Shyh-Dar Li

Professor

Research Interests

biopharmaceutics
drug delivery
nanomedicine
pharmaceutics
Gene delivery and therapy

Relevant Thesis-Based Degree Programs

Research Options

I am available and interested in collaborations (e.g. clusters, grants).
I am interested in and conduct interdisciplinary research.
I am interested in working with undergraduate students on research projects.
 
 

Research Methodology

microfluidic mixing
lipid nanoparticles
polymer nanoparticles
pharmacokinetics
animal models of diseases
cell culture
physical pharmacy
molecular analyses
high performance liquid chromatography

Recruitment

Master's students
Doctoral students
Any time / year round
  1. Development of lipid and polymer based nanoparticles for targeted drug and nucleic acid delivery
  2. Development of child-friendly formulations
  3. Ocular drug delivery
  4. Drug delivery to the brain
  5. Sustained drug release formulations
  6. Needle free delivery of proteins
  7. 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

I am open to hosting Visiting International Research Students (non-degree, up to 12 months).
I am interested in supervising students to conduct interdisciplinary research.

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ADVICE AND INSIGHTS FROM UBC FACULTY ON REACHING OUT TO SUPERVISORS

These videos contain some general advice from faculty across UBC on finding and reaching out to a potential thesis supervisor.

Postdoctoral Fellows

Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Development of a novel Enkephalin-like peptide with pain-relieving and antidepressant-like effects (2023)

Chronic pain affects approximately 20% of Canadians and is a global healthcare burden with limited treatment options. The high incidence of comorbid chronic pain and depression additionally worsens patient’s quality of life and treatment outcomes. Antidepressants are used for the treatment of persistent pain but show limited efficacy and often induce serious side effects. Opioids are highly potent analgesics but are associated with severe adverse effects frequently limiting their use in chronic pain management. Endogenous opioids act on our nervous system to regulate pain and mood. The endogenous opioid peptide Leucine-enkephalin (Leu-ENK) produces analgesia with fewer adverse effects compared to conventional opioids. However, its poor stability and low membrane permeability make Leu-ENK ineffective when administered peripherally. We developed the N-pivaloyl Leu-ENK analog KK-103, which showed a high relative binding affinity for the delta opioid receptor (DOR) and was stable in plasma for 5 h. In the hotplate model, subcutaneous (s.c.) KK-103 showed 10-fold improved antinociception compared to Leu-ENK and produced a longer-lasting antinociceptive activity than morphine. In the formalin model, KK-103 reduced the licking and biting time of mice by ~60% relative to the vehicle group. We demonstrated a similar dose to maximum antinociceptive-effect relationship of KK-103 in the hotplate and formalin foot models. Contrasting morphine, KK-103 did not induce breathing depression, physical dependence, and tolerance in the models and experimental timelines used in this study. Additionally, KK-103’s minimal gastrointestinal inhibition and absence of sedation demonstrated its potential as a safe and effective analgesic. We also demonstrated KK-103’s increased systemic adsorption and plasma exposure compared to Leu-ENK and observed brain uptake of radiolabeled KK-103 after s.c. administration. The antinociceptive effect of KK-103 was primarily mediated by opioid receptors in the central nervous system and specifically the activation of the DOR. We detected the conversion of KK-103 to Leu-ENK in vitro which may induce the observed effects of KK-103 in mice. Finally, we determined an antidepressant-like activity of KK-103, which was comparable to that of the antidepressant desipramine. This work showed the potential application of KK-103 for pain and depression and provides the theoretical framework for future R&D of ENK therapeutics.

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Chemical modification of drugs to promote their self-assembly into nanoparticles for improved delivery (2022)

Many small molecule drugs face challenges with aqueous solubility during their development, which can lead to issues with drug delivery. A commonly employed method to improve the solubility and delivery of drug-like molecules is to modify the compounds with hydrophilic groups. However, it can be very challenging to incorporate these groups without sacrificing the activity of the molecule. Alternative approaches include encapsulating the hydrophobic drug into a delivery vessel, such as a nanoparticle (NP), or introducing functional groups that help with solubility and delivery of the drug-like molecule but are cleaved in biological settings to release the original drug molecule (for example, a prodrug approach). Combining these approaches, a hydrophilic group such as water-soluble polymer poly(ethylene glycol) (PEG) can be added to a hydrophobic drug molecule to produce an “amphiphile”. These amphiphiles can self-assemble in aqueous media to form NPs where the hydrophobic, poorly water-soluble drug is protected in the core and the water-soluble polymer forms the outer shell. These NPs can have prolonged circulation, reduced clearance, and may therefore enhance efficacy. These PEG groups are appended to the molecule via a functional group that can be cleaved under biological conditions to release the active drug molecule. The physicochemical and pharmacological properties of these NPs can be modulated by altering different aspects of the amphiphilic drug-PEG conjugate. To optimize these conjugates and maximize their therapeutic potential, it is important to take a structure-activity relationship (SAR)-based approach when undertaking such an investigation. To facilitate the rapid and facile generation of drug conjugates, this thesis focused on developing a new platform technology using azide-alkyne click chemistry. Small molecule drugs with poor aqueous solubility were “clicked” to linear short-chain PEG. The resulting PEG conjugates then self-assembled into NPs. Multiple conjugates were generated to demonstrate the robustness and versatility of this technology. This thesis demonstrated that the developed click chemistry platform is a robust synthetic technology that has potential application to improve the delivery of poorly soluble drugs.

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Development of novel phospholipid-free small unilamellar vesicles for liver targeting (2022)

Life threatening liver diseases such as cirrhosis and viral hepatitis accounts for 2 million global deaths annually. The major limitations of the current pharmacological therapies are the inability to deliver sufficient concentrations of therapeutic drugs to the diseased liver cells and the activation of undesired systemic side effects. The development of lipid-nanoparticles (LNPs) for small molecular drugs delivery has grown rapidly in the past decades. Although some were successful in targeting the liver, not so many were able to target the hepatocytes, where most liver diseases reside. To address this issue this dissertation is focused on the development of a novel hepatocyte-targeting formulation, called Phospholipid-Free Small Unilamellar Vesicles (PFSUVs), to improve the treatment of many liver diseases including liver stage malaria and viral hepatitis. The developed formulation is composed of high cholesterol content (~ 83%) and TWEEN 80, a non-ionic surfactant.The first part of this dissertation explored the effect of PFSUVs’ size on the intrahepatic distribution. We found that small size PFSUVs (60 nm) selectively target the hepatocytes, whereas larger PFSUVs with an average size of 120 nm accumulate in the Kupffer cells. The second and third parts of the dissertation explored two different hepatocyte-related disease applications. First, we examined the ability of PFSUVs to improve the treatment of liver-stage malaria by efficiently delivering primaquine to the hepatocytes and reducing its hemolytic toxicity. The second application focused on enhancing the treatment of hepatitis B virus (HBV). This was achieved by stimulating the immune system to trigger the production of endogenous interferon-α, a proinflammatory cytokine. We evaluated the efficacy of PFSUVs in significantly reducing hepatitis B surface antigen (HBsAg) in a mouse model when delivering an immunomodulatory agent to the hepatocytes. The fourth part of this thesis was to explore the mechanism behind the selectivity of PFSUVs to hepatocytes. In addition to the small size of PFSUVs, we demonstrated the effect of serum proteins, specifically apolipoproteins, on the internalization of PFSUVs into hepatocytes. This work demonstrated the importance of cell-specific targeting and the potential of PFSUVs to improve the treatment in many hepatocytes-associated diseases.

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Development of a fast and efficient liposomal drug loading technology for poorly water soluble drugs: formulation, characterization, and potential applications (2018)

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.

Exploring the feasibility of in situ gene editing on skin for the treatment of genodermatoses (2023)

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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Pharmacokinetic and pharmacodynamic properties of cationic liposomal delivery of the immunomodulatory agent R848 to the mouse peritoneal cavity for the treatment of advanced peritoneal cancer (2020)

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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Comparison of pharmacokinetics and biodistribution of doxorubicin loaded in PEGylated liposomes and a phospholipid-free small unilamilar vesicle (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 (
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Pharmacokinetics, Biodistribution and Intratumoral Distribution of Celludo Nanoparticles (2016)

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

 
 

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