Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate

Abstract

Binding-induced conformation change of hairpin peptide can be used to design integrin-targeted drug delivery system.

Multivalent Binding of a Ligand-Coated Particle: Role of Shape, Size, and Ligand Heterogeneity

“…2 we estimated ∆H b = −12.22 k B T for IB and ∆H b = −1.71 k B T for WB. The values of ∆H b computed through the two methods are in excellent agreement with each other and also with experimentally obtained binding energies [74,75]; this comparison is displayed in Table 1. Explicit calculations show that the receptor-ligand interactions follow a Bell potential: The PMFs shown in Fig.…”

“…The SB system corresponds to an Inter-cellular adhesion molecule (ICAM aka CD54) receptor interacting with its YN1 antibody, while the IB and WB systems correspond to the α 5 β 1 domain of integrin interacting with peptide sequences KGGEPRGDTYR and GERGDGSFFAFRSPF, both of which contain the well-recognized RGD (Arg-Gly-Asp) binding domain. These sequences are peptidomimetics that mimic the integrin binding domains found in the extracellular matrix proteins, fibronectin and collagen, respectively [74][75][76][77]. The interaction energies of each of these pairs are listed in Table 1, and the snapshots of the IB and WB systems in their respective bound states are shown in Suppl.…”

Cellular Uptake and Cytotoxicity of Drug–Peptide Conjugates Regulated by Conjugation Site

“…Covalent linkage of two chemically distinct moieties into one conjugated molecule presents a facile yet effective chemistry approach to achieve new molecular characteristics and synergistic properties. Examples include the incorporation of a small auxiliary group to a biologically, electronically, or optically active segment to create self-assembling amphiphilic molecules, − and the use of polyethylene glycol (PEGylation) to reduce protein immunogenicity. , In the context of anticancer drug delivery, drug–peptide conjugates have been used as a widely adopted strategy to increase the drug’s aqueous solubility, to create enzyme-cleavable prodrugs, to modify the drug’s pharmacokinetic properties, to achieve cell penetration or selectivity, , and to target a subcellular organelle . Unlike the design of fusion proteins, in which the effect of fusion site ( N - or C -terminal) is already under serious consideration, − the effect of conjugation site in drug–peptide conjugate design is still largely ignored, but could be very important .…”

Synthesis and Evaluation of a Monomethyl Auristatin E─Integrin αvβ6 Binding Peptide–Drug Conjugate for Tumor Targeted Drug Delivery

“…Tumor-targeted drug delivery approaches, such as PDCs, can improve accumulation of the therapeutic in the diseased tissue, reduce damage to healthy tissues and minimize unwanted side-effects. PDCs have been developed for targeting a wide range of receptors, including integrins, − with a variety of cytotoxic agents including doxorubicin (Dox), paclitaxel (PXT), camptothecin (CPT), and MMAE. ,,,− One emerging therapeutic target in oncology is the integrin α v β 6 , a cell surface receptor highly overexpressed in a wide range of malignancies with little to no expression on normal tissue. − The integrin α v β 6 is present in approximately 90% of pancreatic cancers and nearly all cases of metastatic disease. − Pancreatic cancer remains one of the most lethal malignancies worldwide with a 5 year survival of less than 10%, in part due to limited treatment options. Surgery is the only cure and unfortunately less than 20% of patients are eligible for resection at the time of diagnosis due to the presence of metastasis. − A clear unmet need for more effective and targeted treatments exists.…”