bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2649: Whole body vibration effects on binding kinetics and targeting of near-infrared dye conjugated bisphosphonate
Authors: Papineni Rao V. , Orton Sean , McLaughlin William , Vizard Douglas , Ji Tao , Schmitthenner Hans , Pan Jingyi 
Published: February 2011

Abstract
A non-invasive means of targeting bisphophonate to specific skeletal sites, along with the passive binding/decay kinetics of the near-infrared bisphosphanate analog to the skeleton are determined. Bone is the third common site where breast, lung, and prostate cancer cells spread and metastasize. Debilitating pain is the major complication resulting from bone metastases in nearly 70% of the patients. The palliative bone pain management includes the bisphosphanate therapy. Bisphosphonates, a potent inhibitor of bone resorption, gives both pain relief and improves bone health. However these medications result in complications such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Combinations of low-risk exercise programs along with reduced drug dosage are a likely alternative to counter such drug-related side effects. Site-selective skeletal targeting of bisphosphonates, if feasible, is however ideal to overcome drug-related side effects. We utilized whole body vibration (WBV), to target NIR dye conjugate bisphosphonate to specific skeletal sites. Using near-infrared (NIR) fluorescence imaging, both the targeting and the passive binding of the bisphosphonate in vivo was determined. Vibration loading, utilizing whole body vibration (WBV) was performed on twelve mice by subjecting them to vibration frequency of 35 Hz for fifteen min (5-10 times/week) duration. Alendronate was conjugated to near-infrared tricarbocyanine, cyclic enamine-functionalized dye, and was injected intravenously after 21-day exercise regime. Yet to be reported, we show that NIR-alendronate probe bound to the lumbar L6 vertebrae, resultant of direct high-frequency WBV stimulation. This is besides several other specific targeting sites. Further, both the passive binding and the decay kinetics of the NIR signal at the skeleton was determined in a six-week non-invasive longitudinal study of mouse pups. This provides opportunity to utilize such approaches in future translational studies in assessing the role of bisphosphonates in preventing spreading of cancer cells at other secondary sites, especially bone. The targeted drug binding in response to the vibratory protocol also provides hope in the development of whole body vibration (WBV) as a bisphosphonate-therapeutic aid. Further, to develop strategies in reducing the drug dosage in treatment of other morbidity factors that stem from complications from bone metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2649.
Abstract 2653: Thermally targeted delivery of an acid-labile derivative of doxorubicin by elastin-like polypeptide
Authors: Robinson Leslie , Kratz Felix , Raucher Drazen 
Published: February 2011

Abstract
Doxorubicin (Dox) is an anthracycline used in the treatment of many types of cancer. It intercalates into the strands of DNA to inhibit the progression of topoisomerase II, stopping the cell from replicating. The side effects, however, are severe and include neutropenia, alopecia, nausea, myelosuppression, and cardiotoxicity. The drug is nonspecific; as a result, high doses are needed to treat cancer cells. These high doses are inadvertently harmful to normal cells. Therefore, there is a need for an efficient drug delivery system in order to deliver doxorubicin to the tumor site. Our lab has developed a macromolecular carrier that can provide this targeted delivery. This elastin-like polypeptide (ELP) is thermally responsive as it remains in solution at physiological temperature and aggregates upon heating at 42 °C.
The N-terminus of ELP was modified with three different cell penetrating peptides (CPPs) - Bac, Tat, and SynB1. These peptides are derived from the bactenecin family of antimicrobial peptides, truncated version of the HIV-1 Tat protein, and porcine leukocytes, respectively. This study compared the efficiency of these three CPP-ELP carriers to deliver doxorubicin to the cells. ELP was attached to a hydrazone derivative of doxorubicin (DOXO) by conjugation of a 6-maleimidocaproyl moiety on the drug with a terminal cysteine residue on ELP. This linker allows the drug to be cleaved at acidic pH in the cell. The three CPP-ELP-DOXO conjugates had transition temperatures within the range of 38-42°C. All three carriers of DOXO inhibited MCF-7 breast cancer cell proliferation 2-fold more at 42 °C than at 37 °C, indicating that the hyperthermia induced phase transition of ELP does increase the local concentration of the drug. Inhibition of cell proliferation may be due to apoptosis, since apoptosis was enhanced 2.3-fold in MCF-7 cells when SynB1-ELP-DOXO aggregation was induced with hyperthermia. CPP-ELP-DOXO accumulated in cells to the same level as free Dox. Confocal imaging showed that when cells were treated with any of the three CPP-ELP-DOXO derivatives, Dox localized in the nucleus, similar to the free Dox. The results suggest that CPP-ELP-DOXO conjugates may provide a means to thermally target solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2653.
Abstract 2656: Association of daunorubicin to a lipidic nanoemulsion (NEM-ODNR) - in vivo tumor growth inhibition
Authors: Contente Thais C. , Kretzer Iara F. , Maria Durvanei A. , Capeto Tathiana , Fock Ricardo , Maranhao Raul C. 
Published: February 2011

Abstract
After injection into blood stream an artificial nanoemulsion (NEm) that mimics LDL composition binds to LDL receptors and concentrates in tumor tissues that show LDL receptor overexpression. NEm has been used as carrier to target drugs against neoplastic tissues and was shown to diminish toxicity while increase tumoral inhibition growth in murine models, showing more effective and selectiveness. Daunorrubicin (DNR) is an anthracycline antibiotic that possesses broad spectrum antineoplastic activity, and is one of the most important anticancer agents in use. However, clinical utility is hampered by cumulative, dose limiting cardiotoxicity, myelosupression, and the development of drug resistence. Derivative form of daunorubicin oleate (ODNR) was synthesized and associated to NEM by prolonged ultrassonication and ultracentrifugation Antitumor activity of NEM-ODNR were tested in B16F10 melanoma bearing mice and compared with commercial formulation (DNR) and control group (saline). Tumor growth, presence of metastatic nodes and hematological profile were evaluated. The cytotoxicity of NEm-ODNR was diminished by five times compared to DNR. In dose acute toxicity studies the NEm-ODNR tolerability was 72-times higher compared to commercial DNR. The tumor growth inhibition rate for NEM-ODNR was over 35% when compared to DNR and 59% compared to saline (p &lt; 0,001). There was a significant reduction in animals bearing metastasis for NEM associated treated group (30%) in comparison to the commercial treated (80%). In control group all animals developed metastatic tumors. Hematological profile showed that NEM-ODNR treatment had a 15% raise for red blood cells, compared to 29% of reduction for DNR, 25% of reduction to white blood cells compared to 55% for DNR and 45% reduction of platelets compared to 57% for DNR. Flow cytometry suggested greater antitumor activity for NEm-ODNR group showing remarkable arrest (47%) on DNA fragmentation phase of cell cycle compared to 26% to DNR. Those tests are essential for evaluating the NEM-ODNR formulation and its implementation of future clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2656.
Abstract 2657: Development of melanoma target-specific drug delivery system
Authors: Ndinguri Margaret , Fields Gregg , Lauer-Fields Janelle 
Published: February 2011

Abstract
While many approved drugs are well-tolerated by most biological systems, numerous drugs could utilize advanced delivery systems to direct them where needed and minimize breakdown as they circulate through the body. We are exploring targeted delivery of doxorubicin using Nanotechnology-based Drug Delivery Systems (nanoDDSs). NanoDDSs have gained recent popularity but they do not posses inherent targeting capabilities. Nanoparticles and micelles can be modified in many ways allowing for specific targeted delivery. Over expression of CD44 in metastatic melanoma and a variety of tumor stem cells has made this receptor an ideal candidate for targeted drug delivery. The sequence to which CD44 binds within the type IV collagen triple helix has been identified as α1(IV)1263-1277. The incorporation of α1(IV)1263-1277 into drug loaded liposomes confers targeting selectivity against cancer cell lines that have CD44 receptors. Doxorubicin is one of the FDA approved drugs widely used for treatment of many types of cancers. The specificity of this drug can be enhanced by targeted delivery to the cancer cells, thereby minimizing deleterious side effects. In this study we present novel targeted doxorubicin-loaded liposomes and investigate the tumor cell selective localization and efficacy of the drug delivery system. Recent results on synthesis, structure and function, toxicity and selectivity will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2657.
Abstract 266: The interaction between MUC1 and erbB3 promotes erbB3 signaling and cell survival
Authors: Su Hsin-Yuan , Schroeder Joyce A. 
Published: February 2011

Abstract
MUC1 is an oncogenic glycoprotein overexpressed in more than 90% of metastatic breast cancers. The expression of MUC1 has been linked to promote cell transformation by interacting with a number of known oncogenes, including the erbB receptors. When coexpressed, MUC1 strongly promotes erbB1-dependent breast cancer in the WAP-TGFalpha transgenic mouse model and inhibits ligand-mediated ubiquitination and degradation of erbB1. ErbB1 belongs to a receptor tyrosine kinase superfamily, including erbB1/EGFR, erbB2/neu, erbB3 and erbB4, all of which have been implicated in cancer progression. ErbB3 is one of the dimerization partners for erbB1 implicated in invasive breast cancer and may be responsible for the resistance to erbB1-directed therapy. In the present study, we set out to understand the effect of interaction between MUC1 and erbB3 on erbB3 stability and signaling. We show that the expression of MUC1 inhibits the degradation of neuregulin1beta (NRG1beta)-stimulated erbB3 and prolongs NRG1beta-dependent dpERK and pAKT activation in BT20 breast cancer cell line. By cell proliferation assay, we demonstrate that MUC1 promotes NRG1beta-dependent survival signals in BT20 cells. ErbB1 is found to complex with erbB3 only in the presence of MUC1 and NRG1beta stimulation. In addition, MUC1 forms a complex with erbB1 and erbB3 only in the presence of NRG1beta stimulation. In summary, the interaction between MUC1 and erbB3 results in inhibition of ligand-induced degradation of erbB3 receptor and prolongation of erbB3 downstream signaling, especially ERK and AKT activation, which leads to cell survival. The possible mechanism is through the formation of functional erbB1/erbB3 heterodimers facilitated by MUC1 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 266.
Abstract 2660: Folate conjugated PLGA silica coreshell nanoparticles for drug delivery
Authors: Sharraya Aschemeyer , Yang Jian , Sandoval Sergio , Alfaro Jesus , Kummel Andrew , Trogler William C. 
Published: February 2011

Abstract
Folate conjugated poly(lactic-co-glycolic acid) (PLGA) silica nanoparticles (NP) are being synthesized as drug carriers to cancer cells. The PLGA nanoparticles are synthesized by first combining PLGA and dye in acetonitrile. This mixture is then dropped into an aqueous solution containing lecithin (a lipid) and poly(ethylene glycol) (PEG) to form an emulsion. The acetonitrile is evaporated leaving the nanoparticles in a water suspension. Silicic acid is used to coat the PLGA NP through the sol-gel process assisted by poly-L-lysine to template the growth of the silica shell. This makes a more hydrophilic and easily modified surface. 3-aminopropyltriethoxysilane is used to coat the silica surface with amine groups. Then folic acid is coupled to the amine modified silica surface. The folic acid acts as a targeting agent which recognizes folate receptors on the membrane surface of cancer cells. A fluorescent dye is loaded into the PLGA core to mimic a hydrophobic drug in these initial studies. Then the ability of PLGA silica NP with folate are allowed to undergo endocytosis into the HeLa cells, and the degree of uptake is assessed by fluorescence microscopy. The results are compared to folate PLGA NP as a control. Detailed synthesis of these silica PLGA nanoparticles, their characterization, surface functionalization, and their applications will be presented.
This presentation was made possible by NIH grants:5P30CA23100; and 1U54CA132379/1U54CA132384.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2660.
Abstract 2663: Preclinical pharmacokinetic characterizations and human pharmacokinetic prediction of AMG 900, an orally available small molecule inhibitor of aurora kinases
Authors: Huang Liyue , Be Xuhai , Berry Loren , Pan Wei-Jiang , Zhao Zhiyang , Lin Min-Hwa Jasmine 
Published: February 2011

Abstract
Introduction: AMG 900 is a small molecule being developed as an orally administered, highly potent and selective pan-aurora kinase inhibitor. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced solid tumors. The objectives of the studies were to characterize single dose pharmacokinetics (PK) of AMG 900 in preclinical species and use the preclinical PK data to predict its human PK. Methods: Following a single intravenous and oral administration of AMG 900 to mice, rats, dogs, and monkeys, blood samples were collected and processed for plasma by centrifugation. AMG 900 plasma concentrations were determined by LC-MS/MS. Non-compartmental analysis of the concentration - time data was performed to calculate PK parameters of AMG 900. Human PK were predicted based on data from preclinical species using the simple allometric scaling method assuming a human body weight of 60 kg. Results: AMG 900 exhibited low (mouse, monkey and dog) to moderate (rat) clearance in the species evaluated. The volume of distribution at steady state was less than 0.5 L/kg across species. Following intravenous administration, the compound had terminal elimination half-life ranging from 0.6 to 2.4 hours. AMG 900 was well absorbed in fasted animals across species with an oral bioavailability ranging from 31% to 104%. The clearance and volume of distribution at steady state in humans were predicted to be 0.03 L/hr/kg and 0.1 L/kg, respectively, with the predicted half-life to be approximately 2.3 hours. Bioavailability after oral administration of AMG 900 was predicted to be 75%, calculated from the mean values observed in non-clinical species. Conclusion: AMG 900 exhibits good PK properties in preclinical species and it was predicted to have low clearance and good oral bioavailability in human. Available PK results from the on-going phase 1 trial are consistent with the allometric scaling predictions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2663.
Abstract 2664: Pharmacokinetics of a novel fumagillol conjugate XMT-1107 in the rat and the dog
Authors: Yurkovetskiy Alexander , Cabral Carolina B. , Meyers Laraine L. , Fram Robert J. , Lowinger Timothy B. 
Published: February 2011

Abstract
XMT-1107 is a novel polymer fumagillol derivative, comprised of the small molecule XMT-1191 conjugated to a 70 kDa biodegradable, hydrophilic polyacetal, poly(1-hydroxymethylethylene hydroxymethylformal) (PHF). The conjugated drug XMT-1107 is a prodrug that improves the pharmacokinetics (PK) of the active compound XMT-1191 and demonstrates significant antitumor activity in multiple rodent xenograft models providing a compelling rationale for clinical development. We evaluated the metabolism and PK of XMT-1107 in the rat and the dog and expect that the preclinical dog toxicokinetic (TK) data provide better guidance than the rat data for the assessment of XMT-1107 safety/PK in humans.
XMT-1107 metabolism was studied in rodent, dog and human plasma as well as in liver microsomes. The PK of XMT-1107 was studied in rat and dog at a variety of doses and schedules. The extent and duration of the exposure was monitored over 120 hours post dosing. The analytical determinations of XMT-1107 and small molecule metabolites were carried out by LC/MS/MS.
XMT-1107 was metabolized in rodent, dog and human plasma producing XMT-1191 and XMT-1201 (via conjugated XMT-1201) as major and minor metabolites, respectively. Considering that XMT-1201 does not bind to or inhibit MetAP2, the molecular target of XMT-1107, conjugated and free XMT-1191 are of most interest since conjugated XMT-1191 is a prodrug and XMT-1191 is its active release product.
In both species the PK of conjugated and free XMT-1191 was approximately dose proportional with no marked gender differences. Consistent 2,000-4,000 fold differences between conjugated XMT-1191 and free XMT-1191 plasma exposure (AUC0–120) and Cmax suggest that observed pharmacological effects may result from extravascular distribution of conjugated XMT-1191 and local release of XMT-1191 rather than from systemic exposure to free XMT-1191. Conjugated XMT-1191 has a low volume of distribution, slow systemic clearance and is characterized by a t1/2 ranging from 27-35 hours in rat and 47-68 hours in dog. The 1.8-2.0-fold increase in conjugated XMT-1191 plasma t1/2 observed in dog relative to rat was accompanied by an approximately proportional increase in dose normalized exposure (AUC0–120) to conjugated XMT-1191 and conjugated XMT-1201. The rates for in vitro release of XMT-1191 and XMT-1201 from XMT-1107 in dog and human plasma were similar and at least 2 times lower than the release rates for corresponding compounds in rat plasma, suggesting that dog TK may be more predictive of human XMT-1107 PK compared to rat TK.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2664.
Abstract 2665: Impact of structural modifications on bioactivity and metabolic stability of indirubins
Authors: Eisenbrand Gerhard , Cheng Xinlai , Zeller Jochen , Merz Karl-Heinz 
Published: February 2011

Abstract
Indirubins are potent inhibitors of a series of protein kinases. They induce cell cycle arrest in G1/S and/or G2/M followed by apoptosis and potently inhibit proliferation of human tumor cells. However, most indirubins are extremely poorly soluble in solvents, resulting in a low bioavailability. Furthermore, they are prone to deactivating metabolic transformations. As reported previously1, incubation of 5-methylindirubin (E224) with bovine and rat liver microsomes in the presence of a NADPH-generating system resulted in the formation of two main hydroxylated metabolites, 6-hydroxy- and 6,7′-dihydroxy-5- methyl-indirubin. The antiproliferative activity of the former metabolite was decreased, the activity of the latter was abrogated nearly completely.
To improve metabolic stability and solubility, novel indirubins were synthesized: 7′-Aza-5-methylindirubin (E844), N,N-dimethylaminophenyl indirubin-5-carboxamide (E744), and indirubins carrying a hydrophilic N-methylpiperazinoethyl group attached to the indirubin core by a 5-carboxamide anchor (E748) or by a 3′-oxime ether link (E857). Compounds were in vitro incubated with liver microsomes (rat and bovine) and metabolites formed were isolated and analyzed. The main metabolites of E844 were identified to be 7′-aza-5-methyl-6-hydroxy-indirubin and 7′-aza-5-hydroxymethyl-indirubin. From incubations of E748, the 7′-hydroxy derivative was isolated as main metabolite and structurally elucidated by 1H-NMR. In contrast to E748 with an N-methylpiperazinoethyl side chain, E744 did not appear to undergo appreciable metabolic transformation. Moreover, E857 and its water soluble hydrochloride (E857a) were found not to be hydroxylated at the respective bisindole positions. Instead, the main biotransformation of E857 occured in the side chain leading to the corresponding N-methylpiperazinoethyl-N-oxide metabolite. The structure was confirmed by synthesis. E857a was found to carry a hydroxylated methylpiperazino group after incubation.
In summary, deactivating metabolic transformation of indirubins is decreased by variation of the electron density of the heterocyclic aromatic system. Furthermore, attachment of appropriate substituents at position 3′ directs metabolic transformation into the side chain of such substituents that ensure improved water solubility, bringing about increased metabolic stability of the pharmacophore.
1 AACR Annual Meeting 2007 abstr. #3957
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2665.