The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis

Colson, Yolonda L.; Liu, Rong; Southard, Emily; Schulz, Morgan D.; Wade, Jacqueline E.; Griset, Aaron P.; Zubris, Kimberly Ann V.; Padera, Robert F.; Grinstaff, Mark W.

doi:10.1016/j.biomaterials.2010.09.059

Cited by 51 publications

(80 citation statements)

References 49 publications

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“…A size reduction leads to an increased surface area and according to the NoyesWitney equation to an increased dissolution velocity. Thus, nanosizing is a potential technique to enhance dissolution and bioavailability of poorly water soluble drugs such as paclitaxel (8). Breakage of micronized drug crystals into nanoparticles creates an increased particle surface area and during milling due to the change of Gibbs free energy, a thermodynamically unstable nanosuspension can be formed.…”

Section: Introductionmentioning

confidence: 99%

Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment

et al. 2012

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Purpose: To develop a nanocrystalline paclitaxel formulation with a high paclitaxel-to-stabilizer ratio which can be used for hyperthermic intraperitoneal chemotherapy (HIPEC).Methods: Paclitaxel (PTX) nanocrystals were prepared via wet milling using Pluronic F127 ® as stabilizer. The suitability of paclitaxel nanosuspensions for HIPEC treatment was evaluated by analyzing the cytotoxicity of both stabilizer and formulation, and by determining the maximum tolerated dose (MTD) and bioavailability. The effect on tumor growth was evaluated by magnetic resonance imaging (MRI) at day 7 and 14 after HIPEC treatment in rats with peritoneal carcinomatosis of ovarian origin.Results: Monodisperse nanosuspensions (±400 nm) were developed using Pluronic F127 ® as single additive. The cytotoxicity and MTD of this nanocrystalline formulation was similar compared to Taxol ® , while its bioavailability was higher. MRI data after HIPEC treatment with a PTX nanocrystalline suspension showed a significant reduction of tumor volume compared to the nontreated group. Although no significant differences on tumor volume were observed between Taxol ® and the nanosuspension, the rats treated with the nanosuspension recovered faster following the HIPEC procedure.Conclusion: Nanosuspensions with a high paclitaxel-to-stabilizer ratio are of interest for the treatment of peritoneal carcinomatosis of ovarian origin via HIPEC.

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Section: Introductionmentioning

confidence: 99%

Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment

et al. 2012

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“…(16,23) Various types of Cremophor EL-free formulations, including nanoparticle paclitaxel, have recently been investigated to reduce the risk of allergic reactions and to take advantage of the EPR effect. (24)(25)(26)(27)(28) For example, Abraxane (Celgene, Summit, NJ, USA), an albumin-bound paclitaxel, is currently in clinical use for the treatment of breast cancer. (29,30) NK105 is a paclitaxel-incorporating "core-shell-type" polymeric micellar nanoparticle formulation.…”

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confidence: 99%

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

et al. 2012

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The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel-incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX-Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX-Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX-Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4 h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX-Cre group (P < 0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX-Cre. Serum paclitaxel concentrations 6, 12, 24, and 48 h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX-Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX-Cre group (24 100 ± 3560 vs 108 ± 25 ng/mL, respectively; P < 0.001), as was the area under the concentration-time curve from 0 to 48 h (191 000 ± 32 100 vs 1500 ± 108 ngÁh/mL, respectively; P < 0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation. (Cancer Sci 2012; 103: 1304-1310 G astric cancer is the fourth leading cause of cancer-related deaths worldwide, and peritoneal dissemination is the most frequent and life-threatening form of metastasis and recurrence in patients with gastric cancer.(1,2) The current systemic chemotherapy regimens for gastric cancer have not achieved satisfactory results, particularly in the treatment of peritoneal dissemination.(3) One of the problems with this type of therapy is the limited delivery of systemically administered drugs to the peritoneal cavity.(4) Intraperitoneal chemotherapy has been shown to be safe and effective in ovarian cancer (5)(6)(7) and is expected to provide a breakthrough in the treatment of gastric cancer with peritoneal dissemination.(8-10) However, in addition to the intraperitoneal administration of drugs, it is necessary to develop new strategies for the treatment of gastric cancer to achieve better results. Research into drug delivery systems (DDS) is ongoing and is mostly aimed at improving the penetration of drugs...

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“…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%

“…Fourth, due to the pH-responsive swelling functionality, where HFR-eNPs expand from ~30 to ~500 nm—described in detail in ref 45 and in refs 29, 31, 36, 42, and 46—the pH of the local microenvironment may play a role in the specificity of the HFR-eNPs for tumors. To determine the relationship of eNP localization and low-pH tumor microenvironments, we immunostained tissues for (1) HIF1 α as an indicator of cellular hypoxia and hypoxia-associated low pH and (2) lactate dehydrogenase-A (LDH-A) expression as an indicator of lowpH tumor microenvironments from the production of lactic acid.…”

Section: Resultsmentioning

confidence: 99%

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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The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis

Cited by 51 publications

References 49 publications

Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment

Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

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

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