Date of Award
2019
Document Type
Dissertation
Degree Name
Doctor of Philosophy (Ph.D.)
Department
Pharmaceutical and Chemical Sciences
First Advisor
Bhaskara R. Jasti
First Committee Member
Xiaoling Li
Second Committee Member
Xin Guo
Third Committee Member
Jerry Tsai
Fourth Committee Member
Eric Boyce
Fifth Committee Member
David Lechuga-Ballesteros
Abstract
Nanocarriers have been established as delivery vehicles to target cancer tumors. However, premature drug leakage is one of the major reasons for inefficient drug delivery of nanocarriers to the tumor. Drug diffusion out of the nanocarriers or destabilization of drug loaded nanocarriers by physiological interactions with blood cells, serum proteins, and cell membranes upon systemic administration contribute to premature drug release. In this study, targeted micelles, liposomes and solid lipid nanoparticles (SLNs) of similar composition were prepared and characterized to compare physicochemical characteristics, in vitro stability, in vitro release rates in release media and in vivo performance. Peptide Amphiphiles (PAs) formed micelles with critical micelle concentration (CMC) values ranging between 23.68 ± 0.72 µM to 38.76 ± 2.27 µM. Transmission Electron Microscopy (TEM) images confirmed the self-assembly of PAs into spherical structures where the largest sizes were seen for C16-(PEG2)6-LDV micelles. Dynamic Light Scattering (DLS) results confirmed the presence of targeted liposomes and SLNs with sizes smaller than 100 nm. Forster Resonance Energy Transfer (FRET) studies revealed that targeted micelles, liposomes and SLNs were all stable upon dilution in aqueous medium, however the stability was significantly reduced in human serum, with micelles being the least stable and SLNs being the most stable. The same trend was observed for the in vitro release profiles, where targeted paclitaxel-loaded micelles (PTX-micelles) had the fastest release rate and paclitaxel-loaded SLNs (PTX-SLN) exhibited the slowest release rate. DLS results showed that sizes of PTX-SLNs were smaller than PTX-liposomes (80.53 ± 5.37 nm vs 123.31 ± 5.87 nm). Cryogenic TEM observation showed increasing size in the order of PTX-micelles (6 to 12 nm) < PTX-SLNs (10-120 nm) < PTX-liposomes (48-145 nm). Drug Loading Content (DLC) of PTX-SLNs was greater than PTX-micelles and PTX-liposomes (7.45 ± 0.41 % vs 1.70 ± 0.42 % and 0.92 ± 0.09 %). Compared to initial aqueous dispersions, reconstituted spray dried formulations maintained their nanosize and paclitaxel content over 7 days at 4⁰C. In A375 melanoma xenograft mouse model, the tumor volumes were significantly smaller for mice treated with PTX-SLNs compared to the control group. Furthermore, tumor volumes were significantly smaller for mice treated with PTX-SLNs compared to those treated with PTX-micelles and PTX-liposomes. These studies demonstrate the potential of stable PTX-SLNs for targeted delivery in cancer.
Pages
171
Recommended Citation
Dattani, Poonam. (2019). Development and Characterization of LDV Peptide Targeted Nanocarriers for Paclitaxel Delivery: A Comparative Study of Micelles, Liposomes and Solid Lipid Nanoparticles. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/3623
Included in
Medicinal and Pharmaceutical Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons
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