Dissertation
The use of nanoparticles in treatment of glioblastoma
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2022
DOI: 10.25820/etd.006598
Abstract
The central nervous system has a series of barriers to protect itself from exogenous pathogens and neurotoxic molecules. The most essential part of these protective barriers is the blood-brain barrier (BBB) which consists of endothelial cells and neurovascular units. The neurovascular units maintain homeostasis of the BBB and provide nutrients to the BBB while the endothelial cells can deliver molecules to, and remove them from, the brain via several pathways. The same features which make the BBB important for brain protection, also contribute to it being a major obstacle to drug delivery to the brain. However, nanoparticle (NP) mediated drug delivery systems can potentially assist drugs crossing into the brain and may be an effective treatment for cerebral diseases, especially brain cancer. Glioblastoma multiforme (GBM) is the most malignant type of brain tumor, possessing an extremely poor prognosis. Surgery is the standard treatment for GBM which is then followed by radiation and/or chemotherapy (temozolomide (TMZ)). Treatment of GBM is a challenge due to tumor recurrence after surgery, lack of target specificity of anticancer drugs and the obstacle that the BBB imparts to therapeutic drugs. Paclitaxel (PTX), a widely used efficient chemotherapeutic drug with broad anticancer activities has limited activity in vivo against GBM, while demonstrating enhanced anti-GBM activity in vitro, compared to the TMZ. This discrepancy is attributed to its limited capacity to penetrate the BBB.
NPs developed using biodegradable polymers (e.g. poly(lactic-co-glycolic) acid (PLGA)) and NPs surface-modified with polyethylene glycol (PEG) and poly(amido amine) (PAMAM) or poly(ethylenimine) (PEI) can deliver drugs or active ingredients across the BBB via adsorptive-mediated transcytosis. Moreover, surface modifiers can reduce cytotoxicity, prolong blood circulation times as well as improve uptake of NPs. In these studies, it was demonstrated that novel therapeutic NPs, loaded with PTX, can overcome the BBB and mediate GBM therapy. Biodistribution studies revealed that PLGA-PEG-PAMAM (PGM) NPs penetrate the BBB significantly more than either PLGA-PEG NP or PLGA-PEG-PEI NP formulations (p-values < 0.05). PTX-loaded PGM NPs had an average diameter of ~185.4 ± 3.4 nm, exhibited sustained drug release in dissolution media (pH 7.4) for up to 400 hours, and exhibited drug loading of 24.3% ± 1.2. PTX-loaded PGM NPs demonstrated the ability to deliver PTX to the brain to treat GBM in a mouse model, where the median survival period of mice intravenously (IV) administrated PTX-loaded PGM NPs (38 days) was significantly greater than mice treated with soluble PTX (32 days) or the untreated control group (31 days).
A simple, accurate and precise high performance liquid chromatography (HPLC) method for PTX was developed. Different analytical parameters such as specificity, accuracy, precision, linearity, limit of detection (LOD), and limit of quantification (LOQ) were determined as per the FDA guidelines. The analytical parameters demonstrated that the HPLC method was sufficiently sensitive to detect PTX and no interference occurred between the PTX peak and other components in the tissues. The calibration curves demonstrated linearity between PTX concentrations of 0.039 – 20 µg/mL in plasma (r2 of 0.9999). The method was shown to have an accuracy between 94.04 -107.24% for plasma samples and the intra-day and inter-day precision exhibited %RSD < 6.92%. The LOD was 0.019 µg/mL, and the LOQ was 0.039 µg/mL. Thus, the analytical HPLC method was reliable, accurate and precise and can be used for quantitative and qualitative analysis of PTX concentrations in mouse organ samples after IV injection of PTX formulations. Additionally, pharmacokinetics and biodistribution of PTX-loaded PGM NPs were investigated following IV administration to mice compared to mice administered with PTX in solution. Concentrations of PTX in plasma and organs of these mice were analyzed by HPLC following liquid-liquid extraction. The results demonstrated that the PGM NPs significantly enhanced PTX accumulation in the brain compared to when soluble PTX was delivered. Safety studies with this formulation revealed no toxicity in a healthy mouse model.
In conclusion, these novel PTX-loaded PGM NPs are a promising potential alternative or supplemental GBM treatment aimed at improving GBM patients’ survival and overall quality of life.
Details
- Title: Subtitle
- The use of nanoparticles in treatment of glioblastoma
- Creators
- Kanawat Wiwatchaitawee
- Contributors
- Aliasger K. Salem (Advisor)Jonathan A. Doorn (Committee Member)Lewis L. Stevens (Committee Member)Marie Gaine (Committee Member)Reza Nejadnik (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Spring 2022
- DOI
- 10.25820/etd.006598
- Publisher
- University of Iowa
- Number of pages
- xx, 137 pages
- Copyright
- Copyright 2021 Kanawat Wiwatchaitawee
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 122-137).
- Public Abstract (ETD)
The blood-brain barrier (BBB) prevents the entry of toxic agents and potentially harmful organisms into the brain; however, the same feature which make the BBB an important protective feature, also contributes to it being a major obstacle to drug delivery to the brain for the treatment of brain diseases. Nanoparticles (NPs) coated with hydrophilic layers on their surfaces, and loaded with the desired drug, can potentially assist drugs crossing into the brain and may be an effective treatment strategy for brain cancer.
Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer, possessing an extremely poor prognosis. Although surgery is the standard treatment for GBM which is then followed by radiation and/or treatment with chemotherapy, treatment of GBM is a challenge due to tumor recurrence after surgery and the obstacle that the BBB imparts to chemotherapeutic drugs. Paclitaxel (PTX), a widely used efficient chemotherapeutic drug with broad anticancer activities has limited activity in vivo against GBM, while demonstrating enhanced anti-GBM activity in vitro. This discrepancy is attributed to its limited capacity to penetrate the BBB. Therefore, these studies involved the development and testing of a novel NP system to assist chemotherapeutic drugs such as PTX crossing the BBB and improve anticancer efficacy for GBM treatment.
In this study, a simple, accurate and precise analytical method for PTX was developed as per the FDA guidelines. The results demonstrated that the analytical method was reliable, accurate and precise and can be used for quantitative and qualitative analysis of PTX. PTX-loaded NPs demonstrated the ability to deliver PTX to the brain to treat GBM in a mouse model and these mice showed an increased probability of survival rate of 1.2-fold in comparison to untreated mice. Additionally, pharmacokinetic studies (which involves assessing the fate of drugs within the body) of PTX-loaded NPs demonstrated that the NPs significantly enhanced PTX accumulation in the brain compared to when soluble PTX was delivered. Safety studies with PTX-loaded NP formulations revealed no toxicity in a healthy mouse model.
As a conclusion, these novel PTX-loaded NPs are a promising potential alternative or supplemental GBM treatment aimed at improving GBM patients’ survival and overall quality of life.
- Academic Unit
- Pharmacy; Craniofacial Anomalies Research Center
- Record Identifier
- 9984271056102771
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