Systematic review and meta-analysis on coronary calcifications in COVID-19.

Chest CT is valuable to detect alternative diagnoses/complications of COVID-19, while its role for prognostication requires further investigation. Non-pulmonary radiological findings such as cardiovascular calcifications could increase the predictivity of clinical outcomes of COVID-19 patients beyond pulmonary involvement. Several observational studies have reported mixed results on the role of coronary calcifications in COVID-19 patients as a predictor of hospitalization, ventilatory support, and mortality. The purpose of the study is to systematically review the available evidence on the predictive role of cardiovascular calcifications in SARS-CoV2 disease. The meta-analysis confirms the prognostic significance of coronary calcifications on hospital mortality, and coronary calcifications (CAC ≠ 0) were associated with an OR for mortality of 2.19 (95% CI 1.36-3.52). CAC was neutral on respiratory outcomes, but it was associated with an increased trend of cardiovascular events. Coronary calcium appears as a promising biomarker imaging even in short-term outcomes (MACEs, hospital mortality) in a non-cardiovascular disease such as Sars-CoV2 infection. Further large studies are needed to confirm promising results of this imaging biomarker in non-cardiovascular disease.

Silicon-on-insulator free-carrier injection modulators for the mid-infrared.

Experimental demonstrations of silicon-on-insulator waveguide-based free-carrier effect modulators operating at 3.8 µm are presented. PIN diodes are used to inject carriers into the waveguides, and are configured to (a) use free-carrier electroabsorption to create a variable optical attenuator with 34 dB modulation depth and (b) use free-carrier electrorefraction with the PIN diodes acting as phase shifters in a Mach-Zehnder interferometer, achieving a VπLπ of 0.052 V·mm and a DC modulation depth of 22 dB. Modulation is demonstrated at data rates up to 125 Mbit/s.

High-speed Si/GeSi hetero-structure Electro Absorption Modulator.

The ever-increasing demand for integrated, low power interconnect systems is pushing the bandwidth density of CMOS photonic devices. Taking advantage of the strong Franz-Keldysh effect in the C and L communication bands, electro-absorption modulators in Ge and GeSi are setting a new standard in terms of device footprint and power consumption for next generation photonics interconnect arrays. In this paper, we present a compact, low power electro-absorption modulator (EAM) Si/GeSi hetero-structure based on an 800 nm SOI overlayer with a modulation bandwidth of 56 GHz. The device design and fabrication tolerant process are presented, followed by the measurement analysis. Eye diagram measurements show a dynamic ER of 5.2 dB at a data rate of 56 Gb/s at 1566 nm, and calculated modulator power is 44 fJ/bit.

Suspended low-loss germanium waveguides for the longwave infrared.

Germanium is a material of high interest for mid-infrared (MIR) integrated photonics due to its complementary metal-oxide-semiconductor (CMOS) compatibility and its wide transparency window covering the 2-15 µm spectral region exceeding the 4 and 8 µm limit of the silicon-on-insulator platform and Si material, respectively. In this Letter, we report suspended germanium waveguides operating at a wavelength of 7.67 µm with a propagation loss of 2.6±0.3 dB/cm. To the best of our knowledge, this is the first demonstration of low-loss suspended germanium waveguides at such a long wavelength. Suspension of the waveguide is achieved by defining holes alongside the core providing access to the buried oxide layer and the underlying Si layer so that they can be wet etched using hydrofluoric acid and tetramethylammonium hydroxide, respectively. Our MIR waveguides create a new path toward long wavelength sensing in the fingerprint region.

Suspended silicon waveguides for long-wave infrared wavelengths.

In this Letter, we report suspended silicon waveguides operating at a wavelength of 7.67 µm with a propagation loss of 3.1±0.3 dB/cm. To our knowledge, this is the first demonstration of low-loss silicon waveguides at such a long wavelength, with loss comparable to other platforms that use more exotic materials. The suspended Si waveguide core is supported by a sub-wavelength grating that provides lateral optical confinement while also allowing access to the buried oxide layer so that it can be wet etched using hydrofluoric acid. We also demonstrate low-loss waveguide bends and s-bends.

Suspended silicon mid-infrared waveguide devices with subwavelength grating metamaterial cladding.

We present several fundamental photonic building blocks based on suspended silicon waveguides supported by a lateral cladding comprising subwavelength grating metamaterial. We discuss the design, fabrication, and characterization of waveguide bends, multimode interference devices and Mach-Zehnder interferometers for the 3715 - 3800 nm wavelength range, demonstrated for the first time in this platform. The waveguide propagation loss of 0.82 dB/cm is reported, some of the lowest loss yet achieved in silicon waveguides for this wavelength range. These results establish a direct path to ultimately extending the operational wavelength range of silicon wire waveguides to the entire transparency window of silicon.

Suspended SOI waveguide with sub-wavelength grating cladding for mid-infrared.

We present a new type of mid-infrared silicon-on-insulator (SOI) waveguide. The waveguide comprises a sub-wavelength lattice of holes acting as lateral cladding while at the same time allowing for the bottom oxide (BOX) removal by etching. The waveguide loss is determined at the wavelength of 3.8 µm for structures before and after being underetched using both vapor phase and liquid hydrofluoric acid (HF). A propagation loss of 3.4 dB/cm was measured for a design with a 300 nm grating period and 150 nm holes after partial removal (560 nm) of BOX by vapor phase HF etching. We also demonstrate an alternative design with 550 nm period and 450 nm holes, which allows a faster and complete removal of the BOX by liquid phase HF etching, yielding the waveguide propagation loss of 3.6 dB/cm.

Mid-infrared wavelength division (de)multiplexer using an interleaved angled multimode interferometer on the silicon-on-insulator platform.

A low-cost and high-performance wavelength division (de)multiplexing structure in the mid-IR wavelength range is demonstrated on the silicon-on-insulator platform using an interleaved angled multimode interferometer (AMMI). As compared to a single AMMI, the channel count was doubled and the channel spacing halved with negligible extra insertion loss and crosstalk and with only a slight increase in device footprint. The device requires only single lithography and etching steps for fabrication. Potential is also shown for achieving improved performance with further optimized design.

Recruitment of trimeric proliferating cell nuclear antigen by G1-phase cyclin-dependent kinases following DNA damage with platinum-based antitumour agents.

BACKGROUND: In cycling tumour cells, the binary cyclin-dependent kinase Cdk4/cyclin D or Cdk2/cyclin E complex is inhibited by p21 following DNA damage to induce G1 cell-cycle arrest. However, it is not known whether other proteins are also recruited within Cdk complexes, or their role, and this was investigated. METHODS: Ovarian A2780 tumour cells were exposed to the platinum-based antitumour agent 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum(IV) (DAP), which preferentially induces G1 arrest in a p21-dependent manner. The Cdk complexes were analysed by gel filtration chromatography, immunoblot and mass spectrometry. RESULTS: The active forms of Cdk4 and Cdk2 complexes in control tumour cells have a molecular size of ~140 kDa, which increased to ~290 kDa when inhibited following G1 checkpoint activation by DAP. Proteomic analysis identified Cdk, cyclin, p21 and proliferating cell nuclear antigen (PCNA) in the inhibited complex, and biochemical studies provided unequivocal evidence that the increase in ~150 kDa of the inhibited complex is consistent with p21-dependent recruitment of PCNA as a trimer, likely bound to three molecules of p21. Although p21 alone was sufficient to inhibit the Cdk complex, PCNA was critical for stabilising p21. CONCLUSION: G1 Cdk complexes inhibited by p21 also recruit PCNA, which inhibits degradation and, thereby, prolongs activity of p21 within the complex.

Effects on the monocyte-macrophage system and antitumor activity against L1210 leukemia of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane -platinum (II) encapsulated in multilamellar vesicles.

Multilamellar vesicles (MLVs) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a molar ratio of 7:3 were used as carriers of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane-p latinum (II) (CPDP). The encapsulation efficiency of liposomal CPDP (L-CPDP) was 87.6%, and its stability in normal saline at 14 days was 94.4%. The in vitro and in vivo effects on the function of the monocyte-macrophage system and the antitumor activity against L1210 leukemia were investigated in CD-1 and (C57BL/6J X DBA/2J)F1 mice. L-CPDP and cisplatin (CDDP) caused a comparable inhibition of murine-resident peritoneal macrophage (PM) protein and RNA synthesis and superoxide anion release. PM-mediated tumor cell cytotoxicity was completely inhibited at a concentration of 10 micrograms CDDP and L-CPDP/ml but not at concentrations of 1 and 5 micrograms/ml. The differences in plasma clearance of 99mTc-labeled MLV and phagocytic capacity of the liver among animals pretreated with the maximum tolerated doses of L-CPDP (25 mg/kg), empty liposomes, or CDDP (10 mg/kg) were not statistically significant (plasma clearance % of control: 105, 110, and 100, respectively: P greater than .05; liver uptake % of control: 87, 96, and 104, respectively: P greater than .05). At the maximum tolerated doses, the antitumor activity of L-CPDP against L1210 leukemia was similar to that of CDDP when a single dose was administered [median survival of treated mice/median survival of control mice X 100 (%T/C): 181 vs. 175] and slightly higher with the use of a triple-dose schedule (%T/C: 275 vs. 225). L-CPDP is easy to prepare, has a high-encapsulation efficiency and stability, is not more toxic than CDDP to the monocyte-macrophage system, and is at least as effective as CDDP against L1210 leukemia.

Lipophilic cisplatin analogues entrapped in liposomes: role of intraliposomal drug activation in biological activity.

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), a lipophilic cisplatin analogue containing two branched leaving groups of 10 carbon atoms, is undergoing clinical evaluation in a liposomal formulation. In previous studies, NDDP entrapped in multilamellar vesicles composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a 7:3 molar ratio was non-nephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastases whereas free NDDP was devoid of in vivo antitumor activity at the optimal dose of L-NDDP and barely active at higher doses. To elucidate the mechanisms by which the liposomal carrier enhances the biological properties to this class of antitumor agents, we studied the effect of the liposome composition, size of the branched leaving groups of the platinum compound, and pH and composition of the aqueous phase on the entrapment efficiency, drug leakage, drug stability, and in vivo toxicity and antitumor activity of different liposomal formulations of these agents. In experiments using normal saline as aqueous phase, the presence of DMPG in the lipid bilayer resulted in a decreased stability and an increased biological activity of NDDP, whereas NDDP entrapped in liposomes composed of DMPC alone (not containing DMPG) was stable but devoid of antitumor activity. In studies with structurally related analogues with branched leaving groups of 5, 6, 7, and 9 carbon atoms, similar trends were observed. In addition, the number of carbon atoms in the leaving groups was directly and inversely related to the entrapment efficiency and stability of the analogues, respectively, independently of lipid composition; increasing the size of the branched leaving groups resulted in an increased in situ degradation of the platinum compound and enhanced biological activity and potency. These results suggest that this class of platinum compounds exerts its biological activity through the formation of active intermediates in situ within the lipid bilayers and that the activation reaction is highly dependent on the presence of DMPG and the size of the lipophilic leaving group.

Axial ligands and alicyclic ring size modulate the activity and biochemical pharmacology of ammine/cycloalkylamine-platinum(IV) complexes in tumor cells resistant to cis-diamminedichloroplatinum(II) or trans-1R,2R-1S,2S-diaminocyclohexanetetrachloroplatinum(IV).

A platinum(II) and 3 platinum(IV) ammine/cycloalkylamine homologous series were evaluated for cytotoxicity and biochemical pharmacology in murine leukemia L1210/0, cis-diamminedichloroplatinum(II)- resistant L1210/DDP, and diaminocyclohexaneplatinum-resistant L1210/1,2-diaminocyclohexane (DACH) cells. Within each series, which contained 4 homologues with differing alicyclic (cycloalkyl) ring size (cyclopropane, cyclobutane, cyclopentane, or cyclohexane), cytotoxicity increased with increasing ring size. This appeared to be due to an increase in partition coefficient, and the resulting increase in drug accumulation and intracellular DNA adducts in ascending each of the series. There were exceptions to this generalization, predominantly in L1210/DACH cells, where the biochemical pharmacology was not entirely consistent with the cytotoxic response and suggested that other factors may be at play. The relationship between structure and ability to circumvent cis-diamminedichloroplatinum(II) and/or trans-1R,2R-1S,2S- diaminocyclohexanetetrachloroplatinum(IV) resistance was complex. Ascending the platinum(II) series caused resistance factors to decrease in L1210/DDP cells but increase in L1210/DACH cells. An increase in resistance factors was also observed in ascending the axial chloroplatinum(IV) series in the L1210/DACH line. In contrast, ascending the axial chloroplatinum(IV) series in the L1210/DDP line and axial acetatoplatinum(IV) and axial hydroxoplatinum(IV) series in both cell lines resulted in increases in resistance factors for the first stepwise increase in the cycloalkylamine ring size, but resistance factors then decreased progressively with further increases in ring size. Reduction of the platinum(IV) analogues to the platinum(II) congener appears to be necessary for binding to DNA. The similarity in biological actions between the platinum(II) and axial chloroplatinum(IV) series is likely due to the rapid reduction of tetravalent members to platinum(II) forms. The axial acetatoplatinum(IV) and axial hydroxoplatinum(IV) complexes were reduced more slowly, which may explain their lower potency, but not the ability of the higher member to circumvent both cis-diamminedichloroplatinum(II) and trans-1R,2R-1S,2S- diaminocyclohexanetetrachloroplatinum(IV) resistances. Explanation for this will require additional studies. The results have demonstrated high dependencies on ring size of the carrier amine ligand, valence state of platinum, and the nature of the axial ligand for modulation of potency, cross-resistance property, and biochemical pharmacology of ammine/cycloalkylamine complexes.

Biochemical pharmacology of homologous alicyclic mixed amine platinum(II) complexes in sensitive and resistant tumor cell lines.

Three homologous alicyclic mixed amine cis-(NH3)(R-NH2)Cl2Pt(II) complexes, in which R = C3H5, C6H11, and C8H15 (complexes abbreviated C3, C6, and C8, respectively), were evaluated with reference compounds cisplatin and tetraplatin for antitumor activities and biochemical pharmacology in wild-type (murine leukemia L1210/0 and human ovarian A2780) and corresponding variant cell lines resistant to cisplatin (L1210/DDP and 2780CP) and tetraplatin (L1210/DACH and 2780TP). Cytotoxicities, measured by either a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or a clonogenic assay, were maximal for the C6 complex, which was up to 12-, 40-, and 6-fold more potent than C3 against wild-type, cisplatin-resistant, and tetraplatin-resistant models, respectively, and up to 2-fold more potent than C8 against these cell lines. In general, cross-resistance to mixed amine analogues was partial in cisplatin- and tetraplatin-resistant cells and decreased (in L1210/DDP and 2780CP) or increased (in L1210/DACH and 2780TP) with increase in the alicyclic ring size. The increase in ring size resulted in a corresponding increase in partition coefficient, which correlated directly with intracellular accumulations of mixed amine analogues in all cell lines. However, the intracellular DNA-platinum adducts, and not cellular platinum content, was the pharmacological entity that corresponded closely to potencies of the molecules. DNA adduct formation was disproportionate to the level of cellular drug accumulation. For instance, complex C8, which accumulated to the greatest extent in any given cell line, produced adduct levels that were similar to or lower than those produced by C6. A partial explanation for this observation was the demonstrated reduced rate of binding of C8 to DNA. This study has highlighted the significance of alicyclic ring size in modulating the potency, cross-resistance profile, and biochemical pharmacology of mixed amine platinum(II) complexes in sensitive and cisplatin- or tetraplatin-resistant tumor cells.

Treatment and prophylaxis of experimental liver metastases of M5076 reticulosarcoma with cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) encapsulated in multilamellar vesicles.

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +-(II) (NDDP) was encapsulated in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a 7:3 molar ratio. Compared with cisplatin, i.v. administration of an equimolar dose of liposome-encapsulated NDDP (L-NDDP) resulted in 15-fold higher peak platinum levels in the spleen (204.7 versus 13.3 micrograms/g dry tissue), 5-fold higher in the lungs (116.4 versus 21.0 micrograms/g dry tissue), 3-fold higher in the liver (71.6 versus 23.9 micrograms/g dry tissue), and 4-fold higher in the blood (14.8 versus 3.9 micrograms/ml). At the optimal dose and schedule, L-NDDP administered i.p. in mice bearing peritoneal L1210 leukemia resulted in the percentage of median survival time of treated mice divided by median survival time of control mice (%T/C) of 312 versus 225 for cisplatin and free NDDP. When administered i.v., L-NDDP was also more active than cisplatin against L1210 leukemia inoculated i.v. (%T/C 186 versus 142). L-NDDP was markedly active against L1210 leukemia resistant to cisplatin (%T/C, 200 versus 112 for cisplatin). In mice bearing liver metastases of M5076 reticulosarcoma, L-NDDP was significatnly more effective than cisplatin at equimolar doses (mean survival time, 57 +/- 9 (SD) days for L-NDDP versus 42 +/- 3 days for cisplatin, P less than 0.05). L-NDDP was also effective in preventing liver metastases of M5076 when administered up to 24 h prior to tumor inoculation (mean survival, 28 +/- 2 days for L-NDDP versus 22 +/- 2 days for cisplatin, P less than 0.05). L-NDDP is significantly non-cross-resistant with cisplatin and more effective against phagocytic and nonphagocytic murine tumors.

Toxicity and antitumor activity of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) encapsulated in multilamellar vesicles.

The potential of multilamellar vesicles (MLVs) as carriers of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) (CPDP), a lipophilic cisplatin derivative, was assessed. MLVs composed of dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), and cholesterol at different molar ratios were tested. The MLV-CPDP preparation with the highest antitumor activity against L1210 leukemia in vivo was DMPC:DMPG 7:3-CPDP. The encapsulation efficiency of this preparation was 66 +/- 4% (SD); the stability in 0.9% NaCl solution at 4 degrees C was 89% at 14 days and 93% 18 h after incubation in human AB serum at 37 degrees C. The toxicities of DMPC:DMPG 7:3-CPDP and free CPDP (suspended in hydroxypropyl cellulose) administered i.p. were similar (50% lethal dose = 75 versus 91 mg/kg; blood urea nitrogen values 96 h after the administration of the 50% lethal dose = 32.0 versus 34.4 mg/dl). The mean %T/C [(median survival time of treated mice divided by median survival time of control mice) X 100] obtained after a single i.p. injection of the optimal dose of each preparation tested was 215 (range 200 to 232) for DMPC:DMPG 7:3-CPDP, 175 (range 158 to 209) for DMPG-CPDP, 162 (range 136 to 179) for free CPDP, and 178 (range 169 to 189) for cisplatin. Using a multiple i.p. injection schedule (injections on Days 1, 5, and 9), DMPC:DMPG 7:3-CPDP was more active than free CPDP and cisplatin (%T/C: 403, 284, and 253% respectively). DMPC:DMPG 7:3-CPDP is less toxic and more active against L1210 leukemia in vivo than is cisplatin. The encapsulation of CPDP in MLVs composed of DMPC:DMPG 7:3 provides an adequate vehicle for the administration of this lipophilic compound and enhances its antitumor activity against L1210 leukemia.

Modulation of cytotoxicity and cellular pharmacology of 1,2-diaminocyclohexane platinum (IV) complexes mediated by axial and equatorial ligands.

Isomers (R,R-, S,S-, and cis-) of 1,2-diaminocyclohexane (DACH) platinum(IV) complexes with selected axial and equatorial ligands were synthesized and evaluated for in vitro antitumor activity, cellular uptake, and total DNA-Pt adducts. L1210 cells, sensitive to cis-diamminedichloroplatinum(II) (CDDP) and tetraplatin (L1210/0), 160-fold resistant to CDDP [L1210/diamminedichloroplatinum (DDP)], or 70-fold resistant to tetraplatin (L1210/DACH), were used in conjunction with compounds having the general structure DACH-Pt(IV)-X2Y2, where X and Y are axial and equatorial ligands and X2Y2 are specifically Cl2Cl2,Ac2Cl2, (TFA)2Cl2, (OH)2Cl2, and Cl2CBDCA (Cl, chloro; Ac, acetato; TFA, trifluoroacetato; OH, hydroxo; CBDCA, 1,1-cyclobutanedicarboxylato). Comparison of cytotoxicities between isomers of Cl2Cl2,Ac2Cl2, or Cl2CBDCA indicated that R,R-isomers were the most effective against all three cell lines. The relatively lower activity of the S,S- and cis-isomers was cell line dependent: against L1210/DACH, both isomers of Cl2Cl2 were only 2- to 3-fold less effective, and this contrasted with 7- and 26-fold lower cytotoxicities, respectively, against L1210/DDP. Cross-resistance factors in the L1210/DDP and L1210/DACH lines depended on both isomeric form and the nature of axial or equatorial ligand. The L1210/DDP cells were 6- to 9-fold cross-resistant to the R,R-isomer, 8- to 15-fold to S,S-isomer, and 13- to 38-fold to cis-isomer. The L1210/DACH line was only 4- to 7-fold cross-resistant to the three isomers of Ac2Cl2 but cross-resistance to the isomers was 47- to 79-fold for Cl2Cl2 and 22- to 56-fold for Cl2CBDCA complexes. Compared with CDDP, accumulation (2 h at 100 microM drug concentration) of Ac2Cl2 in the three L1210 cell lines was 26-50%, while uptake of Cl2Cl2 and (TFA)2Cl2 was 100-170% and 320-570%, respectively. The greatest DNA binding was seen with Cl2Cl2 in all cell lines, followed by (TFA)2Cl2, CDDP, and Ac2Cl2. DNA binding correlated directly with potency (1/concentration producing 50% inhibition) in the L1210/0 model (r = 0.973, P < 0.016) but not in the L1210/DDP and L1210/DACH models. Accumulation and DNA-binding studies indicated that binding efficiency to DNA was: Cl2Cl2 > Ac2Cl2 > CDDP > (TFA)2Cl2. In a nonreducing environment, the Pt(IV) complexes (20 microM) did not react with salmon sperm DNA. Reduced glutathione (100 microM), as a reducing agent, rendered full binding capacity to Cl2Cl2; binding was 25-30% of the expected maximum for (TFA)2Cl2, while Ac2Cl2 remained inert.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased cytotoxicity and reversal of resistance to cis-diamminedichloro-platinum(II) with entrapment of cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in multilamellar lipid vesicles.

The role of liposome entrapment in modulating the cytotoxicity of a lipophilic cisplatin derivative was assessed. cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP) was tested in suspension (free NDDP) or entrapped in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol (L-NDDP). Against LoVo colon carcinoma cells sensitive to cisplatin, L-NDDP was two times more cytotoxic in vitro than free NDDP and cisplatin (Do 7 microM for L-NDDP, 15 microM for free NDDP, and 16 microM for cisplatin). Against LoVo cells resistant to a concentration of 3 micrograms/ml of cisplatin, L-NDDP was three times more cytotoxic than free NDDP and cisplatin (Do 14 microM for L-NDDP, 45 microM for free NDDP, and 48 microM for cisplatin). In in vivo studies, free NDDP was less potent and less active than L-NDDP against i.p. L-1210 leukemia (free NDDP, optimum %T/C 148 at a dose of 75 mg/kg; L-NDDP, optimum %T/C 185 at a dose of 25 mg/kg) and i.p. L1210/PDD leukemia (free NDDP, optimum %T/C 128 at a dose of 50 mg/kg on Days 1, 5, and 9; L-NDDP, optimum %T/C 200 at a dose of 12.5 mg/kg on Days 1, 5, and 9). Free NDDP administered i.v. was inactive against liver metastases of M5076 reticulosarcoma (%T/C 102) while L-NDDP showed significant activity (%T/C 140). The single dose i.v. LD50 in mice of free NDDP and L-NDDP were similar (79.4 mg/kg for free NDDP and 64.5 mg/kg for L-NDDP). These studies show that NDDP is a liposome-dependent drug since it can only be satisfactorily formulated in the liposomal form and since the liposomal carrier plays a crucial role in determining its antitumor activity.

Water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes as potential antitumor agents.

A series of water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results obtained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cis-dichloro-diammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice inoculated with L1210 leukemia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were administered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against L1210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1, 5, and 9 following i.p. inoculation of B16 melanoma to B6D2F1 mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). N-Benzyl-iminodiacetato(1,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containing material. The exact chemical identity of the active component of this mixture is currently under investigation. The results obtained to date, however, suggest that the N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.

Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) in A2780/S and A2780/PDD cells.

We studied the cytotoxicity, cellular accumulation, and DNA interactions induced by liposome-entrapped NDDP (L-NDDP) and cisplatin in A2780 human ovarian carcinoma cells sensitive (A2780/S) and resistant (A2780/PDD) to cisplatin. L-NDDP was 2-fold more cytotoxic than cisplatin against A2780/S cells with 5-h or 24-h drug exposure. Both cell lines were equally sensitive to L-NDDP, while A2780/PDD cells were 4-fold resistant to cisplatin (resistance indexes, 1.30-1.85 and 4.02-4.50, respectively). Using a drug exposure time of 24 h, L-NDDP cytotoxicity was independent of the liposome composition used, whereas with shorter drug exposure (5 h), the cytotoxicity of L-NDDP was directly related to the relative content of DMPG in the liposome carrier. However, changes in liposome composition or drug exposure time did not alter the resistance index of L-NDDP in this cell system. The cellular accumulation of L-NDDP was similar in both cell lines and 2- to 5-fold higher than that of cisplatin in A2780/S cells, whereas the cellular accumulation of cisplatin was reduced by 2- to 3-fold in A2780/PDD cells. The presence of DMPG in the lipid bilayer enhanced by 2-fold the cellular accumulation of L-NDDP, in good correlation with the direct relation between cytotoxic potency of L-NDDP and the presence of DMPG in the liposome carrier. Pt/DNA levels were determined at different time points after drug exposure for 1 h. Peak Pt/DNA levels were observed at 6 h for cisplatin and at 9 h for L-NDDP. Peak Pt/DNA levels and Pt/DNA over time of L-NDDP were about 1.5- and 3-fold higher than those of cisplatin in A2780/S and A2780/PDD cells, respectively, when equimolar concentrations of both drugs were used. Cisplatin induced significant DNA interstrand and DNA-protein cross-links in A2780/S cells, and a good correlation was observed between cytotoxicity against both cell lines and both types of lesions. In contrast, equimolar concentrations of L-NDDP induced only minimal DNA interstrand cross-links in either cell line.(ABSTRACT TRUNCATED AT 400 WORDS)

Ascorbato(1,2-diaminocyclohexane):platinum(II) complexes, a new series of water-soluble antitumor drugs.

Dichloro-1,2-diaminocyclohexane (DACH):platinum(II), the prototype DACH:platinum complex, had good antitumor activity, was not cross-resistant with cis-dichlorodiammineplatinum(II) (DDP), but was, unfortunately, virtually insoluble in water and was, therefore, not evaluated clinically. This paper summarizes some of the chemical and biological attributes of a series of cis-bisascorbato-DACH:platinum(II) complexes (DAP). Although the primary emphasis has been placed on the DAP complex consisting of the isomeric mixture DACH, a series of complexes using the isomers of either DACH or ascorbic acid have also been synthesized. The synthetic procedure entailed reacting the water-soluble sulfato-DACH:platinum(II) with barium ascorbate, and the water-soluble product DAP was removed from the BaSO4 precipitate by filtration. Based upon elemental analysis, all the complexes had stoichiometric composition of one DACH:one platinum and two ascorbate monoanions. High-pressure liquid chromatography of cis-bisascorbato (mixed-isomer DACH):platinum revealed a series of platinum-containing, ultraviolet-absorbing peaks. All the DAP complexes had significant in vitro cytotoxicity against L1210 leukemia cells (L1210/0) with 50%-inhibitory dose values ranging from 2 to 5 micrograms/ml. None of the complexes was cross-resistant with DDP when tested in vitro against L1210 cells 50-fold resistant to DDP (L1210/DDP). The cis-bisascorbato (mixed-isomer DACH):platinum (DAP-1) was administered i.p. to C57BL X DBA/2 F1 mice inoculated i.p. with 10(6) L1210/0 cells. When administered on Days 1, 5, and 9, the DAP-1 complex consistently produced treated:control values in excess of 200% with several long-term survivors (alive 60 days after tumor inoculation). Further, the DAP-1 complex was totally non-cross-resistant with DDP when tested in vivo against a DDP-resistant L1210 line. Toxicological investigations revealed that DAP-1 was relatively nonnephrotoxic but did cause the expected bone marrow and gastrointestinal toxicity. In summary, the DAP complexes are highly water-soluble, nonnephrotoxic platinum complexes with sufficient antitumor activity to warrant further pharmacological, biochemical, and chemical investigations.