Ligand Coupling

It has been demonstrated that ligand-conjugated drug carriers can selectively and efficiently accumulate in target cells.168-172 The addition of biomolecules to the surface of micelles enables the drug-loaded micelles to enter the cells via receptor-mediated endocytosis as shown in Figure 17.5. Through the highly specific binding affinity between the ligand-receptor complex, the attachment of ligands to micelles surface allows for targeted drug delivery to specific cells that express the corresponding cell surface receptors. In particular, many types of cancer cells express a higher-than-normal level of cell surface receptors that have binding affinities for growth-dependent

molecules as a result of their rapid growth rate. Ligands such as sugar moieties, trans ferrin,178-180 folate,78,95,181 epidermal growth factor (EGF),115,167,178 and antibody fragments182 have been attached to the surface of copolymer micelles to target different types of cancers.

Kabanov's group was one of the first to apply the ligand coupling concept to micellar drug delivery systems. The authors demonstrated that by chemically conjugating a2-glycoprotein, a ligand that targets brain glial cells, to FITC-containing Pluronic® micelles, the accumulation of FITC in brain tissues was increased and clearance of FITC by the lung was decreased in comparison to delivery using conventional Pluronic® micelles.126,183 Recently, another ligand, folate, was conjugated to PEG-b-PLGA micelle system for targeting folate receptor over expressing cancers. The doxorubicin-loaded folate-PEG-b-PLGA micelles were found to enhance the intra-cellular accumulation of doxorubicin and resulted in a lower IC50 in folate receptor overexpressing KB epidermal carcinoma cells. In vivo studies revealed that treatment with doxorubicin-loaded folate-PEG-b-PLGA micelles resulted in a high suppression of tumor growth.78

In cases where nuclear targeting is desired, ligands such as EGF and the HIV-1 TAT peptide that have nuclear translocation properties, may be employed.6,115,184 Zeng et al. reported on an EGF-conjugated PEG-b-poly(S-valerolactone) (PEG-b-PVL) micelle system that targets EGFR-over expressing breast cancers. The EGF-PEG-b-PVL micelles were shown to mainly localize in the perinuclear region and in the nucleus of MDA-MB-468 breast cancer cells as shown in Figure 17.7.115 Nuclear targeting is critical for the delivery of anti-cancer drugs and oligonucleotides whose site of action is located in the nucleus. Wagner's group has developed EGF- and transferrin-conjugated PEG-b-poly(ethylenimine) (PEG-b-PEI) micelle systems for gene delivery


to tumor tissues. , , , Molecules such as oligonucleotides are more susceptible to degradation in the endosomal or lysosomal compartments; therefore, pH-responsive micelles that are capable of destabilizing the endosomal or lysosomal membranes could potentially improve the therapeutic effect of these molecules.

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