Showing papers by "Yolonda L. Colson published in 2017"

Breast Cancer Spheroids Reveal a Differential Cancer Stem Cell Response to Chemotherapeutic Treatment.

Abstract: An abnormal multicellular architecture is a defining characteristic of breast cancer and, yet, most in vitro tumor models fail to recapitulate this architecture or accurately predict in vivo cellular responses to therapeutics. The efficacy of two front-line chemotherapeutic agents (paclitaxel and cisplatin) are described within three distinct in vitro models employing the triple-negative basal breast cancer cell line MDA-MB-231 and the luminal breast cancer cell line MCF7: a) a 3D collagen embedded multicellular spheroid tumor model, which reflects the architecture and cellular heterogeneity of tumors in vivo; b) a 3D collagen model with a single cell-type diffusely embedded; and c) a 2D monolayer. The MDA-MB-231 embedded spheroid tumor model exhibited the most robust response to chemotherapeutic treatment, and possessed the greatest cancer stem cell (CSC) content. CSC-related genes are elevated across all MDA-MB-231 in vitro models following paclitaxel treatment, indicating that paclitaxel enrichment of chemoresistant CSCs is less dependent on microenvironmental tumor structure, while cisplatin showed a more context-dependent response. In the MCF7 cell models a context-dependent response is observed with paclitaxel treatment increasing the CSC related genes in the 2D monolayer and 3D diffuse models while cisplatin treatment afforded an increase in ALDH1A3 expression in all three models.

Embedded Spheroids as Models of the Cancer Microenvironment.

Abstract: To more accurately study the complex mechanisms behind cancer invasion, progression, and response to treatment, researchers require models that replicate both the multicellular nature and 3D stromal environment present in an in vivo tumor. Multicellular aggregates (i.e., spheroids) embedded in an extracellular matrix mimic are a prevalent model. Recently, quantitative metrics that fully utilize the capability of spheroids are described along with conventional experiments, such as invasion into a matrix, to provide additional details and insights into the underlying cancer biology. The review begins with a discussion of the salient features of the tumor microenvironment, introduces the early work on non-embedded spheroids as tumor models, and then concentrates on the successes achieved with the study of embedded spheroids. Examples of studies include cell movement, drug response, tumor cellular heterogeneity, stromal effects, and cancer progression. Additionally, new methodologies and those borrowed from other research fields (e.g., vascularization and tissue engineering) are highlighted that expand the capability of spheroids to aid future users in designing their cancer-related experiments. The convergence of spheroid research among the various fields catalyzes new applications and leads to a natural synergy. Finally, the review concludes with a reflection and future perspectives for cancer spheroid research.

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

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 ∼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-mil...

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

Abstract: 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 by 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. WIREs Nanomed Nanobiotechnol 2017, 9:e1451. doi: 10.1002/wnan.1451 For further resources related to this article, please visit the WIREs website.

Synthesis of poly(1,2-glycerol carbonate)–paclitaxel conjugates and their utility as a single high-dose replacement for multi-dose treatment regimens in peritoneal cancer

Abstract: Current chemotherapeutic dosing strategies are limited by the toxicity of anticancer agents and therefore rely on multiple low-dose administrations. As an alternative, we describe a novel sustained-release, biodegradable polymeric nanocarrier as a single administration replacement of multi-dose paclitaxel (PTX) treatment regimens. The first synthesis of poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) is described, and its use enables high, controlled PTX loadings of up to 74 wt%. Moreover, the polymer backbone is composed of biocompatible building blocks-glycerol and carbon dioxide. When formulated as nanoparticles (NPs), PGC-PTX NPs exhibit PTX concentrations >15 mg mL-1, sub-100 nm diameters, narrow dispersity, storage stability for up to 6 months, and sustained and controlled PTX release kinetics over an extended period of 70 days. A safely administered single dose of PGC-PTX NPs contains more PTX than the median lethal dose of standard PTX. In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable curative effect to PTX administered as a multi-dose IP treatment regimen.

Pneumonectomy is safe and effective for non-small cell lung cancer following induction therapy.

Abstract: Background: Uncertainty surrounds the safety and efficacy of pneumonectomy in the setting of induction chemoradiation for non-small cell lung cancer (NSCLC). We sought to evaluate fifteen years of experience with pneumonectomy with and without induction therapy. Methods: Over a 15-year period [1999–2014], data were extracted from medical records of patients undergoing pneumonectomy for NSCLC. Primary outcomes were 5-year overall survival and mortality at 30, 60 and 90 days following operation. Morbidity data was also reviewed. Statistical comparisons were performed using the Chi-Square test. Kaplan-Meier curves were compared using the log rank test. Significance was defined as a P value less than 0.05. Patients with a prior cancer history, bilateral lung nodules and oligometastatic disease at presentation were excluded. Results: After exclusion criteria were applied, 240 patients were analyzed and 137 (57%) underwent induction therapy prior to pneumonectomy. Five-year overall survival was 38.5%. Mortality at 90 days was 7.94%. There was no statistically significant difference in perioperative mortality with the addition of induction therapy. In fact, in the subset of patients with N2 disease (n=65), induction therapy was associated with improved 5-year overall survival (10.7% vs. 32.7%, P=0.014). Thirty-five percent of patients with N2 disease exhibited a complete response in the nodal basin following induction therapy; however, this did not confer a statistically significant overall or disease-free survival benefit. Conclusions: Pneumonectomy can safely be performed in the setting of induction chemoradiation. In patients with N2 disease, induction therapy may confer a survival benefit when the surgery can be done with limited morbidity and mortality.

A Glimpse of the Future With Intraoperative Molecular Imaging.

Abstract: I n reading the article by Predina et al entitled ‘‘Intraoperative Molecular Imaging: The Surgical Oncologist’s North Star ’’ in the Annals of Surgery, it becomes evident that surgery is embarking on a new era. The concept of intraoperative molecular imaging (IMI) has been of greatest interest to the surgical oncologist as it leverages the unique characteristics and molecular behaviors of tumors to preferentially take up or concentrate optical contrast agents, allowing improved intraoperative visualization of malignant disease versus normal surrounding tissues. This is particularly appealing with the recognition that several systemically administered optical contrast agents are able to accumulate in a wide variety of tumors throughout the body including lung, gastrointestinal, thymic, neurologic, and genitourinary malignancies. The ability to accurately delineate diseased from normal tissue, particularly in terms of the surgical resection of cancer, has been the holy grail for surgical oncology, and the authors of this manuscript have 1 of the largest, if not the largest, clinical experience with IMI, having just enrolled their 500th patient. Their success has come from critical advances in both the imaging technology itself and the tumor specificity of the contrast agents. The development of near-infrared (NIR) imaging systems with improved depth of penetration, enhanced detection, and intrinsically lower biologic background interference due to lower light absorption and scattering and a higher signal-to-noise ratio, has fueled the growing interest in this technology to improve intraoperative assessment for a variety of clinical needs. Although initially filling the footprint of a refrigerator, NIR imaging systems are now readily mobile, offering improved imaging functionality and both video-assisted and robotic minimally invasive capabilities. Applications for NIR imaging during surgical resection of cancers are of particular interest, with significant efforts being focused on tumor