Periodic Reporting for period 1 - EmboPore (An injectable and programmable drug-eluting embolic device)
Período documentado: 2023-06-01 hasta 2024-11-30
Chemoembolization is a minimally invasive cancer treatment that blocks blood flow to tumors while delivering localized chemotherapy. It is primarily used for liver cancer, kidney cancer, and neuroendocrine tumors. Liver cancer, particularly Hepatocellular Carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer deaths worldwide, with HCC accounting for 90% of liver cancer cases. HCC is typically managed with transarterial chemoembolization (TACE), which aims to control, not cure, the disease. Less than 30% of patients qualify for curative treatments like surgery or liver transplants, leaving most to receive palliative therapies such as TACE, transarterial embolization, chemotherapy, and radioembolization.
TACE combines embolization (blocking blood flow) with drug delivery. However, conventional TACE has limitations. Blocking blood flow prevents effective drug delivery, reducing treatment efficacy. Additionally, the sudden lack of blood supply creates extreme hypoxia in the tumor, triggering harmful signals like VEGF and HIF-1, which promote tumor growth, metastasis, and drug resistance.
Our proposed Solution: A novel two-step platform, EmboPore, addresses these issues. Porous degradable beads act as "mini-stents," allowing gradual drug delivery while maintaining partial blood flow. Over time, the beads degrade, fully blocking blood vessels to induce controlled tissue necrosis. This gradual approach reduces harmful stress signals and enhances drug delivery. The biodegradable, injectable design is compatible with standard clinical catheters and offers potential applications beyond HCC, including metastatic liver and gastrointestinal diseases.
Our results showed that porous drug eluting beads were superior than dense ones. Moreover by combining two drugs with synergic activity we obtained a dramatic efficacy against liver tumor in rat models of orthotopic liver cancer. The finding are very promising and can be a basis for future clinical translation.
TACE combines embolization (blocking blood flow) with drug delivery. However, conventional TACE has limitations. Blocking blood flow prevents effective drug delivery, reducing treatment efficacy. Additionally, the sudden lack of blood supply creates extreme hypoxia in the tumor, triggering harmful signals like VEGF and HIF-1, which promote tumor growth, metastasis, and drug resistance.
Our proposed Solution: A novel two-step platform, EmboPore, addresses these issues. Porous degradable beads act as "mini-stents," allowing gradual drug delivery while maintaining partial blood flow. Over time, the beads degrade, fully blocking blood vessels to induce controlled tissue necrosis. This gradual approach reduces harmful stress signals and enhances drug delivery. The biodegradable, injectable design is compatible with standard clinical catheters and offers potential applications beyond HCC, including metastatic liver and gastrointestinal diseases.
Our results showed that porous drug eluting beads were superior than dense ones. Moreover by combining two drugs with synergic activity we obtained a dramatic efficacy against liver tumor in rat models of orthotopic liver cancer. The finding are very promising and can be a basis for future clinical translation.
We aimed to investigate a novel drug delivery system (DDS) fabricated using a microfluidics platform in a clinically relevant and advanced rat liver cancer model. Currently, transarterial chemoembolization (TACE), which combines blockage of the tumor's hepatic arterial blood supply with chemotherapy, is the most common treatment for intermediate and advanced-stage unresectable hepatocellular carcinoma (HCC). However, HCC remains a challenging disease with poor prognosis and high recurrence rates (~30%). This is partly due to the hypoxic, pro-angiogenic, and pro-cancerous microenvironment created by both the tumor niche and the embolization treatment itself.
Existing TACE approaches are limited by rapid drug clearance, non-bioresorbable and polydisperse particles, and inadequate adaptation to the hypoxic tumor microenvironment. These shortcomings often render embolization treatments ineffective or even harmful. To address these challenges, we developed biodegradable, calibrated polymeric carriers with controlled drug release capabilities. These carriers can deliver a combination of drugs, such as the cytotoxic agent doxorubicin (DOX) and the hypoxia-activated prodrug tirapazamine (TPZ), to enhance therapeutic outcomes.
Through extensive in vivo studies in a rat liver embolization model, we compared porous and non-porous particle morphologies. Our findings highlight that particle morphology significantly influences clinical outcomes. Additionally, the combination therapy of DOX and TPZ outperformed monotherapies, demonstrating the importance of tailoring treatments to the hypoxic tumor microenvironment. This suggests that the traditional approach of simultaneous vascular blockage and chemotherapy may not be optimal for treating blood-rich solid tumors.
Our novel strategy and embolic DDS represent a promising step forward in cancer treatment. We believe this approach warrants further clinical testing and could be expanded to address other types of cancers.
The comprehensive study led to a published paper (highlighted in the cover):
Amoyav B. , Bloom AI, Goldstein Y., Miller R., Sharam M., Fluksman A, Benny O. Drug-eluting porous embolic microspheres for trans-arterial delivery of dual synergistic anticancer therapy for the treatment of liver cancer. Adv Healthc Mater. 2023 Jun 14:e2301548.
A provisional patent application
and the technology is now being optioned for licensing trough Yissum (HUJI TTO).
Existing TACE approaches are limited by rapid drug clearance, non-bioresorbable and polydisperse particles, and inadequate adaptation to the hypoxic tumor microenvironment. These shortcomings often render embolization treatments ineffective or even harmful. To address these challenges, we developed biodegradable, calibrated polymeric carriers with controlled drug release capabilities. These carriers can deliver a combination of drugs, such as the cytotoxic agent doxorubicin (DOX) and the hypoxia-activated prodrug tirapazamine (TPZ), to enhance therapeutic outcomes.
Through extensive in vivo studies in a rat liver embolization model, we compared porous and non-porous particle morphologies. Our findings highlight that particle morphology significantly influences clinical outcomes. Additionally, the combination therapy of DOX and TPZ outperformed monotherapies, demonstrating the importance of tailoring treatments to the hypoxic tumor microenvironment. This suggests that the traditional approach of simultaneous vascular blockage and chemotherapy may not be optimal for treating blood-rich solid tumors.
Our novel strategy and embolic DDS represent a promising step forward in cancer treatment. We believe this approach warrants further clinical testing and could be expanded to address other types of cancers.
The comprehensive study led to a published paper (highlighted in the cover):
Amoyav B. , Bloom AI, Goldstein Y., Miller R., Sharam M., Fluksman A, Benny O. Drug-eluting porous embolic microspheres for trans-arterial delivery of dual synergistic anticancer therapy for the treatment of liver cancer. Adv Healthc Mater. 2023 Jun 14:e2301548.
A provisional patent application
and the technology is now being optioned for licensing trough Yissum (HUJI TTO).
The study lead to mant innovations beyond the state of the art, and it was found to be patentable due to these innovaitons. The main innovations in our research:
1) We have described in details a novel and first in its kind in vitro model for embolism based on microfluidics
2) We have described porous particles with high loading of drugs in the scaffold
3) we have described a novel synergic therapy of chemotherapy drug with hypoxia-activated drug. The synergy was shown in vitro and in vivo in liver cancer rat model.
1) We have described in details a novel and first in its kind in vitro model for embolism based on microfluidics
2) We have described porous particles with high loading of drugs in the scaffold
3) we have described a novel synergic therapy of chemotherapy drug with hypoxia-activated drug. The synergy was shown in vitro and in vivo in liver cancer rat model.