Shyh-Dar Li
Research Classification
Research Interests
Relevant Thesis-Based Degree Programs
Research Options
Research Methodology
Recruitment
- Development of lipid and polymer based nanoparticles for targeted drug and nucleic acid delivery
- Development of child-friendly formulations
- Ocular drug delivery
- Drug delivery to the brain
- Sustained drug release formulations
- Needle free delivery of proteins
- Gene therapy and vaccine
1. Excellent communication skills
2. Prior expereince in research and documented with sholarly publications
3. Committed to improving equity, diversity, and inclusion in research and their community
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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
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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.
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Peritoneal cancer, defined as malignancies on the lining of the abdominal viscera, often originates from metastatic lesions in the ovaries, stomach and colon. The diffuse spreading of this cancer in the abdominal cavity makes it difficult to treat and causes relatively high recurrence rates. Currently, peritoneal cancer is treated by cytoreductive surgery and locoregional chemotherapeutic regimes. This procedure is associated with high morbidity and mortality, while not being sufficiently effective in diminishing recurrence rates. We hypothesized that peritoneal cancer treatment could benefit from an immunotherapeutic approach to reduce recurrence via generation of an anti-tumour immune response and modulation of the tumour microenvironment. To address this, we developed a liposome-based delivery system for the immune boosting agent Resiquimod (R848). We found that the liposomes incorporated with a positively charged lipid 1,2-stearoyl-3-trimethylammonium-propane (DSTAP) delivered by intraperitoneal (IP) injection increased peritoneal retention of R848 while minimizing its systemic absorption. Specifically, we observed that the peritoneal area under the curve concentration of R848 was 14 times greater when in the DSTAP-liposomes relative to the free drug formulation. Within 1 h post IP injection, ~60% of monocytes and macrophages, ~10% dendritic cells and ~8% natural killer (NK) cells in the peritoneal fluid were found to contain the liposomes. DSTAP-R848 significantly upregulated the production of TNF-α (2-fold), IL-6 (4-fold) and IFN-α (10-fold) mRNA relative to PBS control, leading to significantly reduced tumour progression in an IP metastasis model of CT-26 colorectal cancer in mice. Free R848 was ineffective in inducing the immune promoting cytokines nor antitumour efficacy. We demonstrated that DSTAP-R848 increased the trafficking of innate immune cells, specifically NK cells, in the peritoneal cavity.
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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 (
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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.
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Publications
- Breaking the niche: multidimensional nanotherapeutics for tumor microenvironment modulation (2023)
Drug Delivery and Translational Research, 13 (1), 105-134 - In Vitro Properties and Pharmacokinetics of Temporarily PEGylated Onc72 Prodrugs (2023)
Advanced Healthcare Materials, 12 (11) - Protamine-mediated efficient transcellular and transmucosal delivery of proteins (2023)
Journal of Controlled Release, 356, 373-385 - Bioinspired Nanocomplexes Comprising Phenolic Acid Derivative and Human Serum Albumin for Cancer Therapy (2022)
Nano Letters, 22 (24), 10040-10048 - Chemically engineering the drug release rate of a PEG-paclitaxel conjugate using click and steric hindrance chemistries for optimal efficacy (2022)
Biomaterials, 289 - Development of a child-friendly oral drug formulation using liposomal multilamellar vesicle technology (2022)
International Journal of Pharmaceutics, 625 - Hepatocyte-targeted delivery of imiquimod reduces hepatitis B virus surface antigen (2022)
Journal of Controlled Release, 350, 630-641 - Improved Liver Delivery of Primaquine by Phospholipid-Free Small Unilamellar Vesicles with Reduced Hemolytic Toxicity (2022)
Molecular Pharmaceutics, 19 (6), 1778-1785 - Interplay between the linker and polymer molecular weight of a self-assembling prodrug on the pharmacokinetics and therapeutic efficacy (2022)
Biomaterials Science, 10 (12), 3122-3136 - Introducing the Molecular Pharmaceutics Special Issue on “Tiny Things, Big Impact: Nanomedicine in Canada” (2022)
Molecular Pharmaceutics, 19 (6), 1657-1658 - Simultaneous Chromatographic Quantitation of Drug Substance and Excipients in Nanoformulations Using a Combination of Evaporative Light Scattering and Absorbance Detectors (2022)
Molecular Pharmaceutics, 19 (6), 1882-1891 - The mechanism of Hepatocyte-Targeting and safety profile of Phospholipid-Free small unilamellar vesicles (2022)
International Journal of Pharmaceutics, 628 - Altering the intra-liver distribution of phospholipid-free small unilamellar vesicles using temperature-dependent size-tunability (2021)
Journal of Controlled Release, 333, 151-161 - An effective and safe enkephalin analog for antinociception (2021)
Pharmaceutics, 13 (7) - Liposomal resiquimod for enhanced immunotherapy of peritoneal metastases of colorectal cancer (2021)
Pharmaceutics, 13 (10) - Recent trends in bioresponsive linker technologies of Prodrug-Based Self-Assembling nanomaterials (2021)
Biomaterials, 275 - Targeting intracellular mycobacteria using nanosized niosomes loaded with antibacterial agents (2021)
Nanomaterials, 11 (8) - Lipid-based nanoparticle technologies for liver targeting (2020)
Advanced Drug Delivery Reviews, 154-155, 79-101 - Utilization of click chemistry to study the effect of poly(ethylene)glycol molecular weight on the self-assembly of PEGylated gambogic acid nanoparticles for the treatment of rheumatoid arthritis (2020)
Biomaterials Science, 8 (16), 4626-4637 - Development and characterization of the solvent-assisted active loading technology (SALT) for liposomal loading of poorly water-soluble compounds (2019)
Pharmaceutics, 11 (9) - Phospholipid-Free Small Unilamellar Vesicles for Drug Targeting to Cells in the Liver (2019)
Small, 15 (43) - Robust microfluidic technology and new lipid composition for fabrication of curcumin-loaded liposomes: effect on the anticancer activity and safety of cisplatin (2019)
Molecular Pharmaceutics, 16 (9), 3957-3967 - A celebration of Professor Leaf Huang’s contribution to the field of drug delivery and his lifetime achievement award (2018)
Journal of Drug Targeting, 26 (5-6), 384 - Cancer theranostic applications of lipid-based nanoparticles (2018)
Drug Discovery Today, 23 (5), 1159-1166 - Current update of a thermosensitive liposomes composed of DPPC and Brij78 (2018)
Journal of Drug Targeting, 26 (5-6), 407-419 - Docetaxel-carboxymethylcellulose nanoparticles ameliorate CCl 4 -induced hepatic fibrosis in mice (2018)
Journal of Drug Targeting, 26 (5-6), 516-524 - Recent advancements in the field of nanotechnology for the delivery of anti-Alzheimer drug in the brain region (2018)
Expert Opinion on Drug Delivery, 15 (6), 589-617 - Recent advances in applying nanotechnologies for cancer immunotherapy (2018)
Journal of Controlled Release, 288, 239-263 - Systemic study of solvent-assisted active loading of gambogic acid into liposomes and its formulation optimization for improved delivery (2018)
Biomaterials, 166, 13-26 - Cabazitaxel-conjugated nanoparticles for docetaxel-resistant and bone metastatic prostate cancer (2017)
Cancer Letters, 410, 169-179 - Cancer treatment response evaluation using photoacoustic signal envelop statistics: A preliminary study (2017)
2016 International Conference on Bio-Engineering for Smart Technologies, BioSMART 2016 - Comparison of Tumor Penetration of Podophyllotoxin-Carboxymethylcellulose Conjugates with Various Chemical Compositions in Tumor Spheroid Culture and in Vivo Solid Tumor (2017)
Bioconjugate Chemistry, 28 (5), 1505-1518 - Current Update of a Carboxymethylcellulose-PEG Conjugate Platform for Delivery of Insoluble Cytotoxic Agents to Tumors (2017)
AAPS Journal, 19 (2), 386-396 - Development of a Rapidly Dissolvable Oral Pediatric Formulation for Mefloquine Using Liposomes (2017)
Molecular Pharmaceutics, 14 (6), 1969-1979 - Photoacoustic signal characterization of cancer treatment response: Correlation with changes in tumor oxygenation (2017)
Photoacoustics, 5, 25-35 - Selective targeting and therapy of metastatic and multidrug resistant tumors using a long circulating podophyllotoxin nanoparticle (2017)
Biomaterials, 137, 11-22 - A simple and improved active loading method to efficiently encapsulate staurosporine into lipid-based nanoparticles for enhanced therapy of multidrug resistant cancer (2016)
Pharmaceutical Research, 33 (5), 1104-1114 - Modifying the tumor microenvironment using nanoparticle therapeutics (2016)
Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 8 (6), 891-908 - Photoacoustic imaging of cancer treatment response: Early detection of therapeutic effect from thermosensitive liposomes (2016)
PLoS ONE, 11 (10) - Photoacoustic radiofrequency spectroscopy for monitoring cancer treatment response (2016)
IEEE International Ultrasonics Symposium, IUS, 2016-November - Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect (2016)
Bioconjugate Chemistry, 27 (1), 226-237 - A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors (2015)
Biomaterials, 52 (1), 335-346 - A Study of Liposomal Formulations to Improve the Delivery of Aquated Cisplatin to a Multidrug Resistant Tumor (2015)
Pharmaceutical Research, 32 (10), 3261-3268 - Docetaxel-carboxymethylcellulose nanoparticles target cells via a SPARC and albumin dependent mechanism (2015)
Biomaterials, 59, 66-76 - Probing the in vivo changes in oxygen saturation with photoacoustic imaging as a non-invasive means of assessing treatment progression (2015)
Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 9323 - Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle (2015)
Journal of Controlled Release, 206, 122-130 - Carboxymethylcellulose-based and docetaxel-loaded nanoparticles circumvent p-glycoprotein-mediated multidrug resistance (2014)
Molecular Pharmaceutics, 11 (8), 2592-2599 - Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer (2014)
International Journal of Pharmaceutics, 471 (1-2), 224-233 - Longitudinal monitoring of oxygen saturation with photoacoustic imaging (2014)
IEEE International Ultrasonics Symposium, IUS, 357-360 - Recent progress in the development of polysaccharide conjugates of docetaxel and paclitaxel (2014)
Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 6 (4), 349-368 - Docetaxel conjugate nanoparticles that target a-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis (2013)
Cancer Research, 73 (15), 4862-4871 - Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles (2013)
Journal of Controlled Release, 172 (3), 782-794 - Hyperthermia-induced drug targeting (2013)
Expert Opinion on Drug Delivery, 10 (4), 511-527 - Immune responses of therapeutic lipid nanoparticles (2013)
Nanotechnology Reviews, 2 (2), 201-213 - Theranostic Nanoparticles for Cancer Imaging and Therapy (2013)
Nanomaterials in Drug Delivery, Imaging, and Tissue Engineering, 369-393 - Thermosensitive liposomes for the delivery of gemcitabine and oxaliplatin to tumors (2013)
Molecular Pharmaceutics, 10 (12), 4499-4508 - A docetaxel-carboxymethylcellulose nanoparticle outperforms the approved taxane nanoformulation, Abraxane, in mouse tumor models with significant control of metastases (2012)
Journal of Controlled Release, 162 (3), 575-581 - A thermosensitive liposome prepared with a Cu 2+ gradient demonstrates improved pharmacokinetics, drug delivery and antitumor efficacy (2012)
Journal of Controlled Release, 161 (1), 142-149 - Limitations and niches of the active targeting approach for nanoparticle drug delivery (2012)
European Journal of Nanomedicine, 4 (2-4), 89-93 - Preclinical pharmacokinetic, biodistribution, and anti-cancer efficacy studies of a docetaxel-carboxymethylcellulose nanoparticle in mouse models (2012)
Biomaterials, 33 (5), 1445-1454 - Thermosensitive liposomes in cancer therapy (2012)
Recent Patents on Biomedical Engineering, 5 (2), 148-158 - Tumor-targeted drug delivery using MR-contrasted docetaxel - Carboxymethylcellulose nanoparticles (2012)
Biomaterials, 33 (15), 3931-3941 - Deciphering causal and statistical relations of molecular aberrations and gene expressions in NCI-60 cell lines (2011)
BMC Systems Biology, 5 - Efficient tumor regression by a single and low dose treatment with a novel and enhanced formulation of thermosensitive liposomal doxorubicin (2011)
Journal of Controlled Release, 152 (2), 303-309 - MRI monitoring of intratumoral drug delivery and prediction of the therapeutic effect with a multifunctional thermosensitive liposome (2011)
Biomaterials, 32 (27), 6570-6578 - Optimization of a novel and improved thermosensitive liposome formulated with DPPC and a Brij surfactant using a robust in vitro system (2011)
Journal of Controlled Release, 154 (3), 290-297 - Synthetic modification of carboxymethylcellulose and use thereof to prepare a nanoparticle forming conjugate of docetaxel for enhanced cytotoxicity against cancer cells (2011)
Bioconjugate Chemistry, 22 (12), 2474-2486 - Ultrasound drug targeting to tumors with thermosensitive liposomes (2011)
IEEE International Ultrasonics Symposium, IUS, 1-4 - Anti-tumor activity of splice-switching oligonucleotides (2010)
Nucleic Acids Research, 38 (22), 8348-8356 - CD44-targeted microparticles for delivery of cisplatin to peritoneal metastases (2010)
Molecular Pharmaceutics, 7 (1), 280-290 - Stealth nanoparticles: High density but sheddable PEG is a key for tumor targeting (2010)
Journal of Controlled Release, 145 (3), 178-181 - Nanoparticles evading the reticuloendothelial system: Role of the supported bilayer (2009)
Biochimica et Biophysica Acta - Biomembranes, 1788 (10), 2259-2266 - An efficient and low immunostimulatory nanoparticle formulation for systemic siRNA delivery to the tumor (2008)
Journal of Controlled Release, 131 (1), 64-69 - Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles (2008)
Journal of Controlled Release, 126 (1), 77-84 - Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA (2008)
Molecular Therapy, 16 (5), 942-946 - Pharmacokinetics and biodistribution of nanoparticles (2008)
Molecular Pharmaceutics, 5 (4), 496-504 - Targeted delivery of siRNA by nonviral vectors: Lessons learned from recent advances (2008)
Current Opinion in Investigational Drugs, 9 (12), 1317-1323 - Tumor-targeted delivery of siRNA by self-assembled nanoparticles (2008)
Molecular Therapy, 16 (1), 163-169 - Non-viral is superior to viral gene delivery (2007)
Journal of Controlled Release, 123 (3), 181-183 - Sine-wave current for efficient and safe in vivo gene transfer (2007)
Molecular Therapy, 15 (10), 1842-1847 - Gene therapy progress and prospects: Non-viral gene therapy by systemic delivery (2006)
Gene Therapy, 13 (18), 1313-1319 - Surface-modified LPD nanoparticles for tumor targeting (2006)
Annals of the New York Academy of Sciences, 1082, 1-8 - Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells (2006)
Molecular Pharmaceutics, 3 (5), 579-588 - Kinetic and dynamic studies of liposomal bupivacaine and bupivacaine solution after subcutaneous injection in rats (2002)
Journal of Pharmacy and Pharmacology, 54 (9), 1221-1227 - Determination of plasma levels of bupivacaine by high-performance liquid chromatography (1999)
Chinese Pharmaceutical Journal, 51 (2), 163-170
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