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Redirecting extracellular proteases to molecularly guide radiosensitizing drugs to tumors
Dina V Hingorani1, Jessica L Crisp2, Matthew K Doan1
1Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
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.
Insights
Researchers developed targeted drug delivery systems for cancer radiotherapy. Protease-activated cell-penetrating peptides showed more promise than antibody-drug conjugates for delivering radiosensitizers to tumors.
Area of Science:
- Oncology
- Drug Delivery
- Radiotherapy
Background:
- Combined radiotherapy and chemotherapy for advanced cancers have poor curability and severe side effects.
- Developing tumor-specific radiosensitizers is crucial for improving treatment efficacy and reducing toxicity.
- Current strategies face challenges in achieving precise tumor targeting of radiosensitizing drugs.
Purpose of the Study:
- To evaluate two distinct drug delivery platforms for enhancing tumor selectivity of small molecule radiosensitizers.
- To compare the efficacy of antibody-drug conjugates versus protease-activated cell-penetrating peptides in combination with radiotherapy.
- To investigate the potential of harnessing matrix metalloproteinases for targeted drug delivery.
Main Methods:
- Synthesized antibody-drug conjugates and activatable cell-penetrating peptide scaffolds.
- Conjugated a DNA damage response inhibitor (AZD7762) to both platforms.
- Utilized tumor-overexpressed receptors for antibody targeting and matrix metalloproteinase cleavage for peptide targeting.
- Administered drug delivery platforms in combination with radiotherapy to assess tumor radiosensitization.
Main Results:
- Antibody-drug conjugates targeting cell surface receptors showed limited efficacy with the radiosensitizer AZD7762.
- Activatable cell-penetrating peptide scaffolds demonstrated accumulation within tumors via matrix metalloproteinase cleavage.
- Protease-triggered cell-penetrating peptides proved advantageous over antibody-drug conjugates for delivering small molecule amine radiosensitizers.
Conclusions:
- Protease-activated cell-penetrating peptide scaffolds offer a promising strategy for targeted radiosensitizer delivery.
- This approach enhances tumor selectivity by exploiting tumor-specific matrix metalloproteinase activity.
- Targeted delivery systems are essential for improving the therapeutic ratio of radiotherapy in advanced cancers.
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