ABSTRACT
Novel drug delivery systems are developed to improve the biological behavior of poorly soluble drugs and to improve therapeutic outcomes. In melanoma therapy, the goal is efficient drug delivery and mitigation of drug resistance. Melphalan (Mel), a currently used therapeutic agent for melanoma, requires solvent system for solubilization, leading to poor chemical stability. Moreover, drug resistance often renders the drug inefficient in clinical setting. A novel ß-cyclodextrin-modified gemini surfactant (CDgemini) delivery system was developed to incorporate Mel in order to improve its physicochemical and biological behavior. Melphalan nanoparticles (Mel-NP) showed optimal particle size in the 200-250 nm range for endocytosis and induced significantly higher cell death compared with Mel (50% of inhibitory concentration [IC50] of 36 µM for the complexes vs 82 µM for Mel). The CDgemini delivery system did not alter the pathway of the cellular death triggered by Mel and caused no intrinsic toxicity to the cells. The Mel-NP complexes induced significant cell death in melanoma cells that were rendered resistant to Mel. These findings demonstrate in principle the applicability of the CDgemini delivery system as safe and efficient alternative to the current melanoma therapy, especially in chemoresistant cases.
Subject(s)
Drug Delivery Systems/methods , Melanoma/drug therapy , Nanoparticles/administration & dosage , Quaternary Ammonium Compounds/chemistry , beta-Cyclodextrins/chemistry , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/chemistry , Cell Death/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Humans , Inhibitory Concentration 50 , Melanoma/pathology , Melphalan/administration & dosage , Melphalan/chemistry , Nanoparticles/chemistry , Nanoparticles/toxicity , Particle Size , Solubility , Surface-Active Agents/chemistryABSTRACT
AIM: Recently, we synthesized amino acid- and peptide-substituted gemini surfactants, 'biolipids' that exhibited high transfection efficiency in vitro. In this study, we developed these plasmid DNA and gemini surfactant lipid particles for noninvasive administration in vaginal cavity. MATERIAL & METHODS: Novel formulations of these gene delivery systems were prepared with poloxamer 407 to induce in situ gelling of the formulation and diethylene glycol monoethyl ether to improve their penetration across mucosal tissue. RESULTS: Poloxamer at 16% w/v concentration in diethylene glycol monoethyl ether aqueous solution produced dispersions that gelled near body temperature and had a high yield value, preventing leakage of the formulation from the vaginal cavity. Intravaginal administration in rabbits showed that the glycyl-lysine-substituted gemini surfactant led to a higher gene expression compared with the parent unsubstituted gemini surfactant. CONCLUSION: This provides a proof-of-concept that amino acid substituted gemini surfactants can be used as noninvasive mucosal (vaginal) gene delivery systems to treat diseases associated with mucosal epithelia.
