Evaluation of Expansile Nanoparticle Tumor Localization and Efficacy in a Cancer Stem Cell-Derived Model of Pancreatic Peritoneal Carcinomatosis

Herrera, Victoria L. M.; Colby, Aaron H.; Tan, Glaiza A.; Moran, Ann Marie; O’Brien, Michael J.; Colson, Yolonda L.; Ruiz-Opazo, Nelson; Grinstaff, Mark W.

doi:10.2217/nnm-2015-0023

Cited by 20 publications

(43 citation statements)

References 39 publications

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“…However, characterization via dynamic light scattering (DLS) suggested a mean diameter of >200 nm for all particles with a significantly larger average diameter (~360 nm) for the 2% HRF-eNPs (Figure 1a,c). The disparity in results between these two methods are in agreement with previous reports 31,32 and are attributed to the bias toward a low number of larger (100–400 nm) nanoparticles that skew DLS results. An in-depth discussion of the factors that lead to DLS bias toward larger particles ( i.e.…”

Section: Resultssupporting

confidence: 90%

“…20 Moreover, these results are consistent with our previously published findings in an identical model of PDAC-PC demonstrating time-dependent eNP accumulation, wherein 1 h after injection the fluorescent eNPs were still in the peritoneal fluid and not localized to tumors; in contrast, 4 h after injection, tumor localization was significant with negligible particle fluorescence in the peritoneal fluid. 31 By 24 h, tumor localization was prominent with no residual fluorescence in the peritoneal fluid. 31 …”

Section: Resultsmentioning

confidence: 94%

“…31 By 24 h, tumor localization was prominent with no residual fluorescence in the peritoneal fluid. 31 …”

Section: Resultsmentioning

confidence: 94%

“…HFR-eNPs demonstrated negligible cytotoxicity in vitro below concentrations of 37 μ g/mL, similar to previously reported eNP formulations (Figure 1d). 29,31,34–36 …”

Section: Resultsmentioning

confidence: 99%

“…31 Specifically, we determined the sensitivity and specificity of HFR-eNPs for pancreatic peritoneal tumors. Using histopathological examination as the gold standard for positive/negative identification of malignant tissues, a combination of 455 tumor nodules and different normal tissue sites from three rats were surveyed for gross visual identification of HFR-eNP fluorescence as well as histological confirmation of malignancy and fluorescence (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

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Highly Specific and Sensitive Fluorescent Nanoprobes for Image-Guided Resection of Sub-Millimeter Peritoneal Tumors

et al. 2017

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A current challenge in the treatment of peritoneal carcinomatosis is the inability to detect, visualize, and resect small or microscopic tumors of pancreatic, ovarian, or mesothelial origin. In these diseases, the completeness of primary tumor resection is directly correlated with patient survival, and hence, identifying small sub-millimeter tumors (i.e., disseminated disease) is critical. Thus, new imaging techniques and probes are needed to improve cytoreductive surgery and patient outcomes. Highly fluorescent rhodamine-labeled expansile nanoparticles (HFR-eNPs) are described for use as a visual aid during cytoreductive surgery of pancreatic carcinomatosis. The covalent incorporation of rhodamine into ~30 nm eNPs increases the fluorescent signal compared to free rhodamine, thereby affording a brighter and more effective probe than would be achieved by a single rhodamine molecule. Using the intraperitoneal route of administration, HFR-eNPs localize to regions of large (~1 cm), sub-centimeter, and sub-millimeter intraperitoneal tumor in three different animal models, including pancreatic, mesothelioma, and ovarian carcinoma. Tumoral localization of the HFR-eNPs depends on both the material property (i.e., eNP polymer) as well as the surface chemistry (anionic surfactant vs PEGylated noncharged surfactant). In a rat model of pancreatic carcinomatosis, HFR-eNP identification of tumor is validated against gold-standard histopathological analysis to reveal that HFR-eNPs possess high specificity (99%) and sensitivity (92%) for tumors, in particular, sub-centimeter and microscopic sub-millimeter tumors, with an overall accuracy of 95%. Finally, as a proof-of-concept, HFR-eNPs are used to guide the resection of pancreatic tumors in a rat model of peritoneal carcinomatosis.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 94%

“…31 By 24 h, tumor localization was prominent with no residual fluorescence in the peritoneal fluid. 31 …”

Section: Resultsmentioning

confidence: 94%

“…HFR-eNPs demonstrated negligible cytotoxicity in vitro below concentrations of 37 μ g/mL, similar to previously reported eNP formulations (Figure 1d). 29,31,34–36 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Highly Specific and Sensitive Fluorescent Nanoprobes for Image-Guided Resection of Sub-Millimeter Peritoneal Tumors

et al. 2017

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Boolean logic in synthetic biology and biomaterials: Towards living materials in mammalian cell therapeutics

Bressler

Adams

Liu

et al. 2023

Clinical & Translational Med

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Background: The intersection of synthetic biology and biomaterials promises to enhance safety and efficacy in novel therapeutics. Both fields increasingly employ Boolean logic, which allows for specific therapeutic outputs (e.g., drug release, peptide synthesis) in response to inputs such as disease markers or bio‐orthogonal stimuli. Examples include stimuli‐responsive drug delivery devices and logic‐gated chimeric antigen receptor (CAR) T cells. In this review, we explore recent manuscripts highlighting the potential of synthetic biology and biomaterials with Boolean logic to create novel and efficacious living therapeutics. Main body: Collaborations in synthetic biology and biomaterials have led to significant advancements in drug delivery and cell therapy. Borrowing from synthetic biology, researchers have created Boolean‐responsive biomaterials sensitive to multiple inputs including pH, light, enzymes and more to produce functional outputs such as degradation, gel‐sol transition and conformational change. Biomaterials also enhance synthetic biology, particularly CAR T and adoptive T cell therapy, by modulating therapeutic immune cells in vivo. Nanoparticles and hydrogels also enable in situ generation of CAR T cells, which promises to drive down production costs and expand access to these therapies to a larger population. Biomaterials are also used to interface with logic‐gated CAR T cell therapies, creating controllable cellular therapies that enhance safety and efficacy. Finally, designer cells acting as living therapeutic factories benefit from biomaterials that improve biocompatibility and stability in vivo. Conclusion: By using Boolean logic in both cellular therapy and drug delivery devices, researchers have achieved better safety and efficacy outcomes. While early projects show incredible promise, coordination between these fields is ongoing and growing. We expect that these collaborations will continue to grow and realize the next generation of living biomaterial therapeutics.

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Nanoparticle drug‐delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle

Colby

Oberlies

Pearce

et al. 2017

WIREs Nanomed Nanobiotechnol

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Nanoparticle (NP) based drug delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH-responsive expansile nanoparticle (eNP) specifically designed to leverage the intraperitoneal route of administration to treat intraperitoneal malignancies, such as mesothelioma, ovarian and pancreatic carcinomatoses. This review describes the design, evaluation and evolution of the eNP technology and, specifically, a Materials-Based Targeting paradigm that is unique among the many active and passive targeting strategies currently employed among NP delivery systems. pH-responsive eNP swelling is responsible for the extended residence at the target tumor site as well as the subsequent improvement in tumoral drug delivery and efficacy observed with paclitaxel-loaded eNPs (PTX-eNPs) compared to the standard clinical formulation of paclitaxel, Taxol®. Superior PTX-eNP efficacy is demonstrated in two different orthotopic models of peritoneal cancer—mesothelioma and ovarian cancer; in a third model—of pancreatic cancer—PTX-eNPs demonstrated comparable efficacy to Taxol with reduced toxicity. Furthermore, the unique structural and responsive characteristics of eNPs enable them to be used in three additional treatment paradigms, including: treatment of lymphatic metastases in breast cancer; use as a highly-fluorescent probe to visually-guide the resection of peritoneal implants; and, in a two-step delivery paradigm for concentrating separately administered NP and drug at a target site. This case study serves as an important example of using the targeted disease-state’s pathophysiology to inform the NP design as well as the method of use of the delivery system.

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Evaluation of Expansile Nanoparticle Tumor Localization and Efficacy in a Cancer Stem Cell-Derived Model of Pancreatic Peritoneal Carcinomatosis

Abstract: eNPs are a promising tool for the detection and treatment of PPC.

Cited by 20 publications

References 39 publications

Highly Specific and Sensitive Fluorescent Nanoprobes for Image-Guided Resection of Sub-Millimeter Peritoneal Tumors

Highly Specific and Sensitive Fluorescent Nanoprobes for Image-Guided Resection of Sub-Millimeter Peritoneal Tumors

Boolean logic in synthetic biology and biomaterials: Towards living materials in mammalian cell therapeutics

Nanoparticle drug‐delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle

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