iRGD, a tumor-penetrating peptide for tumor-specific drug delivery
36 Slides8.76 MB
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iRGD, a tumor-penetrating peptide for tumor-specific drug delivery Tatiana Hurtado de Mendoza Casaus Sanford Burnham Medical Research Institute
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Current problems in cancer treatment Some drugs affect not only the cancer cells but also the healthy cells in the body- Toxic side effects – Need for specific delivery of the drugs to the tumor Poor penetration of drugs into the tumor- Affects efficacy of the therapy – Need to improve amount of drug that gets inside the tumor Metastasis – Need to prevent metastasis from happening
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Tumor penetrating peptide iRGD iRGD (CRGDKGPDC) is a peptide discovered by phage display screening for peptides that recognized tumor blood vessels in a human prostate cancer model With its RGD motif is able to bind integrins αvβ3 and αvβ5 present only in tumor vasculature It also contains a CendR motif (R/KXXR/K) that mediates cell penetration through the Neuropilin 1 (NRP1) receptor The CendR motif is exposed after cleavage of the peptide by a cell surface associated protease present in the tumor environment The interaction of its CendR motif with NRP1 induces vascular permeability- Bystander effect
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Tumor homing and tissue penetration mechanism of iRGD
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Presentation Overview iRGD specifically homes to tumors and penetrates deep into tumor tissue iRGD can carry therapeutic drugs to tumors and increase their efficacy iRGD-Drug conjugates iRGD and co-injected drug – Bystander effect Systemic and intraperitoneal administration iRGD prevents metastasis
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Tumor homing and treatment experiments Tumor models: – BT474- Breast Cancer – 22RV1-Prostate Cancer – KPC mice- Pancreatic Cancer Tumor Homing: – Intravenous (iv) injection of FAM labeled iRGD – Circulation time 1-2h – Examine the organs under UV ilumination – Imunofluorescence tissue sections Treatment studies: – IV injection of iRGD-drug conjugate or iRGD free drug – Drugs: Small molecules- Doxorubicine Nanoparticles- Abraxane Monoclonal antibodies- Trastuzumab – Evaluation of the amount of drug in tumor and other tissues – Evaluation of tumor weight or tumor volume
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iRGD homes to tumors and penetrates into tumor parenchyma Cancer Cell 2009
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22Rv1 iRGD increases drug concentration in the tumor and improves therapeutic efficacy Cancer Cell 2009
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iRGD increases vascular permeability in the tumor in a NRP1 dependent manner Science 2010
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iRGD increases co-administered Abraxane concentration in BT474 breast tumors and improves its therapeutic efficacy ABX ABX-iRGD ABX iRGD Science 2010
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iRGD increases co-administered Doxorubicin concentration in 22Rv1 prostate tumors and improves its therapeutic efficacy Science 2010
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iRGD increases co-administered Trastuzumab concentration in BT474 breast tumors and improves its therapeutic efficacy Science 2010
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Peritoneal administration of iRGD Systemically administered drugs partially enter the peritoneal fluid Drug concentration is too low to have significant therapeutic effects Tested iRGD tumor penetration and co-administration of Doxorubicin by intraperitoneal (ip) injection Models: – MKN45P- Gastric cancer – Lovo-6- Colon Cancer – Tumor cells express high levels of αv integrins and NRP1 Tested iRGD penetration into human metastasis explants
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Circulation independent targeting of peritoneal tumors by iRGD A B J Con Rel 2015
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Circulation-independent dextran uptake in peritoneal tumors mediated by iRGD co-injection A B J Con Rel 2015
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Increased therapeutic index of IP-Doxorubicin co-injected with iRGD B MKN45P A J Con Rel 2015
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Co-penetration of iRGD and phage nanoparticles into human metastasis explants J Con Rel 2015
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iRGD inhibits spontaneous metastasis iRGD treatment in two models of spontaneous metastasis – PC3- human prostate cancer (GFP labeled) – LMP- mouse pancreatic cancer (mCherry labeled) Mechanism of metastatic inhibition – RGD or CendR motif dependent – Cell attachment – Cell migration
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iRGD inhibits spontaneous metastasis in a prostate cancer mouse model Mol Cancer Ther 2015
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iRGD inhibits spontaneous metastasis in a pancreatic cancer mouse model Mol Cancer Ther 2015
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iRGD inhibits cell attachment and migration in a NRP1 dependent manner Mol Cancer Ther 2015
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Summary and Future Perspective iRGD specifically targets tumors and penetrates deep into tumor parenchyma iRGD-drug conjugation or co-administration increases therapeutic efficacy iRGD can be used for tumor imaging (iRGD-iron oxide nanoworms for MRI) iRGD can be used for treatment of peritoneal tumors by ip administration iRGD prevents spontaneous metastasis Perform toxicology studies Clinical Trials
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Acknowledgements Kazuki Sugahara Tambet Teesalu Erkki Ruoslahti Gary Braun Pablo Scodeller Andrew Lowy (UCSD Moores Cancer Center)
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iRGD AgNP coated on a glass surface repels tumor cells Mol Cancer Ther 2015
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