Date of Award
2023
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Pharmaceutical Sciences
Department
Biomedical and Pharmaceutical Sciences
First Advisor
Jyothi Menon
Abstract
Lung cancer is the leading cause of global cancer-related deaths. Often asymptomatic and diagnosed at advanced stages, about 50 % of lung cancer is diagnosed at stage IV with the cancer's 5-year survival rate being only 16%. Surgery is usually considered for only early-stage cancer, while advanced lung cancer leans towards chemotherapy. However, conventional chemotherapy responses are often limited and come with severe side effects, including potentially fatal pulmonary toxicity. Hence, there is an urgent need in the development of an effective chemo-treatment regimen.
Pulmonary delivery through inhalation provides a direct route for delivering chemotherapeutics to lung pathology, minimizing systemic exposure, and thereby reducing the typical adverse effects associated with systemic administration of chemotherapy. Nanomedicine has demonstrated promising outcomes in the delivery of chemotherapy compared to traditional drugs, attributed to the enhanced permeation and retention effect. However, the lung with its dynamic environment, actively eliminates foreign materials entering the respiratory system through processes like mucociliary clearance, macrophage phagocytosis, and specialized mucosal immune responses. Alveolar macrophages, situated in the alveolar space of the lung, swiftly phagocytose inhaled pathogens or any foreign particles entering the pulmonary tract.
The key aims of this dissertation are: (i) developing and evaluating biomimetic lung-surfactant coated polymeric nanoplatform to evade alveolar macrophage phagocytosis and provide site-specific anti-cancer therapy following nebulization
(ii) investigating the effect of nebulization on the physico-chemical properties, cellular internalization and therapeutic efficacy of the developed lung-surfactant coated polymeric nanoparticles to confirm the retention of desirable properties post nebulization., and (iii) developing and evaluating biomimetic lipid vesicle as an effective nanocarrier for drug combinations and evaluating the therapeutic efficacy for cancer treatment.
Biomimetic lung surfactant-coated polymeric nanoparticles (~200 nm) were fabricated that exhibited stability in phosphate buffered saline, serum and Gamble’s solution (simulated lung fluid). The particles confirmed the cytocompatible nature with dose-dependent uptake by lung cancer cells. Significant decrease in nanoparticle (NP) uptake was observed by the alveolar macrophages in comparison to uncoated NPs. The drug-loaded NPs exhibited a sustained drug-release profile with improved therapeutic efficacy as compared to free drugs. Additionally, in vivo studies confirmed greater retention of intranasally inhaled LS-coated NPs in the lungs of C57BL/6 WT mice compared to uncoated NPs.
Nebulization process did not impact the physico-chemical characterization and therapeutic effectiveness of the developed lung surfactant-coated polymeric NPs, while retaining the drug release kinetics and the therapeutic efficacy of the NPs. Cellular uptake studies demonstrated a substantial reduction in the uptake of nebulized nanoparticles by alveolar macrophages, while effectively being internalized by the lung cancer cells.
Lastly, biomimetic lung surfactant vesicles (LSVs) proved to be an effective drug carrier for the combinatorial treatment of lung cancer. These LSVs effectively released the drugs (gemcitabine from the inner core and curcumin from the lipid bilayer), while maintaining stability for up to 7 days at both 4 °C and 37 °C. The LSVs also exhibited cytocompatibility, and displayed dose-dependent uptake by the lung cancer cells with minimal uptake by alveolar macrophages. The drug loaded LSVs demonstrated significant cytotoxicity and induced apoptosis in cancer cells.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
Gonsalves, Andrea Jennifer, "ENHANCING THE EFFICACY OF INHALABLE NANOPARTICLE FORMULATIONS USING BIOMIMETIC LUNG SURFACTANT" (2023). Open Access Dissertations. Paper 1617.
https://digitalcommons.uri.edu/oa_diss/1617