27 Jul Sticky Hydrogel Can Deliver Triple Therapy Directly To A Tumor
MedicalResearch.com Interview with:
Dr. Natalie Artzi
Natalie Artzi PhD
Assistant Professor at Brigham and Women’s Hospital, Harvard Medical School
Associate member of the Broad Institute of Harvard and MIT.
MedicalResearch.com: What is the background for this study?
Response: We have shown in the last years that dendrimer:dextran adhesive hydrogels represent a platform with ahuge potential for delivery. In 2015, we were able to report that these gels doped with smart nanoparticles could sense and differentially react with the disease microenvironment (e.g. can sense the tissue microenvironment by detecting the expression of specific genes related with multidrug resistance, Conde et al. PNAS 2015), potentiating targeted drug release and uptake in certain disease settings.
Later, these hydrogels prove to be incredibly useful for miRNA delivery by using the self-assembly of a triple-helix forming miRNA structure that lead to nearly 90% levels of tumor shrinkage two weeks post-gel implantation (Conde et al. Nature Materials 2016a).
Here, we took a step-forward, and used these hydrogels to develop a prophylactic patch for gene, chemo and phototherapy in a triple-combination approach to achieve complete tumor resection when applied to non-resected tumors and to the absence of tumor recurrence when applied following tumor resection (Conde et al. Nature Materials 2016b). This study also identifies the molecular and genetic pathways triggered in response to the three therapeutic modalities − photo-, gene- and chemo-therapy − by tumor gene expression profiling in treated mice.
MedicalResearch.com: What are the main findings?
Response: As corroborated by our in vivo data, the triple therapy (i.e. gene, chemo and photo therapy combination) prevented cancer recurrence following resection, unlike the sham group (control) in which 40% of the tumors recurred following resection. In fact, when the patch was used as a prophylactic measure following tumor resection, complete remission was achieved. Outstandingly, even when the tumor was not resected, noninvasive application of the hydrogel patch resulted in complete tumor abrogation, eliminating the need for surgery. Moreover, our results clearly showed the superiority of the local administration when compared to systemic and intratumoral injections.
We were also able to decipher the molecular and genetic mechanisms behind the three therapy strategies, photo-, gene- and chemo-therapies by tumor gene expression profiling in treated mice. The transcript profiling data revealed that altered genes belong to multiple pathways mainly related with metabolism, intracellular transport mechanisms, receptor signaling, cell cycle and apoptosis, immune and defense response and transcription/translation processes. We were able to decode the mechanisms behind photo-therapy, being mainly regulated by genes controlling intracellular transport, such as membrane trafficking; whereas the mechanisms behind both gene- and chemo-therapy approaches were mainly regulated by transcription and metabolism mechanisms.
MedicalResearch.com: What should readers take away from your report?
Response: This study constructs a rational treatment strategy following a comprehensive scrutiny and understanding of the tumor microenvironment and host response to different therapeutic modalities based on genome wide microarray analysis of locally administrated hydrogel patches containing several tunable therapeutic cargos.
We provide new vistas for the delivery of therapeutic payloads using Nanotechnology. Its clear nowadays that the conventional systemic therapy is not that effective, with new studies reporting that between 1-5% of systemically administered nanoparticles reach the tumors. Local therapeutic vehicle opens up new vistas for effective neoadjuvant therapy, with the opportunity to reprogram cancer cells to undergo apoptosis and to prevent tumor recurrence along with local gene and drug release. Local administration allows delivering much higher ‘effective’ dose while enhancing therapeutic molecules’ stability, minimizing side effects and clearance. Of equal importance is the ability to overcome accumulation of therapeutic molecules in the liver and kidneys following systemic administration, which makes targeting to other organs difficult.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: We believe that a non-invasive intra-colonic application of the local triple-therapy platform would improve treatment efficacy and patients’ quality of life. Patients who present clinically with colorectal cancer undergo an aggressive treatment regimen of surgical tumor resection, which often involves restorative anterior or low anterior resection, and abdominal perineal resection with permanent colostomy. Application of an injectable therapeutic platform via colonoscopy can be used for screening and treatment thus eliminating the need for resection while minimizing side effects. In fact, we are now working on a continuation study in which we utilize a non-invasive technique to evaluate the efficacy and optimize the application of this triple therapy in an orthotopic model in rats/rabbits. In an independent study we are developing the setup and optimize the material to enable its non-invasive application during a colonoscopy procedure to enable local therapy in colorectal tumors in larger animal models. For that, SCID Rats are being induced with colorectal tumors via sub-mucosal injections and treated non-invasively with the triple therapy scaffolds injected to the tumor through the working channel of an endoscope with the appropriate fiber optics to enable local material irradiation.
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Last Updated on July 27, 2016 by Marie Benz MD FAAD