ABSTRACT
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 â¼30 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 (â¼1 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.
Subject(s)
Lung Neoplasms/diagnostic imaging , Mesothelioma/diagnostic imaging , Optical Imaging , Ovarian Neoplasms/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Peritoneal Neoplasms/diagnostic imaging , Animals , Cell Survival/drug effects , Combined Modality Therapy , Cytoreduction Surgical Procedures , Disease Models, Animal , Female , Fluorescent Dyes/administration & dosage , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacokinetics , Injections, Intraperitoneal , Lung Neoplasms/surgery , Mesothelioma/surgery , Mesothelioma, Malignant , Mice , Mice, Nude , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Ovarian Neoplasms/surgery , Pancreatic Neoplasms/surgery , Peritoneal Neoplasms/surgery , Rats , Rhodamines/administration & dosage , Rhodamines/chemistry , Rhodamines/pharmacokinetics , Surface-Active Agents/chemistry , Tissue Distribution , Tumor Cells, CulturedABSTRACT
AIM: To evaluate the tumor localization and efficacy pH-responsive expansile nanoparticles (eNPs) as a drug delivery system for pancreatic peritoneal carcinomatosis (PPC) modeled in nude rats. METHODS & MATERIALS: A Panc-1-cancer stem cell xeno1graft model of PPC was validated in vitro and in vivo. Tumor localization was tracked via in situ imaging of fluorescent eNPs. Survival of animals treated with paclitaxel-loaded eNPs (PTX-eNPs) was evaluated in vivo. RESULTS: The Panc-1-cancer stem cell xenograft model recapitulates significant features of PPC. Rhodamine-labeled eNPs demonstrate tumor-specific, dose- and time-dependent localization to macro- and microscopic tumors following intraperitoneal injection. PTX-eNPs are as effective as free PTX in treating established PPC; but, PTX-eNPs result in fewer side effects. CONCLUSION: eNPs are a promising tool for the detection and treatment of PPC.
Subject(s)
Carcinoma/drug therapy , Drug Delivery Systems , Nanoparticles/administration & dosage , Pancreatic Neoplasms/drug therapy , Animals , Carcinoma/pathology , Disease Models, Animal , Humans , Nanoparticles/chemistry , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Paclitaxel/administration & dosage , Paclitaxel/chemistry , Pancreatic Neoplasms/pathology , Peritoneum/drug effects , Peritoneum/pathology , Rats , Rhodamines/chemistry , Xenograft Model Antitumor AssaysABSTRACT
A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo-angiogenesis and invasiveness in nude(nu/nu) rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface 'common receptor coordinator', DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma.
