Synthesis and Evaluation of a Monomethyl Auristatin E─Integrin α_vβ₆ Binding Peptide–Drug Conjugate for Tumor Targeted Drug Delivery

Abstract

Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide–drug conjugates (PDCs) that target tumor-specific receptors such as integrin αvβ6 are emerging as powerful tools to overcome these challenges. The development of an integrin αvβ6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the αvβ6-binding peptide (αvβ6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]­PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin αvβ6-selective internalization, cell binding, and cytotoxicity. Integrin αvβ6-selective tumor accumulation of the [64Cu]­PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]­PDC-1 showed promising in vivo pharmacokinetics. The [natCu]­PDC-1 treatment resulted in prolonged survival of mice bearing αvβ6 (+) tumors (median survival: 77 days, vs αvβ6 (−) tumor group 49 days, and all other control groups 37 days).

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…The work of Sutcliffe et al combines the integrin α v β 6 binding peptide (α v β 6 -BP) with the cytotoxic agent monomethyl auristatin E (MMAE) with the goal to increase efficacy while reducing peripheral toxicity. This peptide–drug conjugate (PDC) was designed to contain a metal chelator (DOTA), enabling radio­labeling with PET radio­nuclides, thus demonstrating utility as a theranostic, and a protease-cleavable linker which is hydrolyzed by an enzyme that is upregulated in cancer cells, resulting in the release of MMAE …”

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…This peptide−drug conjugate (PDC) was designed to contain a metal chelator (DOTA), enabling radiolabeling with PET radionuclides, thus demonstrating utility as a theranostic, and a protease-cleavable linker which is hydrolyzed by an enzyme that is upregulated in cancer cells, resulting in the release of MMAE. 31 Zhou et al report a series of agents targeting fibroblast activation protein (FAP), a potential target for tumor diagnosis and treatment. They demonstrated the radiotracers' ultra-high in vitro and in vivo affinity and specificity for FAP.…”

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315

“…Cancer has become a global health challenge and a major barrier to improving life expectancy worldwide. , Despite considerable progress in anticancer strategies and anticancer drugs, cancer, especially drug-resistant refractory malignancies, remains the major cause of global morbidity and mortality . Among various anticancer strategies, chemotherapy is still the primary option, especially for the advanced and metastatic stages of cancers. , Nevertheless, traditional chemotherapy agents often suffer from potential drug resistance, lack of cancer selectivity, and severe toxicity. − Therefore, developing novel classes of anticancer agents with new mechanisms is of great importance. − Over the last two decades, peptide-based agents have represented a promising approach for cancer prevention and treatments. ,− Strikingly, peptides have exhibited multiple anticancer activities, such as cancer immunotherapy through blocking immune checkpoints, − cytotoxic peptides through membrane disruption/permeation effects, , as well as peptide-drug conjugates (PDCs) through targeting the specific receptor of cancer cells. ,− …”