Delivery of siRNA to tumors: the first nanovector has gone... the second one went...
Multi-stage nanovector siRNA delivery system to cancer tumors
Nanonwesnet based on UTHealth materials: Multistage nanovector system provides sustained delivery of siRNA cancer therapeutic in miceA new study by scientists from the Health Science Center
The University of Texas (The University of Texas – UT) in Houston and the Anderson Cancer Center (MD Anderson Cancer Center) UT can significantly bring the practical application of promising experimental cancer treatment methods – the use of small interfering RNAs (siRNA).
The introduction of siRNA is part of an innovative strategy that reduces the activity of cancer-related genes, which is already widely used to treat other diseases.
In the May issue of the journal Cancer Research, scientists reported that a multi-stage nanovector siRNA delivery system significantly lengthens the therapeutic effect of treatment, which was demonstrated in two independent models of metastatic ovarian cancer in mice (Takemi Tanaka et al., Sustained Small Interfering RNA Delivery by Mesoporous Silicon Particles).
The researchers reported that one dose of intravenously injected siRNAs targeted at the EphA2 cancer protein for three weeks causes the same degree of tumor reduction, which is achieved by six doses without the use of a multi-stage nanovector system over the same period of time.
"The multi-stage delivery system is revolutionary, as it allows therapeutic cargo to penetrate the biological barriers of the body and reach the goal. In addition, it helps to release therapeutic agents directly into the blood for a long period of time, which is unprecedented," says Mauro Ferrari, head of the Department of Nanomedicine and Biomedical Engineering at UT Medical School in Houston, which is part of the UT Health Science Center. "We are very pleased with the results of our work, as it represents the first test of the therapeutic benefits of a multi-stage delivery system in animal models of cancer."
The multi-stage nanovector system consists of carrier particles made of mesoporous silicon (stage 1 – microparticles, S1MP), with a size about 100 times smaller than the thickness of a hair, which can be loaded with tiny fat bubbles called nanoliposomes (dioleoyl phosphatidylcholine – dioleoyl phosphatidylcholine – DOPC) containing EphA2 siRNAs focused on the cancer protein. The system provides the isolation of neutral nanoliposomes and siRNAs.
A single administration of S1MP loaded with EphA2-siRNA-DOPC significantly reduces tumor severity, angiogenesis and cell proliferation compared to the control administration of siRNA alone, without leading to any significant changes in serum biochemistry or in proinflammatory cytokines.
"This is an exciting development, as RNA interference has proven itself well in animal models, but has such a short half-life that it requires frequent use. The dosage calculated for a three–week period is much closer in duration to the dosage required for proper testing of this method of therapy in a clinical setting," says Anil Sood, MD, professor of the Department of Gynecological Oncology and Cancer Biology at UT Anderson Cancer Center.
A multi-stage nanovector delivery system was developed in the Ferrari laboratory, and liposomal siRNA was developed at the Anderson Cancer Center.
"We have for the first time presented in vivo therapeutic confirmation of the effectiveness of a new multi–stage siRNA delivery system for long-term "shutdown" of genes with wide application possibilities in pathology," Takemi Tanaka, PhD, researcher at the Department of Nanomedicine and Biomedical Engineering at UT Medical School in Houston, and other researchers write in the article.
"The EphA2 cancer protein is an important target, since its overexpression is observed in 70% of ovarian cancer cases and is largely associated with low survival and a higher probability of tumor metastasis," says Gabriel Lopez–Berestein, MD, professor of experimental therapies at the Anderson UT Cancer Center.
Overexpression of EphA2 is also observed in melanoma, breast and lung cancer and is associated with a poor prognosis for patients. The protein is not present in normal tissues, and it cannot be affected by more traditional pharmacological approaches.
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