Redirecting extracellular proteases to molecularly guide radiosensitizing drugs to tumors. (July 2020)

• Record Type: Journal Article
• Authors: Hingorani, Dina V.; Crisp, Jessica L.; Doan, Matthew K.; Camargo, Maria F.; Quraishi, Maryam A.; Aguilera, Joseph; Gilardi, Mara; Gross, Larry A.; Jiang, Tao; Li, Wei T.; Ongkeko, Weg M.; Cohen, Ezra E.W.; Gutkind, J. Silvio; Adams, Stephen R.; Advani, Sunil J.
• Is Part Of: Biomaterials. Volume 248(2020:Jul.)
• Publication Date: 2020-07
• Subjects: Targeted drug delivery -- Cell penetrating peptides -- Antibody drug conjugates -- Radiosensitization -- Radiotherapy; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2020.120032
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Patients with advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and treatment side effects severe. Drugs sensitizing tumors to radiotherapy have been developed to improve cell kill, but tumor specificity remains challenging. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting using peptide-based drug conjugates. We attached an inhibitor of the DNA damage response to antibody or cell penetrating peptides. Antibody drug conjugates honed in on tumor overexpressed cell surface receptors with high specificity but lacked efficacy when conjugated to the DNA damage checkpoint kinase inhibitor AZD7762. As an alternative approach, we synthesized activatable cell penetrating peptide scaffolds that accumulated within tumors based on matrix metalloproteinase cleavage. While matrix metalloproteinases are integral to tumor progression, they have proven therapeutically elusive. We harnessed these pro-tumorigenic extracellular proteases to spatially guide radiosensitizer drug delivery using cleavable activatable cell penetrating peptides. Here, we tested the potential of these two drug delivery platforms targeting distinct tumor compartments in combination with radiotherapy and demonstrate the advantages of protease triggered cell penetrating peptide scaffolds over antibody drug conjugates to deliver small molecule amine radiosensitizers. Graphical abstract: Image 1 Highlights: Cell penetrating peptide (CPP) drug conjugates radiosensitize. Activatable cell penetrating peptide (ACPP) engineered scaffolding cloaks CPPs. Tumor overexpressed extracellular proteases cleave ACPPs and guide CPP delivery. ACPP scaffolds increase tumor targeting and decreases normal tissue accumulation. Radiosensitizers conjugated to ACPP given with radiotherapy increase tumor control.