenvironment. We developed a liposome/CO-HA Gel system for the treatment of GBM. We demonstrated that the presence of liposomes did not affect gelling and crosslinking density of the in situ gelling hydrogel and the CO-HA Gel can achieve sustained release of various payloads including a water-soluble molecule and intact nanosized liposomes. More importantly, the liposome/CO-HA hydrogel composite can be easily injected using a 30-gauge needle and showed high payload accumulation and penetration in 3D GBM spheroids. The first-line GBM medication - temozolomide (TMZ) was chosen as the model therapeutic since the oral TMZ therapy leads to rapid chemo-resistance. We encapsulated TMZ into liposomes to facilitate the drug transport to distant tumor regions and deep penetration into tumor tissues. The TMZ liposome/hydrogel composite denoted an excellent in vitro anti-GBM effect and inhibition of the invasiveness of glioma cells.

To tackle the immunosuppressive nature of the GBM microenvironment to improve prognosis, we developed a novel lipid nanoparticle (LNP)-based immunochemotherapy for localized GBM treatment. Glioma-associated microglia/macrophages, accounting for up to 30-50% of the total tumor mass in human GBM, play a pivotal role in tumor growth and cancer immunosuppression. We elucidated for the first time how physicochemical properties (e.g., size, shape, and surface property) of LNPs affect their interaction with macrophages and glioma cells. Based on the endocytosis and exocytosis studies, we have chosen two types of LNPs: 1) a disk-shaped LNP (nanodisc) with demonstrated ability to “escape” from tumor-inhibiting, M1-type macrophages for the model chemotherapeutic, doxorubicin (DOX); and 2) mannose-modified liposomes (M-Lips) with demonstrated targeting ability to pro-tumor, immune-suppressive macrophages (M2-type) for the model immunotherapeutic, BLZ945. We have shown that BLZ-loaded M-Lips successfully programed M2- to M1-type macrophages. Moreover, the combination of BLZ-loaded M-Lips and DOX loaded nanodisc can effectively inhibit glioma cell growth in vitro.

In the last chapter of this dissertation, we investigated the material difference impact on the in vitro performance of a locally-acting vaginal cream for the treatment of vaginal infections. Complex vaginal cream products account for more than 50% of the FDA-approved semi-solid dosage forms that are administered through the vaginal route. At present, there is a lack of understanding of the impact of material attributes of inactive ingredients on critical physicochemical and structural attributes as well as product performance of vaginal creams, which has hampered the development of high-quality and cost-effective generic drug products to ensure the public health. We investigated the impact of variations in two commonly used inactive ingredients (i.e., cetostearyl alcohol and stearic acid) on the critical quality attributes and in vitro performance (i.e., in vitro drug release and permeation) of clindamycin phosphate (CP) vaginal creams. We demonstrated for the first time that variations in such fatty acids and alcohols had an impact on the rheological properties such as yield stress and viscosity, and drug distribution in the cream formulations. Although the material differences in cetostearyl alcohol and stearic acid did not influence in vitro release behavior of CP vaginal creams, its impact on CP permeation across the porcine vaginal membrane was noticeable. The research will facilitate the development of in vitro characterization-based bioequivalence approaches for locally-acting vaginal creams, which will ultimately help enhance the public access to these drug products.

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