Tumor Specific Radiosensitization Through Drug Conjugated Activatable Cell Penetrating Peptides

Sunil J Advani

Session title: (DPD 04) Biology 1 - GI, GU, and Breast CancersSession date: 2014-09-14 16:45Location: Room D-2 Monitor number: 2

Activatable Cell Penetrating Peptides to Preferentially Deliver Tumor Radiosensitizing Monomethyl Auristatin E

Take Home Points MMAE is a potent tumoricidal and radiosensitizing drug ACPP-cRGD-MMAE can be targeted to irradiated tumors with improved tumor

regression compared to non-targeted MMAE delivery IR induced alterations in tumor microenvironment protease activity can be non-

invasively imaged using ratiometric ACPP molecules 

PANC1 cells were treated with vehicle (open bar) or MMAE (filled bar) and IR. A) Neutral Comet Assay. comets images and mean B) gH2Ax foci formation. C) SF2 clonogenic survival. *p<0.01, **p<0.001.  

MMAE is a Potent Radiosensitizer

Ratiometric ACPP Accumulation in Irradiated and Non-Irradiated Tumor Xenografts

Tumor xenografts were grown in both hindlimbs. The right tumor was irradiated and the left tumor shielded. Ratiometric ACPP was IV injected. Ratiometric ACPP has Cy5 on polycationic cell penetrating peptide and Cy7 on autoinhibitory polyanionic peptide portion. Upon linker peptide cleavage by MMPs, Cy5:Cy7 emission ratio increases. Cy5:Cy7 emission ratio measured (pseudocolor scale at far right) of tumors in situ and excised.

Targeted MMAE in Combination with Irradiation Produces Sustained Tumor Xenograft Regression

PANC-1 tumor xenografts were grown to 200 mm3. 6 nmoles of MMAE was given on days 0, 1 either as free drug or conjugated as ACPP-cRGD-MMAE. 3 Gy was given on days 1 and 2. Tumors were measured biweekly. Chart on right shows % of mice whose tumors at day 25 were smaller than their initial tumor volume on day 0.