Abstract 750: Nanoliposomal targeting of Ephrin receptor A2 (EphA2): Clinical translation

Kamoun, Walid S.; Oyama, Shinji; Kornaga, Tad; Feng, Theresa; Luus, Lia; Pham, Minh Thu; Kirpotin, Dmitri B.; Marks, James D.; Geddie, Melissa L.; Xu, Lihui; Lugovskoy, Alexey A.; Murphy, Monica L.; Morrisson, Carl; Drummond, Daryl C.

doi:10.1158/1538-7445.am2016-750

Cited by 2 publications

(2 citation statements)

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“…Merrimack Pharmaceuticals (Cambridge, MA), who developed Onivyde earlier, is currently investigating (NCT03076372) an ephrin receptor A2 (EphA2) antibodydirected liposomal docetaxel in solid tumors, including gastric and pancreatic cancer. The immunohistochemistry of clinical tumor samples was used to develop a framework for screening patients for inclusion in the clinical trial based on EphA2 expression in the patient's tumor (Kamoun et al, 2016). Overall, these approaches suggest that liposomes have many advantages in mitigating the cytotoxicity of chemotherapeutics and other small molecules, and in augmenting therapeutic benefit by improving drug delivery and release in the tumor.…”

Section: Payloads and Applications In Gi Cancer Therapymentioning

confidence: 99%

Liposomal Nanostructures for Drug Delivery in Gastrointestinal Cancers

Das

Huang

2018

J Pharmacol Exp Ther

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Gastrointestinal (GI) cancers like liver, pancreatic, colorectal, and gastric cancer remain some of the most difficult and aggressive cancers. Nanoparticles like liposomes had been approved in the clinic for cancer therapy dating as far back as 1995. Over the years, liposomal formulations have come a long way, facing several roadblocks and failures, and advancing by optimizing formulations and incorporating novel design approaches to navigate therapeutic delivery challenges. The first liposomal formulation for a GI cancer drug was approved recently in 2015, setting the stage for further clinical developments of liposomebased delivery systems for therapies against GI malignancies. This article reviews the design considerations and strategies that can be used to deliver drugs to GI tumors, the wide range of therapeutic agents that have been explored in preclinical as well as clinical studies, and the current therapies that are being investigated in the clinic against GI malignancies. This work is supported by the National Institutes of Health [Grant CA198999]. L.H. is a cofounder of OncoTrap, Inc. No other potential conflicts of interest relevant to this article are reported.

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Section: Payloads and Applications In Gi Cancer Therapymentioning

confidence: 99%

Liposomal Nanostructures for Drug Delivery in Gastrointestinal Cancers

Das

Huang

2018

J Pharmacol Exp Ther

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“…Recent work by our group , and others − demonstrated that combination therapies using light-activated nanoconstructs synergistically enhance efficacy. These, along with ongoing clinical efforts to introduce molecular specificity to chemotherapy-encapsulating nanomedicines for PDAC and other cancers (MM-310, Ephrin A2 targeted liposomal docetaxel), accentuate the high translational potential of our Cet-PINs. As a proof of concept, we also show that encapsulation of the front-line PDAC chemotherapeutics gemcitabine hydrochloride, 5-fluorouracil, and oxaliplatin, within the Cet-PINs, yields chemo-per-Cet payloads that are not achievable with direct antibody conjugates.…”

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confidence: 99%

Impacting Pancreatic Cancer Therapy in Heterotypic in Vitro Organoids and in Vivo Tumors with Specificity-Tuned, NIR-Activable Photoimmunonanoconjugates: Towards Conquering Desmoplasia?

et al. 2019

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Despite untiring efforts to develop therapies for pancreatic ductal adenocarcinoma (PDAC), survival statistics remain dismal, necessitating distinct approaches. Photodynamic priming (PDP), which improves drug delivery and combination regimens, as well as tumor photodestruction are key attributes of photodynamic therapy (PDT), making it a distinctive clinical option for PDAC. Localized, high-payload nanomedicine-assisted delivery of photosensitizers (PSs), with molecular specificity and controlled photoactivation, thus becomes critical in order to reduce collateral toxicity during more expansive photodynamic activation procedures with curative intent. As such, targeted photoactivable lipid-based nanomedicines are an ideal candidate but have failed to provide greater than twofold cancer cell selectivity, if at all, due to their extensive multivariant physical, optical, and chemical complexity. Here, we report (1) a systematic multivariant tuning approach to engineer (Cet, anti-EGFR mAb) photoimmunonanoconjugates (PINs), and (2) stroma-rich heterotypic PDAC in vitro and in vivo models incorporating patient-derived pancreatic cancer-associated fibroblasts (PCAFs) that recapitulate the desmoplasia observed in the clinic. These offer a comprehensive, disease-specific framework for the development of Cet-PINs. Specificity-tuning of the PINs, in terms of PS lipid anchoring, electrostatic modulation, Cet orientation, and Cet surface densities, achieved ∼16-fold binding specificities and rapid penetration of the heterotypic organoids within 1 h, thereby providing a ∼16-fold enhancement in molecular targeted NIR photodestruction. As a demonstration of their inherent amenability for multifunctionality, encapsulation of high payloads of gemcitabine hydrochloride, 5-fluorouracil, and oxaliplatin within the Cet-PINs further improved their antitumor efficacy in the heterotypic organoids. In heterotypic desmoplastic tumors, the Cet-PINs efficiently penetrated up to 470 μm away from blood vessels, and photodynamic activation resulted in substantial tumor necrosis, which was not elicited in T47D tumors (low EGFR) or when using untargeted constructs in both tumor types. Photodynamic activation of the Cet-PINs in the heterotypic desmoplastic tumors resulted in collagen photomodulation, with a 1.5-fold reduction in collagen density, suggesting that PDP may also hold potential for conquering desmoplasia. The in vivo safety profile of photodynamic activation of the Cet-PINs was also substantially improved, as compared to the untargeted constructs. While treatment using the Cet-PINs did not cause any detriment to the mice's health or to healthy proximal tissue, photodynamic activation of untargeted constructs induced severe acute cachexia and weight loss in all treated mice, with substantial peripheral skin necrosis, muscle necrosis, and bowel perforation. This study is the first report demonstrating the true value of molecular targeting for NIR-activable PINs. These constructs integrate high payload delivery, efficient photodestruction,...

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Abstract 750: Nanoliposomal targeting of Ephrin receptor A2 (EphA2): Clinical translation

Cited by 2 publications

References 0 publications

Liposomal Nanostructures for Drug Delivery in Gastrointestinal Cancers

Liposomal Nanostructures for Drug Delivery in Gastrointestinal Cancers

Impacting Pancreatic Cancer Therapy in Heterotypic in Vitro Organoids and in Vivo Tumors with Specificity-Tuned, NIR-Activable Photoimmunonanoconjugates: Towards Conquering Desmoplasia?

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