Grants and Contributions:

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Title:
Development of active loading technologies for encapsulating highly charged molecules into liposomes
Agreement Number:
RGPIN
Agreement Value:
$140,000.00
Agreement Date:
May 10, 2017 -
Organization:
Natural Sciences and Engineering Research Council of Canada
Location:
British Columbia, CA
Reference Number:
GC-2017-Q1-01496
Agreement Type:
Grant
Report Type:
Grants and Contributions
Additional Information:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Recipient's Legal Name:
Li, Shyh-Dar (The University of British Columbia)
Program:
Discovery Grants Program - Individual
Program Purpose:

Over the next 5 years I will focus on developing new active loading technologies to encapsulate highly charged molecules into liposomes to improve their delivery . I will focus on three types of highly charged drugs: positively charged small molecules, negatively charged small molecules and negatively charged macromolecules. I will select one model drug from each class and develop a new active loading technology for each. Hypothesis: An ion-pairing agent will neutralize the charge of a compound to increase its membrane permeability and drive the loading into liposomes .

Obj 1: Develop an active loading method to encapsulate a positively charged small molecule into liposomes. Our model drug is gentamicin (GEN) that has 5 positively charged amino groups. We will develop and optimize a new loading method to prepare liposomal GEN, and will compare its pharmacokinetics (PK) in mice with free GEN and liposomal GEN prepared with passive loading.

Obj 2: Develop an active loading method to encapsulate a negatively charged small molecule into liposomes. Our model drug is clodronate (CLO) that has 2 negatively charged phosphate groups. Liposomal CLO is used to deplete tissue macrophages in animals to generate research models. We will develop and optimize a new loading technology to prepare liposomal CLO, and will compare its macrophage depleting activity in mice with free CLO and liposomal CLO prepared with passive loading.

Obj 3: Develop an active loading method to encapsulate a negatively charged macromolecule into liposomes. Our model drug is small interfering ribonucleic acid (siRNA) used to study gene function. We will develop an ion-pairing active loading method to fabricate liposomal siRNA. We will assess the interaction of the liposomal siRNA with blood components and cells and its biodistribution (BD) in tumor-bearing mice, and compare with free siRNA and cationic liposome-siRNA complex.

Short term goal: Develop active loading technologies to encapsulate GEN, CLO and siRNA into liposomes to improve their delivery. Long term goal: Develop a platform technology to load various types of highly charged drugs into liposomes to improve their PK and BD for increased bioavailability, with potential to create effective in vivo research tools or pharmaceutical products. This program will offer comprehensive training for HQP , including pharmaceutical formulation design, fabrication and characterization, in vitro cell based and molecular assays and in vivo PK/BD studies . These knowledge and skills are highly sought after in academia and industry in the pharmaceutical area, and HQP trained in my program have been highly competitive for these skilled jobs . I have published >25 papers and patents with liposomal technologies and licensed 2 technologies to industry with 2 products in clinical trials. This program will yield new liposomal engineering technologies with high commercialization values.