Targeted Rapamycin Micelle (TRaM) as a therapeutic and for solid organ transplant
Description:
Technology: TRaMs are a novel therapeutic tool for immunosuppression during solid organ transplantation that encompasses a pH sensitive, self-assembling nanocarrier with encapsulated rapamycin and a targeting moiety for endothelial cells. TRaMs internalize more rapidly than non-targeted RaMs, suppress biomarkers of EC inflammation and reduce MHC expression in vitro. Also, in a co-culture model where T cells are pre-sensitized to mouse cardiac endothelial cells (MCECs), TRaM therapy (100 ng ml-1) significantly reduced IL-8 (data not shown) and IFN- (Figure 1-left) compared to controls.
In addition, TRaMs (TR) are superior to free rapamycin (FR) in reducing intimal thickening of aortic allografts 28 days post-transplant in a mouse model. In Figure 2 (right) aortic allografts were harvested and placed in UW solution containing 100 and 1000 ng ml-1 of TR or FR. The intimal expansion was significantly less in the 1000 ng ml-1 TR group compared to the FR group at 28 days. TRaMs have also been shown to be safe in preliminary porcine testing. Overall, this dosing method can likely be provided to the patient prior to a transplant and/or given directly to the donor tissue prior to transplantation to achieve immunosuppression with limited side effects.
Overview: Conventional immunosuppression globally reduces the immunological response by dampening the entire immune system to protect the newly grafted organ. However, side effects such as infections, cancers, and metabolic derangements are among the list of complications that organ transplant recipients suffer while on the necessary organ saving immunosuppressant medications. Furthermore, these therapies have little impact on the cascade induced during IRI. While significant advancements have been made with the design and efficacy of newer immunosuppressive medications, many carry high systemic risk profiles.
Recent studies have shown that treatment of ECs in vitro with the mTOR inhibitor rapamycin, an immunosuppressive drug used clinically, can render ECs tolerogenic. Pre-treatment of EC with rapamycin reduced proliferation of allo-reactive memory T cells, reduced cytokine production, reduced EC activation, and further promoted the differentiation of T regulatory cells in an EC/T cell co-culture system. These elegant studies demonstrate that pre-operative rapamycin therapy provides protection from EC-mediated immune injury.
A potential way to circumvent the systemic side effects of immunotherapeutics like rapamycin and protect the organ graft is to develop strategies to specifically deliver these medications directly to the endothelium of grafted tissues to reduce local injury, inflammation, allopresentation, and the harmful side effects associated with their systemic counterparts.
We have capitalized on these unique findings and have developed a bioengineering solution to deliver rapamycin to the donor organ ECs through endothelial Targeted Rapamycin Micelles (TRaM).
Applications: Pretreatment solution for transplant organ and a therapeutic given to a patient prior to transplant
Advantages: Alleviate the side effects of systemic rapamycin delivery by selective suppression of the immune response
Key Words: Organ transplant, transplantation, nanoparticle, micelle, endothelial cells, cytokines, reperfusion injury, rapamycin, preservation solution, organ storage, immunosuppression
Publication: Nadig, Satish N., et al. "Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity." RSC Advances 5.54 (2015): 43552-43562.
Inventors: Ann-Marie Broome, Suraj Dixit, Satish Nadig, & Carl Atkinson
Patent Status: US 15/107,536; EP 3094314; PCT/US2016/39315
MUSC-FRD Technology ID: P1446; P1577
Licensing Status: This technology is currently licensed to MUSC startup, ToleRaM. Please contact the FRD to be put in touch with ToleRaM
Direct Link: http://musc.technologypublisher.com/technology/14993
Description:
Technology: TRaMs are a novel therapeutic tool for immunosuppression during solid organ transplantation that encompasses a pH sensitive, self-assembling nanocarrier with encapsulated rapamycin and a targeting moiety for endothelial cells. TRaMs internalize more rapidly than non-targeted RaMs, suppress biomarkers of EC inflammation and reduce MHC expression in vitro. Also, in a co-culture model where T cells are pre-sensitized to mouse cardiac endothelial cells (MCECs), TRaM therapy (100 ng ml-1) significantly reduced IL-8 (data not shown) and IFN- (Figure 1-left) compared to controls.
In addition, TRaMs (TR) are superior to free rapamycin (FR) in reducing intimal thickening of aortic allografts 28 days post-transplant in a mouse model. In Figure 2 (right) aortic allografts were harvested and placed in UW solution containing 100 and 1000 ng ml-1 of TR or FR. The intimal expansion was significantly less in the 1000 ng ml-1 TR group compared to the FR group at 28 days. TRaMs have also been shown to be safe in preliminary porcine testing. Overall, this dosing method can likely be provided to the patient prior to a transplant and/or given directly to the donor tissue prior to transplantation to achieve immunosuppression with limited side effects.
Overview: Conventional immunosuppression globally reduces the immunological response by dampening the entire immune system to protect the newly grafted organ. However, side effects such as infections, cancers, and metabolic derangements are among the list of complications that organ transplant recipients suffer while on the necessary organ saving immunosuppressant medications. Furthermore, these therapies have little impact on the cascade induced during IRI. While significant advancements have been made with the design and efficacy of newer immunosuppressive medications, many carry high systemic risk profiles.
Recent studies have shown that treatment of ECs in vitro with the mTOR inhibitor rapamycin, an immunosuppressive drug used clinically, can render ECs tolerogenic. Pre-treatment of EC with rapamycin reduced proliferation of allo-reactive memory T cells, reduced cytokine production, reduced EC activation, and further promoted the differentiation of T regulatory cells in an EC/T cell co-culture system. These elegant studies demonstrate that pre-operative rapamycin therapy provides protection from EC-mediated immune injury.
A potential way to circumvent the systemic side effects of immunotherapeutics like rapamycin and protect the organ graft is to develop strategies to specifically deliver these medications directly to the endothelium of grafted tissues to reduce local injury, inflammation, allopresentation, and the harmful side effects associated with their systemic counterparts.
We have capitalized on these unique findings and have developed a bioengineering solution to deliver rapamycin to the donor organ ECs through endothelial Targeted Rapamycin Micelles (TRaM).
Applications: Pretreatment solution for transplant organ and a therapeutic given to a patient prior to transplant
Advantages: Alleviate the side effects of systemic rapamycin delivery by selective suppression of the immune response
Key Words: Organ transplant, transplantation, nanoparticle, micelle, endothelial cells, cytokines, reperfusion injury, rapamycin, preservation solution, organ storage, immunosuppression
Publication: Nadig, Satish N., et al. "Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity." RSC Advances 5.54 (2015): 43552-43562.
Inventors: Ann-Marie Broome, Suraj Dixit, Satish Nadig, & Carl Atkinson
Patent Status: US 15/107,536; EP 3094314; PCT/US2016/39315
MUSC-FRD Technology ID: P1446; P1577
Licensing Status: This technology is currently licensed to MUSC startup, ToleRaM. Please contact the FRD to be put in touch with ToleRaM
Direct Link: http://musc.technologypublisher.com/technology/14993
Biotinylated bioluminescent probe (YuLu) for the detection of luciferase
Description:The global preclinical imaging market is estimated to reach 910 million in the US alone by 2021, including utilizing bioluminescent probes to study biological processes in vitro and in vivo in real time, image cancer cells, monitor gene delivery and adoptively transferred cells and track pathogen clearance, detect apoptosis and research signal transduction. Current limitations with many bioluminescence probes are the need for an external light source to excite the probe. Lucerifase based probes overcome this issue, however, D-luciferin or other small molecule substrates only last a very short time (15-20 minutes). This requires multiple applications for ongoing imaging, and would not be practical for applications such as tumor removal. There remains a need for a novel bioluminescent luciferase based probe, which does not rely on external light sources and is long lasting.
MUSC researchers have synthesized a novel luciferase-based biotin containing bioluminescent probe, B-YL. This probe contains an aminoluciferin unit as the reporter, a PEG-1000 link for improving cell penetration and a biotin tail for binding to streptavidin. For proof-of-concept, the probe was fitted with an EGF peptide that binds to the EGF receptor, which is overexpressed in high-grade gliomas. In vivo bioluminescence signals of xenograft U87-luc brain tumors was done using the EGF-B-SA-B-YL probe and compared with an untargeted B-SA-B-YL probe. Maximum bioluminescence for the probe was recorded at 24 hours and lasted for six days. In addition, the probe targets are numerous and can be easily modified because of the SA and biotin system.
Overview: Recently, fluorescence imaging has been suggested for use in both cancer detection and resection; however, it is a light dependent method. This strategy uses an external light source to excite exogenously-added fluorescence agents and is not very versatile because many biological molecules present in the body absorb light, and the required external excitation required to generate a response from the fluorescent molecules cannot penetrate body tissues to reach the area of interest.
Although humans and animal models of cancer do not have naturally occurring bioluminescent genes, such as luciferase, the genes or proteins can be introduced via imaging purposes. For instance, either genetically modifying mammalian cells or introducing bacteria encoded with a luciferase gene can be used for cancer detection in vivo. Tumor bioluminescence can be a useful tool during surgery as shown in an animal model. Bioluminescence is able to precisely detect both tumors preoperatively and intra-operatively.
Applications: In vivo imaging, in vitro imaging, tumor imaging, monitoring tumor growth, monitoring gene delivery, tracking pathogen clearance, detecting apoptosis and researching signal transduction.
Advantages: Long lasting probe which does not rely on external excitation, plug-and-play system
Key Words: Research tool, bioluminescence, diagnostic, medical, cancer research, in vivo imaging, animal model, surgery
Publication: Jiang YL, (2017) “A Biotinylated Bioluminescent Probe for Long Lasting Targeted In Vivo Imaging of Xenografted Brain Tumors in Mice”, ACS Chem Neurosci
Inventors: Ann-Marie Broome, PhD and Yu-Lin Jiang, PhD
Patent Status: US Application Filed 3/3/2018
MUSC-FRD Technology ID: P1732
Direct Link: http://musc.technologypublisher.com/technology/25293
Delivery of chemotherapeutics to brain tumors
Description:
Technology: Brain cancer is a life-threatening disease with a poor prognosis. This includes Glioblastoma Multiform (GBM), which has a standard treatment of surgical resection, radiation therapy and concurrent chemotherapy with temozolomide (TMZ). The median survival is 14 months because surgeons are unable to completely remove GBM, radiation does not completely eradicate the tumor tissue and TMZ dosing is limited by toxicity. At standard of care doses, hematologic toxicity of administered TMZ is dose limiting, implying that an increased intratumoral concentration of TMZ could be beneficial to treat GBM.
MUSC has developed TMZ-loaded PEG-PE and PHC micelles as a novel treatment for GBM. The TMZ-loaded micelle is designed to increase permeation across the BBB and is conjugated to a novel moiety targeting the PDGF receptor on GBM tumors. A biocompatible coating reduces cytotoxicity and improves circulation, and a pH dependent triggered carrier releases TMZ at the site of the tumor. Data gathered suggests that the targeted micelles (PMTMZ) increase efficiency of cell killing at lower concentrations of TMZ compared to untargeted TMZ (MTMZ) and free TMZ.
PMTMZ also has superior tumor accumulation compared to MTMZ in brain tumors (white dashed circle) in vivo, imaged by comparing 680 nm flourescence after the micelles were functionalized with a 680 nm flurophore.
Overview: Brain cancer is a life-threatening disease with a 5-year survival rate of 33% (2005-2011), results in more than 15 thousand deaths annually and has an annual incidence of 7.27 per 100,000 people, accounting for 2% of all cancers and 21.1% of pediatric cancers. GBM occurs in 2-3 people per 100,000, with a dismal prognosis and median survival of 14 months. The standard of care therapy includes TMZ, a prodrug that is converted by pH changes in the cytoplasm of cells. This drug has been used for decades, but is unable to cure patients.
Applications: Brain cancer, Glioblastoma multiform (GBM) cancer
Advantages: Lower toxicity, targeting GBM tumor, BBB permeation, pH dependent release, accumulation of payload at tumor site
Key Words: Cancer treatment, Brain tumor, Glioblastoma, glioma, BBB permeation, Micelle, drug delivery, temozolomide, TMZ, Imidazotetrazine, prodrug, nanoparticle, nanocarrier
Publication: Miller et al. “Delivery of a drug cache to glioma cells overexpressing platelet-derived growth factor receptor using lipid nanocarriers” (2016), Nanomedicine 11:6, 581-95.
Inventors: Ann-Marie Broome, Suraj Dixit, Amy-Lee Bredlau
Patent Status: CT application filed 2/23/18
MUSC-FRD Technology ID: P1714
Direct Link: http://musc.technologypublisher.com/technology/25300
Description:
Technology: Brain cancer is a life-threatening disease with a poor prognosis. This includes Glioblastoma Multiform (GBM), which has a standard treatment of surgical resection, radiation therapy and concurrent chemotherapy with temozolomide (TMZ). The median survival is 14 months because surgeons are unable to completely remove GBM, radiation does not completely eradicate the tumor tissue and TMZ dosing is limited by toxicity. At standard of care doses, hematologic toxicity of administered TMZ is dose limiting, implying that an increased intratumoral concentration of TMZ could be beneficial to treat GBM.
MUSC has developed TMZ-loaded PEG-PE and PHC micelles as a novel treatment for GBM. The TMZ-loaded micelle is designed to increase permeation across the BBB and is conjugated to a novel moiety targeting the PDGF receptor on GBM tumors. A biocompatible coating reduces cytotoxicity and improves circulation, and a pH dependent triggered carrier releases TMZ at the site of the tumor. Data gathered suggests that the targeted micelles (PMTMZ) increase efficiency of cell killing at lower concentrations of TMZ compared to untargeted TMZ (MTMZ) and free TMZ.
PMTMZ also has superior tumor accumulation compared to MTMZ in brain tumors (white dashed circle) in vivo, imaged by comparing 680 nm flourescence after the micelles were functionalized with a 680 nm flurophore.
Overview: Brain cancer is a life-threatening disease with a 5-year survival rate of 33% (2005-2011), results in more than 15 thousand deaths annually and has an annual incidence of 7.27 per 100,000 people, accounting for 2% of all cancers and 21.1% of pediatric cancers. GBM occurs in 2-3 people per 100,000, with a dismal prognosis and median survival of 14 months. The standard of care therapy includes TMZ, a prodrug that is converted by pH changes in the cytoplasm of cells. This drug has been used for decades, but is unable to cure patients.
Applications: Brain cancer, Glioblastoma multiform (GBM) cancer
Advantages: Lower toxicity, targeting GBM tumor, BBB permeation, pH dependent release, accumulation of payload at tumor site
Key Words: Cancer treatment, Brain tumor, Glioblastoma, glioma, BBB permeation, Micelle, drug delivery, temozolomide, TMZ, Imidazotetrazine, prodrug, nanoparticle, nanocarrier
Publication: Miller et al. “Delivery of a drug cache to glioma cells overexpressing platelet-derived growth factor receptor using lipid nanocarriers” (2016), Nanomedicine 11:6, 581-95.
Inventors: Ann-Marie Broome, Suraj Dixit, Amy-Lee Bredlau
Patent Status: CT application filed 2/23/18
MUSC-FRD Technology ID: P1714
Direct Link: http://musc.technologypublisher.com/technology/25300
