Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck.

Background: The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format.

Methods: A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire.

ProLindac (AP5346): a review of the development of an HPMA DACH platinum Polymer Therapeutic.

ProLindac (AP5346) is DACH (diaminocyclohexane) platinum polymer prodrug currently in phase II clinical development. It uses a 25 kDa polymer delivery vehicle based on hydroxypropylmethacrylamide (HPMA) to target the active form of the approved drug oxaliplatin to tumors. The pH-sensitive linker that binds platinum to the polymer releases platinum more rapidly in low pH environments, as found typically in many tumors.

Phase I and pharmacokinetic trial of AP5346, a DACH-platinum-polymer conjugate, administered weekly for three out of every 4 weeks to advanced solid tumor patients.

Purpose: To determine the maximum tolerated dose (MTD) safety and pharmacokinetics of AP5346, a copolymer-linked 1,2-diaminocyclohexane(DACH)-platinum compound, in advanced solid tumor patients.

Experimental Design: AP5346 was administered as a 1-hour IV infusion on days 1, 8, 15 of a 28-day cycle. Seven dose levels (DL) were explored: DL1: 40 mg platinum (Pt)/m2 (1 patient); DL2: 80 (1); DL3: 160 (3); DL4: 320 (3); DL5: 640 (6); DL6: 850 (6); DL7: 1280 (6) mg Pt/m2.

Synthesis and characterization of AP5346, a novel polymer-linked diaminocyclohexyl platinum chemotherapeutic agent.

Syntheses of the novel polymer-bound platinum-based chemotherapeutic agent poly(HPMA)-GGG-Ama=Pt=(1R,2R)-DACH, AP5346, and its precursors are reported. The method utilized in preclinical development of AP5346 is described herein. Additionally, an improved synthesis, which has shown that ion exchange resins can be removed, significantly less platinum can be used when the reaction mixture is pH-stated, and the synthesis can be performed at a higher concentration, is reported.

Preclinical efficacy and pharmacokinetics of AP5346, a novel diaminocyclohexane-platinum tumor-targeting drug delivery system.

Purpose: AP5346 is designed to target a diaminocyclohexane platinum (Pt) moiety to tumors through pH-sensitive linkage to a 25 kDa hydroxypropylmethacrylamide polymer. The goal of these studies was to determine the rate of release of Pt as a function of pH, the antitumor activity, and plasma and tumor pharmacokinetics of AP5346 in preclinical models.

Experimental Design: Antitumor activity was assessed in mice bearing B16F10 melanoma and M5076 and 2008 ovarian carcinomas.

Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours.

Targeted chemotherapy for cancer treatment offers a great potential advantage in tumour treatment due to greater specificity of delivery which leads to increased dose of the cytotoxin delivered to the tumour relative to the rest of the body. In order to achieve such selective targeted delivery one needs to identify generic markers that are over-expressed on the surface of tumour cells but are not over-expressed on normal tissue. Work of several authors has shown that some cells, such as those of rapidly dividing, aggressive tumours, over-express surface receptors involved in the uptake of vitamin B(12) [B.

Improved targeting of platinum chemotherapeutics. the antitumour activity of the HPMA copolymer platinum agent AP5280 in murine tumour models.

AP5280 is a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule platinum agents. The platinum-polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound platinum moiety is present as an N,O-Pt chelate at the distal end of a tetrapeptide linker, glycine-phenylalanine-leucine-glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa.

Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280.

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water.

Technetium(V) oxo complexes of substituted propylene diamine dioxime (PnAO) ligands: water-dependent interconversion between syn and anti isomers.

99mTc and (99)Tc complexes of PnAO (propylene diamine dioxime) ligands monosubstituted in the 6-position [PnAO-6-R] were prepared and studied. Ligands substituted with an alkyl group or with no substituent (R = H, CH(3), or CH(2)CH(CH(3))(2)), gave only one Tc complex. However, for several other nonalkyl substituents (R = COOCH(3), OH, OCH(3), OCH(2)CH(3), F, CN, NHCOCH(3), and NHCOCH(2)CH(3)), two Tc complexes A and B were formed.

Dopamine transporter loss and clinical changes in MPTP-lesioned primates.

Single photon emission computed tomography (SPECT) and the dopamine (DA) transporter tracer, 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), were used to determine DA transporter density in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-lesioned monkeys with varying degrees of parkinsonism. The clinical stage of parkinsonism corresponded to SPECT measures of striatal DA transporter density suggesting that more severe parkinsonism was associated with a greater degree of dopaminergic terminal degeneration. These findings are similar to those reported earlier using positron emission tomography (PET) and the DA metabolism tracer, 6-[18F]fluoro-L-m-tyrosine (FMT), indicating that both are good methods for evaluating nigrostriatal degeneration in MPTP primate models.

Delineation of the border zone of ischemic rabbit myocardium by a technetium-labeled nitroimidazole.

Delineation of viable ischemic myocardium is an important problem in nuclear cardiology. To determine the feasibility of using a technetium-labeled nitroimidazole as an indicator of ischemic myocardium at risk of infarction, we characterized the distribution of a 2-nitroimidazole-derivatized PnAO ligand and its 99mTc complex, 99mTcO(PnAO)-1-CH2-(2NI) (BMS-181321) in the ischemic territory of the left anterior descending (LAD) coronary artery of the rabbit. In preliminary experiments, the performance of 14C-deoxyglucose (14C-2DG) and 14C-misonidazole was assessed relative to apparent regional relative myocardial blood flow (rMBF) indicated by 99mTc-teboroxime using double-label autoradiography in the rabbit LAD occlusion model.

Development of a stable single-vial formulation for a new technetium complex using bilayer lyophilization.

The interaction between different components used in the preparation of a new radiodiagnostic agent, BMS-181321, was overcome by its lyophilization as a bilayered product. BMS-181321 is composed of a nitroimidazole ligand BMS-181032, that is complexed with technetium-99m just before it is used in radionuclide imaging studies. Stannous chloride is required to reduce technetium from the +7 to the +5 oxidation state before it can be complexed by the ligand.

BATO complexes derived from dimethoxy dioximes: synthesis, characterization and biodistribution.

To prepare less lipophilic BATO complexes, two new methoxy-substituted dioximes were synthesized: cis-4,5-dimethoxycyclohexane-1,2-dione dioxime (DMCDO) and 1,4-dimethoxybutane-2,3-dione dioxime (DMDMG). 99mTcCl(DMCDO)3BMe (BMe = methylboronic acid) was prepared and characterized. Reversed-phase HPLC analyses of 99mTcCl(DMCDO)3BMe and 99mTcCl(DMCDO)3-p-TBA (p-TBA = p - tolylboronic acid) indicated that both of these complexes were mixtures of four enantiomeric pairs of diastereomers.

Boronic acid adducts of technetium dioxime (BATO) complexes derived from quinuclidine benzilate (QNB) boronic acid stereoisomers: syntheses and studies of their binding to the muscarinic acetylcholine receptor.

We have investigated the possibility of using BATO complexes derivatized with the muscarinic acetylcholine receptor (mAChR) antagonist, quinuclidinyl benzilate (QNB), for mAChR imaging. The BATO complexes, TcCl(DMG)3B-QNB, were prepared using QNB derivatives containing a 4'-boronic acid substituent on one of the benzilic benzene rings (QNB-boronic acid). The QNB-boronic acid molecule has two chiral centers, and all four QNB-BATO stereoisomers were made and evaluated.

The synthesis and in vitro evaluation of a 99mtechnetium-nitroimidazole complex based on a bis(amine-phenol) ligand: comparison to BMS-181321.

We have developed a 99mTechnetium complex for imaging of hypoxic tissue (BMS-181321). Recently, another nitroimidazole derivative, based upon a bis(amine-phenol) ligand, was described in the patent literature. To compare this compound to BMS-181321, we have synthesized the ligand, prepared its 99mTc complex, and evaluated its performance in two in vitro assays of bioefficacy: membrane permeability and uptake in normoxic and anoxic cardiocytes.

TcO(PnA.O-1-(2-nitroimidazole)) [BMS-181321], a new technetium-containing nitroimidazole complex for imaging hypoxia: synthesis, characterization, and xanthine oxidase-catalyzed reduction.

A technetium(V)oxo nitroimidazole complex that shows promise for imaging regional hypoxia in vivo, [BMS-181321, TcO(PnAO-1-(2-nitroimidazole))] (1) was prepared from 3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane -2,10-dione dioxime, a 2-nitroimidazole-containing derivative of propyleneamine oxime (PnAO). The 99Tc complex [99Tc]Oxo[[3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8- diazaundecane-2,10-dione dioximato]-(3-)-N,N',N'',N''']technetium (V) was synthesized both from pertechnetate and [TcO(Eg)2]- (Eg = ethylene glycol). A new synthetic route to TcO(PnAO) (2) is also described.

Synthesis, characterization, and in vitro evaluation of nitroimidazole--BATO complexes: new technetium compounds designed for imaging hypoxic tissue.

Several technetium-99 BATO (boronic acid adduct of technetium dioximes) complexes TcX(dioxime)3BR (X = Cl) that contain a boron cap R which bears a 2- or 4-nitroimidazole moiety have been prepared from either TcCl(dioxime)3 or from Tc(dioxime)3(mu-OH)SnCl3 [dioxime = dimethyl glyoxime (DMG) or cyclohexanedione dioxime (CDO)]. Two hydroxy analogs (X = OH) were isolated by treatment of the corresponding chloro complexes with aqueous NaOH. The complexes have been characterized by elemental analysis, mass spectrometry, NMR, UV/vis spectroscopy, and high-performance liquid chromatography.

Direct analysis of whole blood by internal surface reversed-phase chromatography: an examination of the binding and metabolism of technetium dioxime complexes.

We have developed a method using internal surface reversed-phase (ISRP) packing for rapid on-line separation of small hydrophobic compounds from cellular whole blood components. This is achieved by the use of 75-microns ISRP chromatographic material packed into a small high-performance liquid chromatographic (HPLC) column, in conjunction with column switching. We have applied this analytical method to study the in vitro metabolism of 99mTc-BATO (boronic acid adducts of technetium dioxime) cerebral and myocardial perfusion tracers in whole blood.

Technetium labeling of monoclonal antibodies with functionalized BATOs: 2. TcCl(DMG)3CPITC labeling of B72.3 and NP-4 whole antibodies and NP-4 F(ab')2.

BATO (boronic acid adduct of technetium dioximes) complexes, TcCl(dioxime)3BR, were prepared in which the boron substituent (R) was the protein-reactive 2-carboxy-4-phenyl isothiocyanate (CPITC). The 99Tc complexes, where the dioxime was either dimethylglyoxime (DMG) or cyclohexanedione dioxime (CDO), were prepared and characterized. The 99mTc complex TcCl(DMG)3CPITC was prepared from a freeze-dried kit and used to label B72.

Technetium labeling of monoclonal antibodies with functionalized BATOs. 1. TcCl(DMG)3PITC.

BATO (boronic acid adduct of technetium dioximes) complexes, TcCl(dioxime)3BR, were prepared in which the boron substituent (R) was the protein-reactive m-phenyl isothiocyanate (PITC). The 99TcCl(dioxime)3PITC complexes [dioxime = dimethylglyoxime (DMG) or cyclohexanedione dioxime (CDO)] were prepared from 99Tc(dioxime)3(mu-OH)SnCl3 and characterized. The X-ray crystal structure of 99TcCl(DMG)3PITC was determined.

Chloro----hydroxy substitution on technetium BATO [TcCl(dioxime)3 BR] complexes.

The neutral, seven coordinate complexes of technetium known as the BATO (Boronic acid Adducts of Technetium diOximes) complexes have shown their utility as myocardial and cerebral perfusion agents. The axial chloride ligand of the BATO complexes [99mTcCl(dioxime)3 BR] is labile to substitution by a competitive anion; under physiological conditions, the axial chloride ligand can be replaced by a hydroxy group. The chloro and hydroxy analogs have different biodistributions and single-pass cerebral extraction efficiencies.

Technetium-99m d,l-HM-PAO: a new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion.

Following investigation of a large number of new ligands based upon propylene amine oxime (PnAO) the d,l-diastereoisomer of hexamethyl propyleneamine oxime (HM-PAO) was selected as the preferred ligand for 99mTc as a tracer for cerebral perfusion imaging. The neutral, lipophilic 99mTc complex of d,l-HM-PAO was formed in high yield by stannous reduction of 99Mo/99mTc generator eluate using a kit formulation of the ligand. Two minutes following i.

Technetium-99m-d, 1-HM-PAO: a new radiopharmaceutical for imaging regional brain perfusion using SPECT--a comparison with iodine-123 HIPDM.

A new radiopharmaceutical, technetium-99m hexamethylpropyleneamine oxime (99mTc-d, 1-HM-PAO), has been reported to cross the blood-brain-barrier and to distribute in brain in proportion to regional blood flow. This study reports brain imaging obtained with 99mTc-d,1 HM-PAO in 20 subjects; seven without evidence of cerebral disease and 13 with cerebrovascular disorders. In 16 patients comparative data were available with N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine ([123I]HIPDM).