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<p>Abstract: As a class of important biologically active substances, peptides are widely used in cancer therapy due to their high activity, low immunogenicity, low toxicity, and easy loading. The targeted drug delivery system can selectively concentrate and localize the drug in the target organ, target tissue, and target cells, and modify the surface of the targeted drug delivery system with small molecular polypeptides, which can improve the therapeutic index while reducing the toxic and side effects of traditional chemotherapy drugs.</p>
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<p>This article introduces the application of modified targeted drug delivery systems including epidermal growth factor-specific peptides, tumor neovascularization targeting peptides and cell-penetrating peptides in cancer treatment, indicating that peptide modified drug delivery systems have wonderful potential in cancer treatment.</p>
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<p>Keywords: <strong>peptide</strong>; targeting; drug delivery system; epidermal growth factor; tumor angiogenesis; <strong>cell-penetrating peptide</strong></p>
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<p><strong>Chemotherapy is Main Methods of Cancer Treatment</strong></p>
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<p>Due to the lack of specificity of pharmacological action, chemotherapy can cause serious damage to both tumor tissue and normal tissue of patients. With the continuous improvement of chemotherapy drugs, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275483/"><strong>targeted drug delivery systems</strong></a> have attracted the attention of scientists. </p>
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<p>As a new drug delivery route, targeted drug delivery can increase drug concentration in tumor tissue while reducing drug side effects, and deliver the drug directly to the tumor site, which can specifically kill and inhibit tumor cells in different stages of tumor development and growth .</p>
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<p>Small molecule peptides have the characteristics of small molecular weight, high activity, low immunogenicity, low toxicity, and easy loading, and have been widely used in tumor targeting therapy in recent years. Peptides is easy to synthesize in peptide laboratories, such as <a href="https://www.omizzur.com/"><strong>Omizzur lab</strong></a> .Using some abnormally expressed proteins in tumor tissue, researchers screen out highly active small molecular peptides that can specifically recognize tumor tissue, and connect them to drug carriers through functional groups of amino acid side chains to improve the efficacy of tumor drug treatment.</p>
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<p>Among them, targeted drug delivery systems modified by epidermal growth factor-specific peptides, tumor neovascularization-targeting peptides, and cell-penetrating peptides are more in-depth in cancer treatment, and will be introduced one by one next.</p>
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<p><strong>1. Epidermal Growth Factor-Specific Peptide</strong></p>
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<p>Epidermal growth factor receptor (EGFR), a member of the human epidermal receptor (HER) family, is a receptor for epidermal growth factor (EGF) cell proliferation and signal transduction. EGFR is widely distributed in human tumor epithelial cells, and all of them are overexpressed.</p>
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<p>Common in non-small cell lung cancer, breast cancer, head and neck cancer, gastric cancer, colon cancer, etc. The high expression of EGFR is related to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. Targeted drug delivery systems targeting EGFR have received extensive attention. The targeted drug delivery system modified by specific peptides of epidermal growth factor also has great development prospects in gene therapy.</p>
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<p><strong>2 .Tumor Angiogenesis Targeting Peptide</strong></p>
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<p>Tumor neovascularization provides oxygen and nutrients for tumor growth, transports harmful substances produced by metabolism, and is a necessary condition for maintaining the growth of malignant tumors. Since tumor neovascularization is an abnormally proliferating blood vessel, some proteins that are not expressed or expressed very low in mature blood vessels, such as αv-type integrin and some specific angiogenesis growth factor receptors are expressed in tumor neovascular endothelial cells, becoming New targets for cancer therapy.</p>
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<p><strong>RGD Integrin Binding Peptide</strong></p>
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<p>Integrin is an important adhesion factor in the body, and it is a heterodimer formed by two subunits of α (120-185 kD) and β (90-110 kD), among which αvβ3, αvβ5, α5β1 and α2β1 can affect tumor neogenesis. Angiogenesis, RGD polypeptide can combine with integrins αvβ3 and αvβ5 overexpressed in tumor vasculature.</p>
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<p>Modification of RGD on the surface of an anti-tumor drug delivery system can increase drug targeting properties and make the treatment more effective, precise and safe. In recent years, it has been widely used in nano drug delivery systems such as liposomes, polymer micelles, and gene carriers.</p>
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<p><strong>3. Cell Penetrating Peptides</strong></p>
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<p>Cell-penetrating peptides (CPPs) or <a href="https://www.mdpi.com/2073-4360/10/9/1039"><strong>protein transduction domains</strong></a> (PTDs) are a class of polypeptides with strong membrane-penetrating activity. Exogenous hydrophobic macromolecules (chemotherapy drugs and apoptotic precursor proteins, etc.) enter living cells.</p>
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<p>According to the membrane penetration effect of CPPS, it can effectively improve the permeability of drugs in special structures such as the blood-brain barrier, and in a sense achieve the effect of targeted therapy. The ways of CPPs entering cells are mainly classified into two types: energy-dependent endocytosis and direct uptake through energy-independent membrane bilayer.</p>
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<p>&nbsp;At present, there are two ways to apply CPP to modify the targeted drug delivery system, one is to directly modify the surface of the drug delivery carrier to improve drug delivery efficiency, and the other is to link the amino acid side chain of CPP by forming a covalent bond to have a therapeutic effect.&nbsp;</p>
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<p>The functional peptides, and then the synthesized new peptides are modified on the surface of the delivery carrier for tumor treatment. Specific modifications can be divided into natural peptide modified drug delivery systems and synthetic peptide modified drug delivery systems.</p>
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<p><strong>4. Combined Application of Multiple Targets</strong></p>
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<p>The application of two different peptides linked together can often achieve unexpected effects. For example: poly-arginine has good cell membrane penetration properties, and the chimeric peptide obtained by linking a peptide that recognizes a specific tissue with poly-arginine can not only concentrate in a direction but also penetrate tumor cells. There are also studies that simultaneously modify two peptide sequences that recognize different targets on the surface of the drug delivery system, and the results show a good synergistic effect.</p>
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<p><strong>What Are The Current Problems of Peptide Modification?</strong></p>
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<p>Due to the development of modern biotechnology, the speed of discovering new compounds and highly effective therapeutic molecules continues to accelerate, and traditional anticancer methods are bound to be replaced by new biological treatments. As various functional polypeptides enter the research field, their position in cancer-targeted drug delivery systems cannot be ignored. Drug delivery systems modified by polypeptides have successfully carried various anticancer drugs into cells.</p>
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<p>However, some active groups in the polypeptide structure often undergo side reactions during the introduction into the carrier, resulting in loss of activity. How to protect these effective groups, how to further increase the drug delivery concentration of the local target tissue of the polypeptide modified drug delivery system, and further precise drug delivery sites need to be resolved in depth.</p>
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<p>At the same time, this kind of research is still only based on in vitro cell and animal experiments, and has not yet entered the clinical trial stage. The preparation of stable and precise drug release polypeptide carriers will shorten the distance for such drug delivery systems to enter the clinic.</p>
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