Abstract
Abnormal structural and molecular changes in malignant tissues were thoroughly investigated and utilized to target tumor cells, hence rescuing normal healthy tissues and lowering the unwanted side effects as non-specific cytotoxicity. Various ligands for cancer cell specific markers have been uncovered and inspected for directional delivery of the anti-cancer drug to the tumor site, in addition to diagnostic applications. Over the past few decades research related to the ligand targeted therapy (LTT) increased tremendously aiming to treat various pathologies, mainly cancers with well exclusive markers. Malignant tumors are known to induce elevated levels of a variety of proteins and peptides known as cancer "markers" as certain antigens (e.g., Prostate specific membrane antigen "PSMA", carcinoembryonic antigen "CEA"), receptors (folate receptor, somatostatin receptor), integrins (Integrin αvβ3) and cluster of differentiation molecules (CD13). The choice of an appropriate marker to be targeted and the design of effective ligand-drug conjugate all has to be carefully selected to generate the required therapeutic effect. Moreover, since some tumors express aberrantly high levels of more than one marker, some approaches investigated targeting cancer cells with more than one ligand (dual or multi targeting). We aim in this review to report an update on the cancer-specific receptors and the vehicles to deliver cytotoxic drugs, including recent advancements on nano delivery systems and their implementation in targeted cancer therapy. We will discuss the advantages and limitations facing this approach and possible solutions to mitigate these obstacles. To achieve the said aim a literature search in electronic data bases (PubMed and others) using keywords "Cancer specific receptors, cancer specific antibody, tumor specific peptide carriers, cancer overexpressed proteins, gold nanotechnology and gold nanoparticles in cancer treatment" was carried out.
Highlights
Cancer is a disease with high complexity resulting in abnormal random responses to a variety of cellular signals
The targeting molecules have been expanded recently depending on the targeted cancer cell marker and this includes ligands for receptors known to be highly expressed on the surface of cancer cells, such as antibodies and their recombinant derivatives, in addition to peptides which can be either cell penetrating peptides or tumor homing peptides (Fig. 3)
An antibody against carcinoembryonic antigen (CEA) was conjugated with the enzyme CPG2 that is required for the ac tivity of prodrug (CMDA), but early investigations found non-selective activation of the prodrug in circulation
Summary
Cancer is a disease with high complexity resulting in abnormal random responses to a variety of cellular signals. Some other receptors found to induce their effect by binding to their therapeutic antagonists (as Z-360), concentrating the drug at tumor site to induce their cytotoxic effect without internal ization [21] Such non-internalizing receptors mediated therapy is known to be successful when the targeted receptor is highly expressed on cancer cell and the drug is released from the ligand drug conjugate without the need to internalize the cell, as utilizing the extracellular hydrolytic enzymes (as matrix metalloproteinase 2 (MMP2) and MMP9). The selected ligand can bind to other non-tumor specific isoform of the receptor expressed on other normal cells too, resulting in the unwanted toxic effects in healthy tissue. Such drugs should be highly potent and released after cleavage from endosomal capsule [37]
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