Huiqi Wang | ALES Graduate Seminar

A graduate exam seminar is a presentation of the student’s final research project for their degree.
This is an ALES PhD Final Exam Seminar by Huiqi Wang. This seminar is open to the general public to attend, either in person or online:

https://ualberta-ca.zoom.us/j/97336409881?pwd=RE11aG1xWVBFd2FmQlQ0WGVqTEpSQT09
Meeting ID: 973 3640 9881 Passcode: 648896

Thesis Topic: Design and synthesis of renewable lipid-based nanocarriers with thermosensitivity for targeted drug delivery applications

PhD with Dr. Aman Ullah.

Seminar Abstract:

Numerous drug molecules currently available on the market suffer from short half-life, in vivo instability, poor bioavailability, rapid degradation and inappropriate distribution. While nanocarriers have emerged as a promising solution to address these issues, the primary objective and challenge in modern medicine lie in achieving successful drug delivery in a targeted and controllable manner. Ongoing innovations are exploring the use of biocompatible, biodegradable, and sustainable materials for drug delivery. Among these, lipids, as naturally occurring biomolecules, have been found extensive applications in the pharmaceutical industry. However, examples of utilizing renewable fatty acids as hydrophobic building blocks to fabricate amphiphilic block copolymers for drug delivery are relatively scarce. This study aimed to synthesize and investigate thermoresponsive renewable lipid-based block copolymers, along with their bioconjugates with proteins, as a means of achieving effective anti-cancer drug delivery.

The self-assembly of amphiphilic macromolecules to form polymeric micelles is considered as one of the most potent drug delivery systems. In the first study, a stearic acid-based methacrylate polymer (PSAMA) was synthesized by microwave-assisted RAFT polymerization, and it was subsequently utilized as a macro-CTA to block copolymerize with N-isopropylacrylamide (NIPAM) to produce the thermoresponsive amphiphilic block copolymer PSAMA-b-PNIPAM. These block copolymers with variable hydrophobic block length self-assembled in aqueous media and formed spherical nanoparticles of ~30 nm with low critical micelle concentration (CMC). The hydrophobic model drug, Carbamazepine (CBZ), was chosen to assess the micelles’ performance as nanocarriers, achieving a loading efficiency of 31.6% into PSAMA-b-PNIPAM micelles. The drug release displayed an obvious temperature-triggered response at body temperature, with a sustained and slow release lasting up to 84 h.

In the second study, the impact of fatty acid type on self-assembly and drug encapsulation was explored. Two distinct fatty acids, poly(vinyl stearate) (PVS) and poly(vinyl laurate) (PVL), were synthesized as the hydrophobic segments for the polymeric micelles. The hydrophilic shell was formed using another thermoresponsive polymer, poly(N-vinylcaprolactam) (PNVCL), known for its excellent biocompatibility, biodegradability, and non-toxicity. By varying fatty acid types and adjusting hydrophilic/hydrophobic block lengths, the self-assembly behavior of the block copolymer (PVS/PVL-b-PNVCL) was found to be highly tunable in terms of morphology and particle size. Specifically, PVS-b-PNVCL micelles tended to form smaller, spherical structures (~80 nm) with an increase in hydrophilic block length, while both worm-like and spherical structures with an average size of 111 nm were observed when the repeating unit of PNVCL was 35. Notably, micelles made from PVL-b-PNVL exhibited exclusive spherical morphology and larger particle sizes (130-145 nm) with a relatively broad size distribution. Additionally, PVS-b-NVCL, polymeric micelles demonstrated high drug loading capacity for anticancer drug doxorubicin (DOX), along with good serum stability, controlled drug release, favorable biocompatibility, and efficient in vitro uptake.

The third study outlined the development of a protein-polymer bioconjugate comprising bovine serum albumin (BSA) and a lipid-based thermoresponsive amphiphilic block copolymer (PVS-b-PNVCL). The resulting bioconjugates exhibited a well-defined structure, low cytotoxicity and commendable biocompatibility with different cell lines. In an aqueous environment, the amphiphilic BSA-polymer conjugates can self-assemble into vesicular compartment with a particle size of approximately 200 nm. DOX was effectively encapsulated into the conjugates with a high loading capacity of 25.6%, demonstrating an effective in vitro antitumor activity and efficient cellular uptake. Notably, the lower critical solution temperature (LCST) of the bioconjugates was fine-tuned to around 40 ^oC through the integration of hydrophilic BSA. This temperature modulation facilitated targeted drug delivery to tumors, allowing enhanced therapeutic efficacy of the bioconjugates.

Overall, this study highlights the potential for advancing smart drug delivery nanocarriers platforms by exploring renewable materials as hydrophobic building blocks. The findings hold promise for future advancements in biobased and biocompatible carrier systems in cancer therapies.