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Purpose: Polysaccharides such as chondroitin play a potent role in tumor growth, tissue repair and angiogenesis. These properties make chondroitin a good candidate for novel drug delivery systems. Diammine dicarboxylic acid platinum (DDAP), a novel polymeric platinum compound, was developed by conjugating the platinum analogue to aspartate-chondroitin for drug delivery to tumor cells. DDAP improves platinum solubility which may reduce systemic toxicity and be more efficacious than cisplatin in killing tumor cells., Methods: We tested and compared the cytotoxic effects of DDAP and CDDP on the platinum-sensitive 2008 and A2780 ovarian cancer cell lines and their platinum-resistant sublines 2008.C13 and A2780cis; we also investigated DDAP's mechanism of action., Results: In the platinum-sensitive cell lines, the cytotoxic effects of DDAP and CDDP were comparable. However, in the platinum-resistant sublines, significantly greater cell-growth inhibition was induced by DDAP than by CDDP, especially at lower doses. DDAP also induced more apoptosis than CDDP did in the 2008.C13 subline, which was partially mediated by the caspase 3-dependent pathway. In addition, lower (but not higher) doses of DDAP arrested 90% of S-phase 2008.C13 cells, which might be associated with up-regulation of p21 and maintenance of low cyclin A expression. Furthermore, greater cellular uptake of DDAP was seen in platinum-resistant than in platinum-sensitive ovarian cancer cells., Conclusions: Low-dose DDAP enhances drug delivery to platinum-resistant ovarian cancer cells and substantially inhibits their growth by inducting apoptosis and arresting cells in the S-phase, suggesting that DDAP may overcome platinum resistance in ovarian cancer.

Purpose: The aim of this work was to compare the physicochemical characteristics of the phospholipids complex of puerarin (Pur) prepared by traditional methods (solvent evaporation, freeze-drying and micronization) and a supercritical fluid (SCF) technology. The physicochemical properties of the pure drug and the corresponding products prepared by two different SCF methods were also compared., Methods: Solid-state characterization of particles included differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), solubility, dissolution rate and scanning electron microscopy (SEM) examinations. Besides puerarin phospholipids complex (PPC) by four different methods, the solid-state properties of unprocessed, gas antisolvent (GAS) crystallized and solution enhanced dispersion by supercritical fluid (SEDS) precipitated puerarin samples were also compared. Crystallinity was assessed using DSC and XRPD. Drug-phospholipids interactions were characterized using Fourier transform infrared spectroscopy (FTIR). SEM was used to determine any morphological changes. Pharmaceutical performance was assessed in dissolution rate and solubility tests., Result: The results of the physical characterization attested a substantial correspondence of the solid state of the drug before and after treatment with GAS technique, whereas a pronounced change in size and morphology of the drug crystals was noticed. The GAS-processed puerarin exhibited a better crystal shape confirmed by DSC, XRPD and IR. Polymorphic change of puerarin during SEDS coupled with the dramatic reduction of the dimensions determined a remarkable enhancement of its solubility and in vitro dissolution rate. Phospholipids complex prepared using supercritical fluid technology showed similar properties of physical state, thermal stability and molecular interaction with phospholipids (PC) to those of corresponding systems prepared by other three conventional methods namely solvent evaporation, freeze-drying and micronization as proved by XRPD, DSC, and FTIR. The best dissolution rate was obtained by SEDS-prepared complex, while the highest solubility was obtained for solvent evaporation method., Conclusion: Supercritical fluid technology for the preparation of puerarin and its phospholipids complex has been proven to have significant advantages over the solvent evaporation technique and other conventional methods.

Purpose: DNA markers are useful in assessing cell proliferation. The purpose of this study was to synthesize (99m)Tc-ethylenedicysteine-guanine (EC-Guan) for evaluation of cell proliferation., Methods: Tumor cells were incubated with (99m)Tc-EC-Guan for cell cycle analysis. Prostate tumor cells that were overexpressing the HSV thymidine kinase gene, or various tumor cells were incubated with (99m)Tc-EC-Guan at 0.5-2 h. Thymidine incorporation assays were performed in lung cancer cells incubated with EC-Guan at 0.1-1 mg/well. Tissue distribution, autoradiography, and planar scintigraphy of (99m)Tc-EC-Guan and (99m)Tc-EC (control) were determined in tumor-bearing rodents at 0.5-4 h., Results: Cell culture assays indicated that EC-Guan was incorporated in DNA, and there was no significant uptake difference between HSVTK overexpressed and normal groups. Biodistribution and scintigraphic imaging studies of (99m)Tc-EC-Guan showed increased tumor/tissue count density ratios as a function of time., Conclusions: Our results indicate that (99m)Tc-EC-Guan may be useful as a tumor proliferation imaging agent.

Purpose: To evaluate the feasibility of regional radiochemotherapy of mammary tumors using in situ hydrogel loaded with cisplatin (CDDP) and rhenium-188 ((188)Re)., Methods: Sodium alginate (SA) and calcium chloride were used to create a hydrogel for delivery of CDDP and (188)Re. In vitro studies were performed to evaluate cytotoxic effects of (188)Re-hydrogel and sustained-release ability of the CDDP-hydrogel. Tumor-bearing rats were injected with (188)Re-hydrogel (0.5-1 mCi/rat), (188)Re-perrhenate (0.5-1 mCi/rat, intratumoral, I.T.), CDDP-hydrogel (3 mg/kg), and (188)Re-hydrogel loaded with CDDP (3 mg/kg body weight, 0.5-1 mCi/rat), respectively, and groups receiving (188)Re were imaged at 24 and 48 h postinjection. Tumor volume, body weight, imaging, and kidney function were assessed as required for each group., Results: Successful formation of the hydrogel was demonstrated by cytotoxic effects of (188)Re-hydrogel and slow release of CDDP-hydrogel in vitro. Tumor volume measurements showed significant delay in tumor growth in treated vs. control groups with minimal variation in normal kidney function for the CDDP-hydrogel group. Scintigraphic images indicated localization of (188)Re-hydrogel in the tumor site up to 48 h postinjection., Conclusions: Our data demonstrate the feasibility of using hydrogel for delivery of chemotherapeutics and radiation locally. This technique may have applications involving other contrast modalities as well as treatment in cases where tumors are inoperable.

Purpose: The assessment of tumor hypoxia by imaging modality prior to radiation therapy would provide a rational means of selecting patients for treatment with radiosensitizers or bioreductive drugs. This study aimed to develop a 99mTc-labeled metronidazole (MN) using ethylene-dicysteine (EC) as a chelator and evaluate its potential use to image tumor hypoxia., Methods: EC was conjugated to amino analogue of MN using Sulfo-N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl as coupling agents, the yield was 55%. Tissue distribution of 99mTc-EC-MN was determined in breast tumor-bearing rats at 0.5, 2, and 4 hrs. Planar imaging and whole-body autoradiograms were performed. The data was compared to that using 99mTc-EC (control), [18F]fluoromisonidazole (FMISO) and [(131)I] iodomisonidazole (IMISO)., Results: In vivo biodistribution of 9mTc-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and tumor-to-muscle ratios as a function of time. Conversely, tumor-to-blood values showed time-dependent decrease with 9mTc-EC in the same time period. Planar images and autoradiograms confirmed that the tumors could be visualized clearly with 99mTc-EC-MN from 0.5 to 4 hrs. There was no significant difference of tumor-to-blood count ratios between 99mTc-EC-MN and [(131)I]IMISO at 2 and 4 hrs postinjection. From 0.5 to 4 hrs, both 9mTc-EC-MN and [(131)I]MISO have higher tumor-to-muscle ratios compared to [18]FMISO., Conclusions: It is feasible to use 9mTc-EC-MN to image tumor hypoxia.

Chemoembolization using microspheres of 100- to 200-microns is a useful way to treat primary and secondary hepatic tumors. In a search for a better embolic material, we described in detail the preparation and characterization of a poly(benzyl l-glutamate) (PBLG) microspheres containing cisplatin (CDDP). We determined the optimal experimental conditions to produce spherical free-flowing microspheres that were able to release drug content (44% [w/w] CDDP) in a sustained manner. We found that solvent viscosity played a key role in determining the resulting microsphere characteristics. Microscopic studies showed that increasing the polymer concentration (to 10% [w/v]) and the viscosity of the organic phase produced microspheres with uniform drug distribution. Increasing polymer concentration also markedly improved drug incorporation efficiency. In vitro release studies revealed that the release of CDDP was a function of drug loading; microspheres with a higher amount of entrapped CDDP had a slower release rate. This observation and the fact that CDDP/PBLG microspheres did not show "burst effect" at higher loading is ascribed to the formation of uniformly distributed drug crystal networks within the polymer matrix. The favorable properties of the CDDP/PBLG system warrants its further evaluation on experimental animal models for the treatment of hepatic tumors.

We describe the synthesis of new fluorotamoxifen analogues with the fluorine atom positioned on the end of the aliphatic chain of tamoxifen. The binding of fluorotamoxifens to cytosol estrogen receptors of rat uteri was determined with [3H]estradiol (5 nM). The fluorotamoxifens had similar or superior binding affinities compared with tamoxifen. The IC50 value was as follows: tamoxifen, 5 x 10(-7) M; fluorotamoxifen (VII), 5 x 10(-7) M; N,N-diethylfluorotamoxifen (IV)-cis, 1 x 10(-6) M, and trans, 2 x 10(-7) M; and (cis) fluoromethyl-N,N-diethyltamoxifen (VI) 1 x 10(-7) M. Therefore, the fluorinated tamoxifens have potential use in imaging estrogen receptors by PET.

The glutamate analogue N-methyl-D-aspartate (NMDA) binds to a subset of glutamate receptors that are coupled to a voltage-sensitive cation channel. This NMDA-linked channel is the likely binding locus of the potent anticonvulsant MK-801. To develop single-photon emission computed tomography (SPECT) probes of this brain channel, we synthesized (+/)1-iodo-MK-801 and (+/-)1-[125I]iodo-MK-801. The effect of (+/-)1-iodo-MK-801 on ligand binding to the NMDA-linked glutamate receptor site was assessed using a rat brain homogenate assay. (+/-)1-Iodo-MK-801 displaced the dissociative anesthetic ligand [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding with an IC50 of 1 microM, which is a 10-fold lower binding affinity than that of (+/-)MK-801. In in vivo autoradiographic studies, (+/-)MK-801 failed to block selective uptake of (+/-)1-iodo-MK-801 in rat brain. These results suggest that (+/-)1-iodo-MK-801 may not be a suitable ligand for mapping NMDA-linked glutamate receptor channels.