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iRGD, a tumor-penetrating peptide for
tumor-specific drug delivery
Tatiana Hurtado de Mendoza Casaus
Sanford Burnham Medical Research Institute
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
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
Tumor homing and tissue penetration mechanism of iRGD
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
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
iRGD homes to tumors and penetrates into tumor parenchyma
Cancer Cell 2009
22Rv1
iRGD increases drug concentration in the tumor and improves therapeutic efficacy
Cancer Cell 2009
iRGD increases vascular permeability in the tumor in a NRP1 dependent manner
Science 2010
iRGD increases co-administered Abraxane concentration in BT474 breast tumors
and improves its therapeutic efficacy
ABX
ABX-iRGD
ABX+iRGD
Science 2010
iRGD increases co-administered Doxorubicin concentration in 22Rv1 prostate tumors
and improves its therapeutic efficacy
Science 2010
iRGD increases co-administered Trastuzumab concentration in BT474 breast tumors
and improves its therapeutic efficacy
Science 2010
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
Circulation independent targeting of peritoneal tumors by iRGD
A
B
J Con Rel 2015
Circulation-independent dextran uptake in peritoneal tumors mediated by iRGD co-injection
A
B
J Con Rel 2015
Increased therapeutic index of IP-Doxorubicin co-injected with iRGD
B
MKN45P
A
J Con Rel 2015
Co-penetration of iRGD and phage nanoparticles into human metastasis explants
J Con Rel 2015
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
iRGD inhibits spontaneous metastasis in a prostate cancer mouse model
Mol Cancer Ther 2015
iRGD inhibits spontaneous metastasis in a pancreatic cancer mouse model
Mol Cancer Ther 2015
iRGD inhibits cell attachment and migration in a NRP1 dependent manner
Mol Cancer Ther 2015
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
Acknowledgements
Kazuki Sugahara
Tambet Teesalu
Erkki Ruoslahti
Gary Braun
Pablo Scodeller
Andrew Lowy (UCSD Moores Cancer Center)
iRGD AgNP coated on a glass surface repels tumor cells
Mol Cancer Ther 2015