Endocytic mechanisms for targeted drug delivery☆

Abstract

Advances in the delivery of targeted drug systems have evolved to enable highly regulated site specific localization to subcellular organelles. Targeting therapeutics to individual intracellular compartments has resulted in benefits to therapies associated with these unique organelles. Endocytosis, a mechanism common to all cells in the body, internalizes macromolecules and retains them in transport vesicles which traffic along the endolysosomal scaffold. An array of vesicular internalization mechanisms exist, therefore understanding the key players specific to each pathway has allowed researchers to bioengineer macromolecular complexes for highly specialized delivery. Membrane specific receptors most frequently enter the cell through endocytosis following the binding of a high affinity ligand. High affinity ligands interact with membrane receptors, internalize in membrane bound vesicles, and traffic through cells in different manners to allow for accumulation in early endosomal fractions or lysosomally associated fractions. Although most drug delivery complexes aim to avoid lysosomal degradation, more recent studies have shown the clinical utility in directed protein delivery to this environment for the enzymatic release of therapeutics. Targeting nanomedicine complexes to the endolysosomal pathway have serious potential for improving drug delivery for the treatment of lysosomal storage diseases, cancer, and Alzheimer's disease. Although several issues remain for receptor specific targeting, current work is investigating a synthetic receptor approach for high affinity binding of targeted macromolecules.

In vivo evaluation of riboflavin receptor targeted fluorescent USPIO in mice with prostate cancer xenografts

“…Ammonia (NH 3 ≥ 25%), N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES, ≥99.5%), hydrochloric acid (HCl, 37%), K 4 [Fe(CN) 6 ], nuclear fast red, and hematoxylin and eosin were purchased from Carl Roth GmbH (Karlsruhe, Germany). Guanosine-5′-monophosphate disodium salt hydrate (GMP, 98%), gelatin (ph.…”

“…After incubation for 1 or 3 h, cells were washed thrice with PBS and fixed using 4% paraformaldehyde solution. Subsequently, the fixed cells were treated for 5 min with an aqueous solution of K 4 Fe(CN) 6 (10%) and then with a 1:1 mixture of K4Fe(CN)6 (10%) and HCl acid (20%) for 30 min. Subsequently, cells were counterstained with Nuclear Fast Red (Carl Roth, Karlsruhe, Germany).…”

“…In this context, a rapid translocation of the vitamin-tagged cargo into cancer cells was observed via receptor-mediated endocytosis, e.g. for folic acid-and riboflavin (Rf)-tagged agents [6][7][8][9][10][11][12]. In this study, we focused on Rf, an essential vitamin that mediates various biochemical, physiological, and metabolic (e.g.…”

A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery

“…Furthermore, mice treated with radioactive formulations exhibited lower weight gain without significant hematological or biochemical changes, except for toxicity to hepatocytes (Soares et al, 2012). Cationic liposomes facilitate the cellular uptake by electrostatic absorptive endocytosis due to negative charge on the cell membrane (Bareford et al, 2007). These liposomes after internalization fuse with the endosomal membrane to release their contents into the cytoplasm (Koynova et al, 2006) or exhibit the proton sponge effect leading to swelling and subsequent disruption of endosomal membrane resulting into cytoplasmic delivery of intact liposomes (Shigeta et al, 2007).…”

Application of traditional Chinese medicine preparation in targeting drug delivery system

“…Simultaneously, decrease the using time of drug and reduce its side-effects. At present, there are some targeted agents, and the use of each of these has distinct but interrelated goals (Chilkoti et al, 2002;Krishnaiah et al, 2002;Wang et al, 2003;Patri et al, 2005;Bareford & Swaan, 2007;Sutton et al, 2007). With the development of biomedical science, biomaterials science and molecular biology, the investigation of TDDS now is become a research hotspot.…”