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Larson N.,Theratarget | Larson N.,Nano Institute of Utah | Roberts S.,Theratarget | Ray A.,Theratarget | And 5 more authors.
Macromolecular Bioscience | Year: 2014

HPMA copolymer-RGDfK (HPMA-RGDfK) conjugates bearing either aminohexylgeldanamycin (AHGDM) or docetaxel (DOC)were synthesized and characterized. In vitro stability and bindingwere evaluated. Cytotoxicity toward ovarian cancer cells was evaluated and the ability of the conjugates to induce cell death was assessed by combination index analysis. Conjugates bearing AHGDM were more stable and exhibited slower drug release than those bearing DOC. Both conjugates demonstrated the ability to bind to avb3 integrins. In combination, HPMA-RGDfK conjugates demonstrated marked synergism as compared to their non-targeted counterparts and free drug controls. HPMA-RGDfK conjugates bearing AHGDM and DOC induce synergistic cytotoxicity in vitro, suggesting their potential as a promising combination therapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Larson N.,Nano Institute of Utah | Ghandehari H.,Nano Institute of Utah | Ghandehari H.,University of Utah
Chemistry of Materials | Year: 2012

The field of polymer therapeutics has evolved over the past decade and has resulted in the development of polymer-drug conjugates with a wide variety of architectures and chemical properties. Whereas traditional nondegradable polymeric carriers such as poly(ethylene glycol) (PEG) and N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers have been translated to use in the clinic, functionalized polymer-drug conjugates are increasingly being utilized to obtain biodegradable, stimuli-sensitive, and targeted systems in an attempt to further enhance localized drug delivery and ease of elimination. In addition, the study of conjugates bearing both therapeutic and diagnostic agents has resulted in multifunctional carriers with the potential to both "see and treat" patients. In this paper, the rational design of polymer-drug conjugates will be discussed, followed by a review of different classes of conjugates currently under investigation. The design and chemistry used for the synthesis of various conjugates will be presented with additional comments on their potential applications and current developmental status. © 2012 American Chemical Society. Source


Yu T.,Nano Institute of Utah | Greish K.,Nano Institute of Utah | Greish K.,University of Otago | McGill L.D.,Arup | And 3 more authors.
ACS Nano | Year: 2012

Silica nanoparticles (SiO 2) are widely used in biomedical applications such as drug delivery, cell tracking, and gene transfection. The capability to control the geometry, porosity, and surface characteristics of SiO 2 further provides new opportunities for their applications in nanomedicine. Concerns however remain about the potential toxic effects of SiO 2 upon exposure to biological systems. In the present study, the acute toxicity of SiO 2 of systematically varied geometry, porosity, and surface characteristics was evaluated in immune-competent mice when administered intravenously. Results suggest that in vivo toxicity of SiO 2 was mainly influenced by nanoparticle porosity and surface characteristics. The maximum tolerated dose (MTD) increased in the following order: mesoporous SiO 2 (aspect ratio 1, 2, 8) at 30-65 mg/kg < amine-modified mesoporous SiO 2 (aspect ratio 1, 2, 8) at 100-150 mg/kg < unmodified or amine-modified nonporous SiO 2 at 450 mg/kg. The adverse reactions above MTDs were primarily caused by the mechanical obstruction of SiO 2 in the vasculature that led to congestion in multiple vital organs and subsequent organ failure. It was revealed that hydrodynamic sizes of SiO 2 post-protein exposure had an important implication in relating SiO 2 physicochemical properties with their vasculature impact and resultant tolerance threshold, as the larger the hydrodynamic size in the presence of serum protein, the lower the MTD. This study sheds light on the rational design of SiO 2 to minimize in vivo toxicity and provides a critical guideline in selecting SiO 2 as the appropriate system for nanomedicine applications. © 2012 American Chemical Society. Source


Theisen E.R.,University of Utah | Gajiwala S.,University of Utah | Bearss J.,University of Utah | Sorna V.,University of Utah | And 3 more authors.
BMC Cancer | Year: 2014

Background: Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE.Methods: The effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509.Results: Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p = 0.034).Conclusions: Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma. © 2014 Theisen et al.; licensee BioMed Central Ltd. Source


Arauchi A.,Tokyo Womens Medical University | Yang C.-H.,University of Utah | Cho S.,University of Utah | Jarboe E.A.,University of Utah | And 8 more authors.
Tissue Engineering - Part C: Methods | Year: 2015

Despite the development of a myriad of anticancer drugs that appeared promising in preclinical ovarian cancer animal models, they failed to predict efficacy in clinical testing. To improve the accuracy of preclinical testing of efficacy and toxicity, including pharmacokinetic and pharmacodynamic evaluations, a novel animal model was developed and characterized. In this study, murine ID8 (epithelial ovarian cancer [EOC]) cells as injected cell suspensions (ICS) and as intact cultured monolayer cell sheets (CS) were injected or surgically grafted, respectively, into the left ovarian bursa of 6-8 week-old, female C57BL/6 black mice and evaluated at 8 and 12 weeks after engraftment. Tumor volumes at 8 weeks were as follows: 30.712±18.800 mm3 versus 55.837±10.711 mm3 for ICS and CS, respectively, p=0.0990 (n=5). At 12 weeks, tumor volumes were 128.129±44.018 mm3 versus 283.953±71.676 mm3 for ICS and CS, respectively, p=0.0112 (n=5). The ovarian weights at 8 and 12 weeks were 0.02138±0.01038 g versus 0.04954±0.00667 g for ICS and CS, respectively (8 weeks), p=0.00602 (n=5); and 0.10594±0.03043 g versus 0.39264±0.09271 g for ICS and CS, respectively (12 weeks), p=0.0008 (n=5). These results confirm a significant accelerated tumorigenesis in CS-derived tumors compared with ICS-derived tumors when measured by tumor volume/time and ovarian weight/time. Furthermore, the CS-derived tumors closely replicated the metastatic spread found in human EOC and histopathological identity with the primary tumor of origin. © 2015 Mary Ann Liebert, Inc. Source

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