Enhanced Cellular Cytotoxicity and Antibacterial Activity of 18-β-Glycyrrhetinic Acid by Albumin-conjugated PLGA Nanoparticles

Abstract

The aim of the present work was to encapsulate 18-β-Glycyrrhetinic acid (GLA) in albumin conjugated poly(lactide-co-glycolide) (PLGA) nanoparticles by a modified nanoprecipitation method. Nanoparticles (NPs) were prepared by different drug to polymer ratios, human serum albumin (HSA) content, dithiothreitol (as producer of free thiol groups) content, and acetone (as non-solvent in nanoprecipitation). NPs with a size ranging from 126 to 174 nm were achieved. The highest entrapment efficiency (89.4±4.2%) was achieved when the ratio of drug to polymer was 1:4. The zeta potential of NPs was fairly negative (−8 to −12). Fourier transform infrared spectroscopy and differential scanning calorimetry proved the conjugation of HSA to PLGA NPs. In vitro release profile of NPs showed 2 phases: an initial burst for 4 h (34–49%) followed by a slow release pattern up to the end. The antibacterial effects of NPs against Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa were studied by microdilution method. The GLA-loaded NPs showed more antibacterial effect than pure GLA (2–4 times). The anticancer MTT test revealed that GLA-loaded NPs were approximately 9 times more effective than pure GLA in Hep G2 cells.

Key words

PLGA nanoparticles - albumin conjugation - 18-β-glycyrrhetinic acid - toxicity - antibacterial effect

• References

• 1 Liang HF, Yang TF, Huang CT et al. Preparation of nanoparticles composed of poly (γ-glutamic acid)-poly (lactide) block copolymers and evaluation of their uptake by HepG2 cells. Journal of controlled release 2005; 105: 213-225
• 2 Fattal E, Rojas J, Youssef M et al. Liposome-entrapped ampicillin in the treatment of experimental murine listeriosis and salmonellosis. Antimicrobial agents and chemotherapy 1991; 35: 770-772
• 3 Couvreur P, Fattal E, Andremont A. Liposomes and nanoparticles in the treatment of intracellular bacterial infections. Pharmaceutical research 1991; 8: 1079-1086
• 4 Gulyaev A, Ermekbaeva BA, Kivman GY et al. Nanoparticles as a vector for the directed delivery of antibiotics (a review). Pharmaceutical chemistry journal 1998; 32: 115-118
• 5 Yoo HS, Oh JE, Lee KH et al. Biodegradable nanoparticles containing doxorubicin-PLGA conjugate for sustained release. Pharmaceutical research 1999; 16: 1114-1118
• 6 Dinarvand R, Sepehri N, Manoochehri S et al. Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents. International journal of nanomedicine 2011; 6: 877
• 7 Danhier F, Ansorena E, Silva JM et al. PLGA-based nanoparticles: an overview of biomedical applications. Journal of Controlled Release 2012; 161: 505-522
• 8 Maeda H, Wu J, Sawa T et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of controlled release 2000; 65: 271-284
• 9 Taheri A, Atyabi F, Nouri FS et al. Nanoparticles of conjugated methotrexate-human serum albumin: preparation and cytotoxicity evaluations. Journal of Nanomaterials 2011; 2011: 5
• 10 Elzoghby AO, Samy WM, Elgindy NA. Albumin-based nanoparticles as potential controlled release drug delivery systems. Journal of Controlled Release 2012; 157: 168-182
• 11 Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. Journal of Controlled Release 2008; 132: 171-183
• 12 Alexopoulos A, Kimbaris AC, Plessas S et al. Antibacterial activities of essential oils from eight Greek aromatic plants against clinical isolates of Staphylococcus aureus . Anaerobe 2011; 17: 399-402
• 13 Reiter KC, Sant’Anna FH, d’Azevedo PA. Upregulation of icaA, atlE and aap genes by linezolid but not vancomycin in Staphylococcus epidermidis RP62A biofilms. International journal of antimicrobial agents 2014; 43: 248-253
• 14 Carmeli Y, Troillet N, Eliopoulos GM et al. Emergence of antibiotic-resistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents. Antimicrobial agents and chemotherapy 1999; 43: 1379-1382
• 15 Nitalikar MM, Munde KC, Dhore BV et al. Studies of antibacterial activities of Glycyrrhiza glabra root extract. Int J Pharm Tech Res 2010; 2: 899-901
• 16 Lee CS, Kim YJ, Lee MS et al. 18β-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Life sciences 2008; 83: 481-489
• 17 Kashi TSJ, Eskandarion S, Esfandyari-Manesh M et al. Improved drug loading and antibacterial activity of minocycline-loaded PLGA nanoparticles prepared by solid/oil/water ion pairing method. International journal of nanomedicine 2012; 7: 221
• 18 Adibkia K, Shadbad MRS, Nokhodchi A et al. Piroxicam nanoparticles for ocular delivery: physicochemical characterization and implementation in endotoxin-induced uveitis. Journal of drug targeting 2007; 15: 407-416
• 19 Manoochehri S, Darvishi B, Kamalinia G et al. Surface modification of PLGA nanoparticles via human serum albumin conjugation for controlled delivery of docetaxel. Daru 2013; 1: 58
• 20 Mohammadi G, Valizadeh H, Barzegar-Jalali M et al. Development of azithromycin–PLGA nanoparticles: Physicochemical characterization and antibacterial effect against Salmonella typhi . Colloids and Surfaces B: Biointerfaces 2010; 80: 34-39
• 21 Michnik A, Michalik K, Kluczewska A et al. Comparative DSC study of human and bovine serum albumin. Journal of thermal analysis and calorimetry 2006; 84: 113-117
• 22 Senthilkumar M, Mishra P, Jain NK. Long circulating PEGylated poly (D, L-lactide-co-glycolide) nanoparticulate delivery of Docetaxel to solid tumors. Journal of drug targeting 2008; 16: 424-435
• 23 Chorny M, Fishbein I, Danenberg HD et al. Lipophilic drug loaded nanospheres prepared by nanoprecipitation: effect of formulation variables on size, drug recovery and release kinetics. Journal of Controlled Release 2002; 83: 389-400
• 24 Mainardes RM, Evangelista RC. PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution. International journal of pharmaceutics 2005; 290: 137-144
• 25 Mainardes RM, Gremião MPD, Evangelista RC. Thermoanalytical study of praziquantel-loaded PLGA nanoparticles. Revista Brasileira de Ciências Farmacêuticas 2006; 42: 523-530
• 26 Panyam J, Labhasetwar V. Dynamics of endocytosis and exocytosis of poly (D, L-lactide-co-glycolide) nanoparticles in vascular smooth muscle cells. Pharmaceutical research 2003; 20: 212-220
• 27 Koopaei MN, Maghazei MS, Mostafavi SH et al. Enhanced antibacterial activity of roxithromycin loaded pegylated poly lactide-co-glycolide nanoparticles. DARU Journal of Pharmaceutical Sciences 2012; 20: 92
• 28 Das S, Suresh PK, Desmukh R. Design of Eudragit RL 100 nanoparticles by nanoprecipitation method for ocular drug delivery. Nanomedicine: Nanotechnology, Biology and Medicine 2010; 6: 318-323
• 29 Mishra B, Patel BB, Tiwari S. Colloidal nanocarriers: a review on formulation technology, types and applications toward targeted drug delivery. Nanomedicine: Nanotechnology, biology and medicine 2010; 6: 9-24