Oleanolic Acid Delivery using Biodegradable Nanoparticles for Cancer Therapy

Poster PresentationOleanolic acid (OA) is a naturally occurring pentacyclic triterpenoid widely found in Chinese herbs. It has been extensively studied owing to the beneficial effects such as hepatoprotection, anti-inflammatory and it is recently found to have anti-tumor ability. However, resembling the other hydrophobic drugs, it has poor water solubility and therefore very limited intestinal absorption when administrated orally. Investigations concerning the delivery of OA have been carried out to enhance its dissolution and bioavailability. Nanoparticulate systems involve the reduction of drug particle size into nano-scale thereby increasing the interfacial surface area. As a result, absorption of drug in the body system could be enhanced. Biodegradable polymer-based system can be metabolized by the body system into harmless compounds so it is regarded safe and promising. This study was conducted to evaluate the efficacy of four types of biodegradable copolymers as potential OA delivery nanoparticulate system. Co-polymers consisting a hydrophilic block: poly(ethylene) glycol (PEG) and a hydrophobic block of either poly(lactic-co-glycolic) acid (PLGA) or poly(lactic acid) (PLA) were used to fabricate a novel nanoformulation to improve OA bioavailability. The OA-loaded mPEG-(D,L)PLA, mPEG-(L)PLA, mPEG-(D,L)PLGA and mPEG- (L)PLGA nanoparticles (NPs), prepared by nanoprecipitation, were observed to be spherical in shape under transmission electron microscope. Results indicated that narrow size distributed NPs with mean hydrodynamic diameter of 200±16.0, 233±13.9, 211±10.1 and 229±10.1nm respectively were obtained. mPEG-(D,L)PLA NPs attained the highest encapsulation of OA with 75.8% efficiency while mPEG-(L)PLGA NPs displayed the lowest encapsulation efficiency at 40.8%. The in vitro anti-tumoral activity was evaluated on A549, lung carcinoma epithelial cell lines using MTT assay. All the four types of OA-loaded NPs demonstrated better anti-cancer ability than saturated OA in medium. Moreover, NPs without OA exhibited significantly lower cytotoxicity towards A549 indicating induced cell death was due to the effective delivery of OA as an anti-cancer therapeutic agent.published_or_final_versio

Combination of antimicrobial peptides and isoniazid/rifampicin against multidrug-resistant tuberculosis

Oral Presentation no. OP 11Multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) bearing resistance towards both isoniazid (INH) and rifampicin (RIF) were reported during early 1990s. New anti-TB drug development has been extensively focused, yet the adverse events experienced by patients were substantial. Therefore, innovative approaches to achieve a shortened and safe therapeutic regimen for drug-resistant TB is imperative. The specifi c composition of mycobacterial cell wall giving rise to its extremely high hydrophobicity and impermeability is known to confer Mtb antibiotic resistance. Antimicrobial peptides (AMPs) act selectively on negatively charged bacterial membranes, their pore-forming actions lead to leakage of cellular content and eventually cell death. This killing effect is rapid and potent while making development of resistance to AMPs diffi cult. Our study aims at investigating the combination of novel antimicrobial peptides with fi rst line anti-TB drugs against MDR-TB. D-LAK peptides were shown to exert a detergent-like effect which effectively broke down clumps of bacteria and inhibited the growth of MDR and XDR Mtb strains (1). Therefore, we hypothesize that D-LAK peptides can facilitate the access of anti-TB drugs into mycobacteria by increasing their surface permeability, with the potential of re-sensitizing MDR-TB to fi rst-line anti-TB drugs. Combination treatment of INH and RIF with D-LAK peptides has successfully demonstrated synergistic effect against the growth of MDR-TB strains. Antibacterial assays revealed the effi cacies of bacterial load reduction at a lower anti-TB drug as well as D-LAK peptide concentrations. We have also employed Mycobacterium smegmatis as a model to understand the mechanism of actions of D-LAK peptides. Membrane disruption activity by D-LAK peptides was visualized using transmission electron microscopy (TEM). Prolonged treatment of peptide caused irreversible damage of cell envelope leading to leakage of cellular content. Confocal microscopy has further confi rmed cell surface perturbation action of D-LAK peptides supporting our hypothesis regarding the assistant role of peptides in re-sensitization of MDR-TB towards fi rst-line drugs. Further investigations on the antibacterial mode of action in a whole organism view using nuclear magnetic resonance (NMR) metabolomics is in progress. 1. Lan Y, Lam JT, Siu GK, Yam WC, Mason AJ, Lam JK. Cationic amphipathic D-enantiomeric antimicrobial peptides with in vitro and ex vivo activity against drug-resistant Mycobacterium tuberculosis. Tuberculosis (Edinb). 2014;94(6):678-89