Relevant Degree Programs
1. Development of lipid and polymer based nanoparticles for targeted drug delivery to tumors 2. Development of child-friendly formulations 3. Ocular drug delivery 4. Drug delivery to the brain 5. Sustained drug release formulations 6. Gene delivery
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2019)
More than 70% of drugs exhibit poor water solubility, thereby limiting their clinical applications. Formulating these drugs into liposomes is a feasible approach to increase their solubility and improve the therapeutic efficacy. However, encapsulating hydrophobic drugs into the lipid bilayer of liposomes often results in burst drug release and liposomal instability, due to the weak association between the drugs and the lipid bilayer. Additionally, the capacity of the lipid bilayer is limited, leading to inefficient drug loading. To address this issue, this thesis focused on developing a new loading technology, called Solvent-assisted Active Loading Technology (SALT), to allow stable and efficient loading of poorly water-soluble drugs into the aqueous core of liposomes. This technology involved the addition of a certain amount of a water-miscible organic solvent into the mixture of a poorly soluble drug and preformed liposomes incorporated with a trapping agent inside the aqueous core. The solvent was not only used to help drug dissolution, but also to facilitate drug permeation into the liposomal core to form drug complexes with the trapping agent by increasing the membrane permeability during the drug loading. We have generated multiple examples to demonstrate the robustness and potential utilities of this technology. As a proof-of-principle, the first part of the thesis focused on developing the SALT for stable loading of a model drug, staurosporine (STS, insoluble weakly basic drug), into liposomes and optimizing the fabrication of a liposomal STS formulation for in vivo therapy of tumor. The second part of this dissertation was to explore whether the SALT is a flexible platform for formulating other types of poorly soluble drugs such as gambogic acid (GA, insoluble weakly acidic drug) into liposomes. We also examined whether other miscible solvents (other than DMSO) could be utilized in the system and their roles in promoting drug loading. The third part of this thesis was to demonstrate another utility of the SALT for preparing an oral pediatric formulation of mefloquine with bitterness masking. This thesis work demonstrated that SALT was a robust drug loading technology to develop stable liposomal formulations for poorly soluble drugs with practical utilities.
Master's Student Supervision (2010 - 2018)
The thesis focuses on the development and characterization of an innovative phospholipid-free small unilamellar vesicle (PFSUV) for drug delivery. The optimal PFSUVs composed of Tween80/cholesterol (1/5 molar ratio) were fabricated by microfluidics, exhibiting a mean diameter of 60-80 nm. The PFSUVs displayed a single bilayer spherical structure, similar to that of a standard liposomal formulation. Doxorubicin could be actively loaded into the aqueous core of PFSUVs at a drug-to-lipid ratio of 1/20 (w/w) via an ammonium sulfate gradient, and was stably retained for 6 days when incubated in 50% serum. In the presence of serum, DOX loaded PFSUVs were internalized by EMT6 murine breast tumor cells 2-fold more efficiently compared to the serum-free conditions due to LDL endocytosis pathway, while PEGylated liposomal doxorubicin (PLD, DSPC/Chol/DSPE-PEG2000) displayed little cellular uptake in both conditions. The results suggest that serum component(s) triggered cellular internalization of the PFSUVs. As a result, the in vitro potency of PFSUVs-DOX against EMT6 cells was comparable as free DOX and was significantly increased compared to the PLD. In mice, PFSUVs-DOX displayed rapid clearance from the blood (
Anti-tubulin agents are the most potent and broadest spectrum drugs for cancer therapy, including taxanes and vinca alkaloids. However, there are two major limitations for their clinical use: multidrug resistance (MDR), and significant side effects such as neutropenia and neuropathy. The overexpression of P-glycoprotein (Pgp) is the most commonly found mechanism for MDR in cancer. Our lab has screened several anti-tubulin agents against different MDR tumor cells. The results show that podophyllotoxin (PPT) remained highly active against the resistant cell lines with an IC50 of ~10 nM. However, PPT is insoluble and exhibits significant side effects due to poor selectivity. A nanoparticle dosage form of PPT was developed by covalently conjugating PPT and polyethylene glycol (PEG) to acetylated carboxymethyl cellulose (CMC-Ac) via ester linkages. The optimized polymer conjugates self-assembled into 20 nm particles (named Celludo) and displayed significantly improved efficacy against MDR tumors in mice compared to free PPT and the standard taxane chemotherapies.My thesis focused on developing a robust and reproducible HPLC method to measure PPT concentrations in biological samples in order to compare the pharmacokinetics (PK) and biodistribution (BD) of Celludo and free PPT. The kinetics of intratumoral distribution of the Celludo nanoparticles was also examined. Compared to free PPT, Celludo displayed extended blood circulation with 18-fold prolonged half-life, 9,000- fold higher area under the curve (AUC), and 1,000-fold reduced clearance compared to free PPT. The tumor uptake of Celludo was 500-fold higher than that of free PPT. With Celludo, the overall delivery to the tumor was 4.5-, 3.8-. 3.4-and 1.2- fold higher than that delivered to the liver, lung, heart, and spleen respectively. At 6 h, Celludo nanoparticles accumulated equally in the hypervascular and hypovascular region within the tumor. One and two days post-injection, the amount of Celludo in the hypervascular region remained the same, while the penetration to the hypovascular area increased constantly over 48 h post-injection. The data suggest that Celludo was an effective system targeting PPT to the tumor with enhanced penetration to the tumor core.