Novel Gemcitabine-Re(I) Bisquinolinyl Complex Combinations and Formulations With Liquid Crystalline Nanoparticles for Pancreatic Cancer Photodynamic Therapy

Hui Shan Liew; Chun-Wai Mai; Mohd Zulkefeli; Thiagarajan Madheswaran; Lik Voon Kiew; Lesley Jia Wei Pua; Ling Wei Hii; Wei Meng Lim; May Lee Low

doi:10.3389/fphar.2022.903210

Novel Gemcitabine-Re(I) Bisquinolinyl Complex Combinations and Formulations With Liquid Crystalline Nanoparticles for Pancreatic Cancer Photodynamic Therapy

Front Pharmacol. 2022 Jul 6:13:903210. doi: 10.3389/fphar.2022.903210. eCollection 2022.

Authors

Hui Shan Liew¹, Chun-Wai Mai^{2

3}, Mohd Zulkefeli³, Thiagarajan Madheswaran³, Lik Voon Kiew⁴, Lesley Jia Wei Pua¹, Ling Wei Hii^{2

3}, Wei Meng Lim⁵, May Lee Low^{2

3}

Affiliations

¹ School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia.
² Centre for Cancer and Stem Cell Research, International Medical University, Kuala Lumpur, Malaysia.
³ School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
⁴ Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁵ School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia.

Abstract

With less than 10% of 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal types of cancer. Current literature supports that gemcitabine is the first-line treatment of PDAC. However, poor cellular penetration of gemcitabine along with the acquired and intrinsic chemoresistance of tumor against it often reduced its efficacy and hence necessitates the administration of high gemcitabine dose during chemotherapy. Photodynamic therapy (PDT), a more selective and minimally invasive treatment, may be used synergistically with gemcitabine to reduce the doses utilized and dose-related side effects. This study reports the synergistic use of Re(I) bisquinolinyl complex, a transition metal complex photosensitizer with gemcitabine against PDAC. Re(I) bisquinolinyl complex was found to act synergistically with gemcitabine against PDAC in vitro at various ratios. With the aim to enhance cellular uptake and therapeutic efficiency, the Re(I) bisquinolinyl complex and gemcitabine were encapsulated into liquid crystalline nanoparticles (LCNPs) system. The formulations were found to produce homogeneous drug-loaded LCNPs (average size: 159-173 nm, zeta potential +1.06 to -10 mV). Around 70% of gemcitabine and 90% of the Re(I) bisquinolinyl complex were found to be entrapped efficiently in the formulated LCNPs. The release rate of gemcitabine or/and the Re(I) bisquinolinyl complex loaded into LCNPs was evaluated in vitro, and the hydrophilic gemcitabine was released at a faster rate than the lipophilic Re(I) complex. LCNPs loaded with gemcitabine and Re(I) bisquinolinyl complex in a 1:1 ratio illustrated the best anti-cancer activity among the LCNP formulations (IC₅₀ of BxPC3: 0.15 μM; IC₅₀ of SW 1990: 0.76 μM) through apoptosis. The current findings suggest the potential use of transition metal-based photosensitizer as an adjunctive agent for gemcitabine-based chemotherapy against PDAC and the importance of nano-formulation in such application.

Keywords: Re(I) tricarbonyl complexes; liquid crystalline nanoparticles; nanomedicine; pancreatic cancer; photodynamic therapy.