Study shows the peptide enhances a vascular access pathway for nanocarriers in pancreatic cancer.

UCLA scientists have unlocked an important mechanism that allows chemotherapy-carrying nanoparticles - extremely small objects between 1 and 100 nanometers (a billionth of a meter) – to directly access pancreatic cancer tumors, thereby improving the ability to kill cancer cells and hence leading to more effective treatment outcome of the disease. The researchers also confirmed the key role of a peptide (an extremely small protein) in regulating vascular access of the nanoparticle to the cancer site.

The discovery is the result of a two-year study co-led by Drs. Huan Meng and André Nel, members of UCLA’s Jonsson Comprehensive Cancer Center and the UCLA California NanoSystems Institute. The findings are important as they demonstrate how the delivery of chemotherapy to pancreatic cancer can be improved significantly through the use of smart-designed nanoparticle features.

The study is published online in the Journal of Clinical Investigation.

Pancreatic ductal adenocarcinoma is generally a fatal disease, with a five-year survival rate of less than 6 percent. The introduction of nanocarriers as delivery vehicles for common chemotherapy agents such as the drug irinotecan, has led to improved survival of patients with this disease. However, the reality is that nanocarriers may not always reach their intended target in sufficient numbers because of a constraint on their ability to transit through the blood vessel wall at the tumor site, leading the encapsulated drugs to be diverted or lost before they can deliver their payload.

A key challenge for scientists is how to help nanoparticles travel to and be retained at tumor sites. This can be accomplished by custom-designed or engineered nanoparticles that overcome common challenges, such as the presence of a dense tissue surrounding the pancreas cancer cells. Prior research has identified a major vascular access mechanism that relies on a vesicle transport system, which can be turned with a peptide called iRGD in the blood vessel wall. iRGD is therefore potentially useful to optimize the delivery of cancer drugs by the nanoparticle to the tumor.

The UCLA research team designed a nanoparticle comprised of a hollow silica core surrounded by a lipid bilayer to enhance the delivery of irinotecan in an animal model with pancreatic cancer. The invention is called a silicasome. The researchers proposed that the therapeutic benefit of the irinotecan containing nanoparticles may be enhanced when combined with the injection of iRGD. The investigators used the nanoparticle plus the iRGD to deliver irinotecan in a robust animal model for pancreatic cancer that closely mimics human disease.

“We demonstrated that the co-administration of the iRGD peptide with the particles can enhance the effectiveness of pancreatic cancer treatment in the tumor model, leading to increased tumor shrinkage, disappearance of metastases and enhanced animal survival” said Meng, an adjunct assistant professor of nanomedicine.

“Utilizing the nanoparticle carrier with a core made of gold nanoparticles also made it possible to obtain evidence for the entry of nanoparticles into the tumor; we looked at the tumor under the electron microscope and observed the particles”, said post-doctoral fellow and first author Xiangsheng Liu. This helped to confirm that in addition to relying on leaky blood vessels for nanoparticles to gain access to the tumor, a major inducible vascular transit pathway is available in the form of the vesicle transport system.

Meng and Nel also collaborated with Dr. Timothy Donahue, chief of gastrointestinal and pancreatic surgery and a Jonsson Comprehensive Cancer Center member, to demonstrate that treatment with the iRGD peptide can enhance tumor cell killing for patient-derived pancreatic cancers, growing subcutaneously in a mouse model. The ability to enhance nanoparticle uptake is dependent on the level of expression of a molecule, called NRP-1, to allow the peptide to bind to the tumor blood vessels.

“In the tumor sample from a patient with high NRP-1 expression, there was a significant improvement in the efficacy of the nanoparticle to induce tumor shrinkage,” said Nel. “The enhancing effect was not seen in a patient tumor sample with a low level of NRP-1 expression on the vasculature. This allows for a personalized approach to the treatment of pancreatic cancer with the iRGD peptide in combination with the nanoparticle.”

The paper by Nel and colleagues is accompanied by a commentary in the Journal of Clinical Investigation that explains the utility of co-administrating iRGD with the silicasome. This commentary also points out that in order to obtain effective treatment outcome with the peptide, it is important to consider the biological variation from patient to patient and one tumor model to another in obtaining success by iRGD treatment, as shown in the UCLA led study.

The research was supported by the National Cancer Institute and the Hirshberg Foundation for Pancreatic Cancer Research.

Article: Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer, Andre E. Nel et al., Journal of Clinical Investigation, doi: 10.1172/JCI92284, published 17 April 2017.

Commentary: Access granted: iRGD helps silicasome-encased drugs breach the tumor barrier, Erkki Ruoslahti, Journal of Clinical Investigation, doi: 10.1172/JCI93955, published 17 April 2017.

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