The first is endocytosis dependent pathway which may be either receptor mediated or nonreceptor mediated and the second is based on endocytosis independent pathway which includes diffusion, membrane

fusion, or direct pore transport of the extracellular material into the cell [99]. The process of internalization of CNTs depends on several parameters such as the size, length, nature of functional groups, hydrophobicity, and surface chemistry of CNTs [99, 100]. Figure 5 Pathways for the penetration of CNTs into the cell. (a) Nonreceptor mediated endocytosis: (1) membrane that surrounds the drug loaded functionalized CNTs, (2) internalization Inhibitors,research,lifescience,medical of drug loaded CNTs, and (3) release of drug; (b) receptor mediated endocytosis: … Endocytosis

dependent pathway is an energy and temperature dependent transport process which involves engulfing of extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence Inhibitors,research,lifescience,medical also called as corpuscular or vesicular transport) which is then pinched off intracellularly into the matrix/cytoplasm of the cell [101]. Furthermore, internalization endocyte formation was shown to be clathrin mediated, caveolin-driven endocytosis, and through macropinocytosis [99]. In case of receptor mediated endocytosis (Figure 5(b)), ligand conjugated-drug loaded CNT binds to the complementary transmembrane receptor Inhibitors,research,lifescience,medical proteins and then enters the cell as receptor-ligand complexes in clathrin coated vesicles. After internalization vesicles are formed which were known as early endosomes and due to drop in pH, the ligand dissociates from the receptor. When the receptors are released, the vesicles carrying the extracellular particle fuses with lysosomes Inhibitors,research,lifescience,medical and thus trigger the release of the drug particle by the action lysozymes on the endosomes and simultaneously the free receptors thus formed are being recycled to the plasma membrane

for conjugating with other ligand Inhibitors,research,lifescience,medical conjugated CNTs [102]. An example from the antiangiogenetic area is the Methisazone targeting of integrin αvβ3, which are endothelial cell receptors for extracellular matrix proteins possessing the RGD sequence (arginine-glycine-aspartic acid) and are highly expressed on neovascular endothelial cells. Conjugation of RGD peptides to nanovectors can lead to higher levels of cellular internalization and furthermore affect vascular endothelial growth factor receptor-2 (VEGFR-2) signalling due to intrinsic association with this signalling pathway, leading to downregulation of the receptor and finally to reduced angiogenesis. Another example for active targeting based on ligand-receptor interactions relevant to this area of cancer therapeutics is the interaction of folate with its receptors. Folic acid is a vitamin and necessary for the synthesis of nucleotides, the DNA Brefeldin A order building blocks.