ABSTRACT
During the last decade, intracellular drug delivery has become an emerging area of research in the medical and pharmaceutical field. Many therapeutic agents such as drugs and DNA/oligonucleotides can be delivered not just to the cell but also to a particular compartment of that cell to achieve better activity e.g. proapoptotic drugs to the mitochondria, antibiotics and enzymes to the lysosomes and various anticancer drugs and gene to the nucleus. The lipidic nature of biological membrans is the major obstacle to the intracellular delivery of macromolecular and ionic drugs. Additionally, after endocytosis, the lysosome, the major degradation compartment, needs to be avoided for better activity. To avoid these problems, various carriers have been investigated for efficient intracellular delivery, either by direct entry to cytoplasm or by escaping the endosomal compartment. These include cell penetrating peptides, and carrier systems such as liposomes, cationic lipids and polymers, polymeric nanoparticles, etc. Various properties of these carriers, including size, surface charge, composition and the presence of cell specific ligands, alter their efficacy and specificity towards particular cells. This review summarizes various aspects of targeted intracellular delivery of therapeutics including pathways, mechanisms and approaches. Various carrier constructs having potential for targeted intracellular delivery are also been discussed.
Subject(s)
Cells/drug effects , Drug Delivery Systems , Drug Therapy , Pharmaceutical Preparations/administration & dosage , Animals , Drug Carriers , Genetic Therapy , Humans , Liposomes , Organelles/drug effects , Receptors, Drug/drug effectsABSTRACT
Hepatitis C viral chemotherapy suffers from a relatively short half-life of the interferon alpha-2a (IFN alpha). To address this issue, we investigated the effects of polyethylene glycol modification and their subsequent encapsulation in multivesicular liposomes (MVLs), on the release properties of IFN alpha. In the present study, interferon-alpha was conjugated with methoxy-polyethylene glycol (mPEG, MW 5000). Prepared IFN alpha-mPEG5000 conjugate (IFN alpha-mPEG5000) was purified with size exclusion chromatography. The relative in vitro anti-viral activity of pegylated interferon alpha-2a was found to 87.9% of the unmodified IFN alpha. Pegylated IFN alpha encapsulated multivesicular liposomes were prepared by double emulsification technique followed by evaporation of organic solvents from chloroform ether spherules suspended in water. Prepared MVLs were then characterized for shape, size, vesicle count, encapsulation efficiency, and in vitro release rate. In process stability studies of pegylated IFN alpha protein exhibited better stability when exposed to chloroform: diethyl ether (1:1 ratio) mixture as well as variable vortexing time as compared to native IFN alpha. Relatively high percentage of encapsulation of protein ( approximately 75%) was achieved. In vitro release profile of pegylated IFN alpha-mPEG5000 containing MVLs in the PBS showed lower initial burst release with sustained and incomplete release over a period of 1 week. In contrast, native IFN alpha entrapped MVLs were observed as higher initial burst release, i.e., nearly 35% followed by almost complete release. The results confirmed the possibility of multivesicular liposomes as a long-acting or sustained-release delivery system using a combination of pegylation and encapsulation technique for controlled delivery of interferon alpha.