Progress towards universal health coverage and inequalities in infant mortality: an analysis of 4·1 million births from 60 low-income and middle-income countries between 2000 and 2019.

BACKGROUND: Expanding universal health coverage (UHC) might not be inherently beneficial to poorer populations without the explicit targeting and prioritising of low-income populations. This study examines whether the expansion of UHC between 2000 and 2019 is associated with reduced socioeconomic inequalities in infant mortality in low-income and middle-income countries (LMICs). METHODS: We did a retrospective analysis of birth data compiled from Demographic and Health Surveys (DHSs). We analysed all births between 2000 and 2019 from all DHSs available for this period. The primary outcome was infant mortality, defined as death within 1 year of birth. Logistic regression models with country and year fixed effects assessed associations between country-level progress to UHC (using WHO's UHC service coverage index) and infant mortality (overall and by wealth quintile), adjusting for infant-level, mother-level, and country-level variables. FINDINGS: A total of 4 065 868 births to 1 833 011 mothers were analysed from 177 DHSs covering 60 LMICs between 2000 and 2019. A one unit increase in the UHC index was associated with a 1·2% reduction in the risk of infant death (AOR 0·988, 95% CI 0·981-0·995; absolute measure of association, 0·57 deaths per 1000 livebirths). An estimated 15·5 million infant deaths were averted between 2000 and 2019 because of increases in UHC. However, richer wealth quintiles had larger associated reductions in infant mortality from UHC (quintile 5 AOR 0·983, 95% CI 0·973-0·993) than poorer quintiles (quintile 1 0·991, 0·985-0·998). In the early stages of UHC, UHC expansion was generally beneficial to poorer populations (ie, larger reductions in infant mortality for poorer households [infant deaths per 1000 per one unit increase in UHC coverage: quintile 1 0·84 vs quintile 5 0·59]), but became less so as overall coverage increased (quintile 1 0·64 vs quintile 5 0·57). INTERPRETATION: Since UHC expansion in LMICs appears to become less beneficial to poorer populations as coverage increases, UHC policies should be explicitly designed to ensure lower income groups continue to benefit as coverage expands. FUNDING: UK National Institute for Health and Care Research.

[LASSO regression based risk prediction model for postoperative control in chronic sinusitis with nasal polyps].

Objective:To establish a risk prediction model for postoperative control of chronic sinusitis with nasal polyps. Methods:Retrospective analysis was done on the clinical of patients who underwent endoscopic sinus surgery in the Department of Otolaryngology of the First Affiliated Hospital of Soochow University during August 2020 to June 2021. Patients were classified into uncontrolled group（40 cases） and controlled group（104 cases）, based on the European Position Paper on rhinosinusitis and nasal polyps（EPOS 2020）, and the clinical and pathological characteristics of the two groups were compared. The least absolute shrinkage and selection operator（LASSO） regression was used to screen the factors that might affect the prognosis of chronic sinusitis with nasal polyps and multivariate logistic regression was performed. The Receiver operating characteristic curve（ROC） was ploted, the area under curve（AUC） was calculated, and the ability of the prediction model was evaluated using the consistency index（C-index）. Results:A total of 144 patients with CRS with nasal polyps 1 year after operation were enrolled in this study, including 40 patients in the uncontrolled group and 104 patients in the control group（complete control or partial control）. 12 risk factors（allergic rhinitis, allergic dermatitis, olfactory dysfunction, E/M ratio, serum alkaline phosphatase, number of pathological eosinophils, number of pathological lymphocytes, number of plasma cells in pathological tissues, percentage of eosinophils in pathological tissues, stromal edema, basement membrane thickening, and hyperplasia of goblet cells） were found to be associated with postoperative recurrence of chronic sinusitis with nasal polyps. The seven variables（allergic rhinitis, olfactory dysfunction, E/M ratio, pathological eosinophilic percentage, stromal edema, basement membrane thickening, and hyperplasia of goblet cell） were extracted after reduced by LASSO regression. Multivariate logistic regression analysis showed that the 7 variables were risk factors for postoperative recurrence of chronic sinusitis with nasal polyps（P<0.05）. Nomogram prediction model for postoperative recurrence of chronic sinusitis with nasal polyps were established based on the 7 variables above. The verification results of the model showed that the C-index and AUC of the model were 0.937 and 0.937（95%CI 0.901-0.973）, suggesting that the nomogram model had a relatively accurate prediction ability. Conclusion:Combined with the basic clinical data of patients, the prediction model established in this study can facilitate the risk prediction of postoperative control of chronic sinusitis with nasal polyps, and thus help to formulate better therapeutic plans for patients.

Clinical profiles and mortality rates are similar for metabolic dysfunction-associated steatotic liver disease and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Recently, the term metabolic dysfunction-associated steatotic liver disease (MASLD) has replaced non-alcoholic fatty liver disease (NAFLD). Concern remains regarding whether the evidence generated under the NAFLD definition can be used for MASLD. We compared the clinical profile and outcomes of NAFLD to MASLD using tertiary care- and population-based data. METHODS: Comparison data were obtained from our NAFLD database and the National Health and Nutrition Examination Survey (NHANES III). Clinical profiles and non-invasive tests (enhanced liver fibrosis [ELF] score, fibrosis-4 index [FIB-4] and vibration-controlled transient elastography) were compared. Mortality data were obtained from NHANES-National Death Index. All-cause mortality was assessed by Cox proportional hazards regression models and cause-specific mortality by competing risk analysis. RESULTS: There were 6,429 patients in the NAFLD database (age: 54 ± 12 years, 42% male, BMI 35.4 ± 8.3, waist circumference 112 ± 17 cm, 52% type 2 diabetes). Average scores for ELF, FIB-4 and liver stiffness were 9.6 ± 1.2, 1.69 ± 1.24,14.0 ± 11.8 kPa, respectively; 99% met MASLD criteria; 95% met MASLD on BMI only. Predictive accuracy of ELF and FIB-4 were identical between MASLD and NAFLD. We included 12,519 eligible participants from NHANES (age 43.00 years, 47.38% male, 22.70% obese, 7.28% type 2 diabetes, 82.51% ≥1 cardiometabolic criteria). Among the NHANES study population, there was excellent concordance between MASLD and NAFLD diagnoses: Cohen's kappa coefficient: 0.968 (95% CI 0.962-0.973) with 5.29% of NAFLD cases not meeting MASLD criteria. After a median follow-up of 22.83 years, there were no mortality differences between MASLD and NAFLD diagnoses (p values ≥0.05). CONCLUSIONS: NAFLD and MASLD are similar except individuals with MASLD seem to be older with slightly higher mortality risk, likely owing to cardiometabolic risk factors. Clinical profiles and non-invasive test thresholds were also identical. These data provide evidence that NAFLD and MASLD terminologies can be used interchangeably. For the small proportion of patients with NAFLD who do not meet MASLD criteria, further consideration is needed. IMPACT AND IMPLICATIONS: In June 2023, new terminology (MASLD) was adopted to replace the term NAFLD as a means to better describe what the liver disease is rather than what it is not, as well as to potentially reduce stigma. Given that MASLD requires at least one cardiometabolic risk factor, questions were raised as to whether this change in the definition would nullify the similarities between NAFLD and MASLD and require new evidence to be generated for MASLD. We used our NAFLD database and a US population-based database to show that the vast majority of patients with NAFLD fulfill criteria for MASLD. Non-invasive tests performed similarly in both groups. Mortality risk was slightly higher in those with MASLD, which is attributed to the presence of cardiometabolic risks. These results provide evidence that data generated in the past three decades for NAFLD can be used interchangeably for MASLD.

Breakdown of chemo-immune resistance by a TDO2-targeted Pt(IV) prodrug via attenuating endogenous Kyn-AhR-AQP4 metabolic circuity and TLS-promoted genomic instability.

A tryptophan-2,3-dioxygenase 2 (TDO2)-targeted Pt(IV) prodrug, DN604-TDOi, was designed to prove that the multi-action compound could overcome drug resistance and relieve immunosuppression via introducing a TDO2 inhibitor to the axial position of a six-coordinate Pt(IV) hybrid. Several in vitro biological studies on cisplatin-resistant NSCLC cancer cells suggested that TDO2-targeted Pt(IV) prodrug could combat cisplatin resistance via influencing TDO2-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-Aquaporin-4 (AQP4) metabolic circuity and AhR-human DNA polymerase (hpol) κ-induced translesion DNA synthesis (TLS) genomic instability, which are positive in drug-resistant human tumors associated with malignant progression and poor survival. Remarkably, we observed that DN604-TDOi could inhibit TDO2-mediated constitutive Kyn-AhR-AQP4 signaling pathway and suppress hpol κ expression, leading to potential decrease of cell motility and genomic instability in A549/cDDP cells. It was confirmed that TDO2-targeted Pt(IV) prodrug could harness Kyn-AhR-AQP4 metabolic circuitry and TLS genomic instability, exerting antitumor effects in C57BL6 but not TDO2-/- mice. Moreover, the Pt(IV) prodrug improved the intratumoral infiltration of Teff cells and reduced the recruitment of Treg cells. The results provided compelling preclinical evidence that TDO2-targeted Pt(IV) prodrug could abrogate immune chemotherapeutic resistance via decaying TDO2-mediated Kyn-AhR-AQP4 immunosuppression and AhR-hpol κ-induced TLS genomic instability, underscoring the development of a novel Pt(IV)-based candidate as a potent immunotherapeutic agent for chemo-immune resistance prevention.

Anti-tumor effects and cell motility inhibition of the DN604-gemcitabine combined treatment in human bladder cancer models.

Bladder cancer is one of the major tumors for men in the world, in which therapy the combination of cisplatin and gemcitabine is still fist-line applied to treat with advanced or metastatic bladder cancer. In our early study, we developed a potential Pt(II) agent, DN604, which has anti-tumor effect as potent as cisplatin toward bladder cancers. Herein, we aim at investigating the combinatory application of DN604 with gemcitabine for bladder cancer treatment. In vitro studies proved that the combined treatment of DN604 and gemcitabine could limit cell proliferation by elevating the incidence of DNA damage induced apoptosis. Notably, further researches showed that the DN604-gemcitabine treatment suppressed cell autophagy to inhibit cell motility upon the ROS dependent p38 MAPK signaling pathway, explicating its better anti-tumor activity than single drug treatment or the cisplatin-gemcitabine treatment. In vivo tests confirmed that the DN604-gemcitabine treatment has superior anti-tumor activity with low toxicity to cisplatin or its combination with gemcitabine treatments. DN604 plus gemcitabine, is of great significance for the treatment with human bladder cancer. Our study has provided a potential combination treatment option.

Combination of DN604 with gemcitabine led to cell apoptosis and cell motility inhibition via p38 MAPK signaling pathway in NSCLC.

Non-small-cell lung cancer (NSCLC) is the most common cancer in the world, which is still treated with Pt(II) agents as first-line drugs. As a traditional anticancer agent, gemcitabine is usually used in the combination treatment of various solid tumors with other drugs. Here, we investigate the combinatory application of gemcitabine with a Pt(II) agent (DN604, reported previously in our former research) in the treatment of NSCLC. In vitro biological assays suggested that DN604-gemcitabine treatment can effectively induce cell apoptosis and suppress cell motility, showing better anti-tumor effect than the single drug treatment or the combined treatment of cisplatin and gemcitabine. More importantly, investigation on the mechanism of the combined treatment proved that such combined treatment can suppress cell autophagy to inhibit cell motility via the activation of p38 MAPK signaling pathway. In vivo studies indicated that combination of DN604 with gemcitabine significantly inhibited the growth of tumor with nearly no influence on the normal organs and weight of mice. Our study widened the application scope of Pt(II) agents combined with gemcitabine for NSCLC treatment.

Beclin1 affected by DN604 upregulates chemo-sensitivity of cervix SiHa cancer cells via inhibiting CK2-MRN-DSBs repair.

DN604, containing a functional dicarboxylato ligand as carboplatin analogue, was significantly studied to explore its potency of antitumour activity. In vitro and in vivo experimental evidence indicated that DN604 exhibited superior antitumor activity than present platinum(II)-based agents in cervix squamous carcinoma SiHa cancer cells. Moreover, DN604 showed negligible toxic effects in vivo as confirmed as Pt accumulation and body weights of mice. Mechanistic studies have shown that DN604 suppressed CK2-mediated MRN complex to improve its antitumor efficacy by promoting DNA double-strand breaks repair. Furthermore, DN604 could inhibit Beclin1 and attenuate CK2-mediated several DSBs repair-related pathways, thus leading to cell apoptosis. Taken together, our research demonstrated that DN604 with the functional dicarboxylato ligand as the leaving group could effectively enhance chemo-sensitivity of SiHa cells to platinum-based agents via suppressing Beclin1 and CK2-mediated MRN-DSBs repair.

DN604: A platinum(II) drug candidate with classic SAR can induce apoptosis via suppressing CK2-mediated p-cdc25C subcellular localization in cancer cells.

DN604, a carboplatin analogue with a functional dicarboxylato ligand, was deeply investigated to explore its ability to induce apoptosis as well as its antitumor mechanism of action. Both in vitro and in vivo assays indicated that DN604 could effectively inhibit cell viability of SGC-7901 gastric cancer cells and exhibited stronger antitumor activity than carboplatin and comparable activity to cisplatin. Significantly in contrast to cisplatin, DN604 resulted in negligible toxic effects in vivo with the same tumor growth inhibition effect as cisplatin. The mechanism study indicated that DN604 inhibited CK2-phosphorylated cdc25C activation to decrease p-cdc25C subcellular localization, leading to the inactivation of cdc2/Cyclin B and G2/M cell cycle arrest and apoptosis in SGC-7901 cancer cells. Our research revealed for the first time that the dicarboxylato ligand containing a suitable functional moiety as the leaving group in the platinum(II) complex can effectively induce cell cycle arrest and apoptosis via inhibiting key checkpoint proteins.

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid.

Five new platinum(IV) derivatives of carboplatin each incorporating the histone deacetylase inhibitor 4-phenylbutyrate in axial position were synthesized and characterized by 1H and 195Pt NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis, namely cis,trans-[Pt(CBDCA)(NH3)2(PBA)(OH)] (1), cis,trans-[Pt(CBDCA)(NH3)2(PBA)2] (2), cis,trans-[Pt(CBDCA)(NH3)2(PBA)(bz)] (3), cis,trans-[Pt(CBDCA)(NH3)2(PBA)(suc)] (4) and cis,trans-[Pt(CBDCA)(NH3)2)(PBA)(ac)] (5) (PBA=4-phenylbutyrate, CBDCA=1,1-cyclobutane dicarboxylate, bz=benzoate, suc=succinate and ac=acetate). The reduction behavior in the presence of ascorbic acid was studied by high performance liquid chromatography. The cytotoxicity against a panel of human tumor cell lines, histone deacetylase (HDAC) inhibitory activity, cellular accumulation and the ability to induce apoptosis were evaluated. The most effective complex, compound 3, was found to be up to ten times more effective than carboplatin and to decrease cellular basal HDAC activity by approximately 18% in A431 human cervical cancer cells.

18F-Labeled Carboplatin Derivative for PET Imaging of Platinum Drug Distribution.

Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, emphasizing the need to directly measure the intratumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we contribute to this endeavor by reporting on the development of an 18F-labeled carboplatin derivative (18F-FCP) that has the potential to image drug uptake and retention, including intratumoral distribution, by PET. Methods: Fluorinated carboplatin (19F-FCP) was synthesized using 19F-labeled 2-(5-fluoro-pentyl)-2-methyl malonic acid (19F-FPMA) as the labeling agent to coordinate with the cisplatin-aqua complex. It was then used to treat cell lines and compared with cisplatin and carboplatin at different concentrations. Manual radiosynthesis and characterization of 18F-FCP were performed using 18F-FPMA for coordination with the cisplatin-aqua complex. Automated radiosynthesis of 18F-FCP was optimized on the basis of manual synthesis procedures. The stability of 18F-FCP was verified using high-performance liquid chromatography. 18F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor-bearing animals as well as in KB-3-1 and COLO-205 tumor xenograft-bearing nude mice. Results: In vitro cytotoxicity studies demonstrated that 19F-FCP has an antitumor activity profile similar to that of the parent drug carboplatin. In vivo plasma and urine stability analysis showed intact 18F-FCP at 24 h after injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in the kidneys, indicating substantial renal clearance of 18F-FCP. Using 18F-FCP PET, we could image and identify the intratumor drug profile. Conclusion: Our results demonstrated that 19F-FCP, like carboplatin, retains antitumor activity in various cell lines. 18F-FCP could be a useful imaging tool for measuring the intratumor drug distribution. This strategy of using a new therapeutic carboplatin derivative to quantify and track platinum drugs in tumors using PET has the potential to translate into a clinically useful imaging tool for individual patients.

9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin.

As part of a comprehensive study of N-unsubstituted bispidines, the novel 9,9-difluorobispidine (D) has been synthesized. The compound crystallizes from pentane below 0 °C in the ordered-crystalline phase D-II and undergoes at 0-30 °C a stepwise endothermic phase transition to a dynamically disordered crystalline phase D-I; melting occurs at 227 °C. Single crystalline D-II has been subjected to X-ray structure analysis, revealing association of the molecules to form chains. Reaction of (1,5-hexadiene)PtCl2 with D affords {C7H10F2(NH)2}PtCl2 (D1), which can be converted by conventional routes to {C7H10F2(NH)2}Pt(cbdca)·5H2O (D2) and {C7H10F2(NH)2}Pt(C2O4) (D3). Compound D1 crystallizes solvent-free from water and is isomorphous to the solvent-free parent bispidine analogue (A1). The pentahydrate D2 is isomorphous to the bispidine and 9-oxabispidine homologues (A2 and C2), as shown by X-ray structure analyses. An increased polarity of the bispidine skeleton as a consequence of the high electronegativity of fluorine is seen as the reason for low cytotoxic potency of D1-D3.

Metronomic chemotherapy using orally active carboplatin/deoxycholate complex to maintain drug concentration within a tolerable range for effective cancer management.

Metronomic chemotherapy has translated into favorable toxicity profile and capable of delaying tumor progression. Despite its promise, conventional injectable chemotherapeutics are not meaningful to use as metronomic due to the necessity of frequent administration for personalized therapy in long-term cancer treatments. This study aims to exploit the benefits of the oral application of carboplatin as metronomic therapy for non-small cell lung cancer (NSCLC). We developed an orally active carboplatin by physical complexation with a deoxycholic acid (DOCA). The X-ray diffraction (XRD) patterns showed the disappearance of crystalline peaks from carboplatin by forming the complex with DOCA. In vivo pharmacokinetic (PK) study confirmed the oral absorption of carboplatin/DOCA complex. The oral bioavailability of carboplatin/DOCA complex and native carboplatin were calculated as 24.33% and 1.16%, respectively, when a single 50mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10mg/kg) for 3weeks were showed 19.17% at day-0, 30.27% at day-7, 26.77% at day-14, and 22.48% at day-21, demonstrating its potential for metronomic chemotherapy. The dose dependent antitumor effects of oral carboplatin were evaluated in SCC7 and A549 tumor xenograft mice. It was found that the oral carboplatin complex exhibited potent anti-tumor activity at 10mg/kg (74.09% vs. control, P<0.01) and 20mg/kg dose (86.22% vs. control, P<0.01) in A549 tumor. The number of TUNEL positive cells in the tumor sections was also significantly increased during oral therapy (3.95% in control, whereas 21.37% and 32.39% in 10mg/kg and 20mg/kg dose, respectively; P<0.001). The enhanced anti-tumor efficacy of oral metronomic therapy was attributed with its antiangiogenic mechanism where new blood vessel formation was notably decreased. Finally, the safety of oral complex was confirmed by three weeks toxicity studies; there were no significant systemic or local abnormalities found in mice at 10mg/kg daily oral dose. Our study thus describes an effective and safe oral formulation of carboplatin as a metronomic chemotherapy.

Synthesis and Structures of 9-Oxabispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin.

The literature synthesis of 9-oxabispidine [OC6H10(NH)2, C] has been revisited and optimized, which includes determination of the crystal structures of C, the secondary component trans-(PhSO2)NC4H6O(CH2I)2 (trans-III), and the unexpected solute intermediate OC6H10(NSO2Ph)2·(1)/2py (V·(1)/2py). The reaction of (1,5-hexadiene)platinum dichloride with C yields {OC6H10(NH)2}PtCl2 (C1), which is converted to {OC6H10(NH)2}Pt(cbdca)·5H2O (C2) and {OC6H10(NH)2}Pt(C2O4) (C3). In the crystal, C1 forms a planar 2D network by N-H··Cl and N-H··O hydrogen bonding. In the crystal structure of C2, which is isomorphous to the parent bispidine compound (A2), all complex molecules are encapsulated by a water shell. While complexes C1 and C3 are virtually insoluble in water, C2 dissolves quite well. The low cytotoxicity of compounds C1-C3 is explained by an increased polarity of the bonds in the C skeleton as a consequence of the electronegative O atom.

Bispidine analogues of cisplatin, carboplatin, and oxaliplatin. synthesis, structures, and cytotoxicity.

Bispidine (3,7-diazabicyclo[3.3.1]nonane, C7H14N2) analogues of cisplatin, carboplatin, and oxaliplatin have been prepared. (C7H14N2)PtCl2·DMF (1b), obtained from (1,5-hexadiene)PtCl2 and bispidine in DMF, is dimeric in the solid state. Dissolving 1b in hot N-methylformamide allows crystallization of the solvent-free polymeric (C7H14N2)PtCl2 (1a). Recrystallization of 1a,b from hot water yields the trihydrate (C7H14N2)PtCl2·3H2O (1c). Reaction of 1 with Ag2(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) in water affords the pentahydrate (C7H14N2)Pt{C4H6(CO2)2}·5H2O (2b), which loses water in vacuo to give (C7H14N2)Pt{C4H6(CO2)2} (2a). Reaction of 1 with AgNO3 in water, followed by addition of Na2C2O4, affords the water-free polymeric (C7H14N2)Pt(C2O4) (3). All complexes have been structurally characterized, revealing various patterns of N-H···Cl and N-H···O hydrogen bonds. In the hydrates 1c and 2b the complexes are embedded in intricate three-dimensional water networks. Complexes 1a, 2a, and 3 have been tested for their cytotoxicity against human cancer cell lines K562 (chronic myeloid leukemia), A2780 (ovarian cancer), and its platinum-resistant subline A2780 CisR and are compared to their parent analogues. The new complexes show significant cytotoxic activity along with a low platinum resistance factor.

Design and evaluation of biological activity of diazenecarboxamide-extended cisplatin and carboplatin analogues.

Construction of a library of structurally diverse diazenecarboxamide-extended cis-[Pt(2-picolyl-1,2,3-triazole)Cl2,] and cis-[Pt(propan-1,3-diamine)CBDCA] (CBDCA = 1,1 -cyclobutanedicarboxylate) complexes 1-4 is described. These compounds retain oxidative properties of parent diazenecarboxamides against glutathione as demonstrated by NMR spectroscopy and high resolution mass spectrometry experiments. Cytotoxic activity of 1-4 was investigated against human cervical carcinoma HeLa cells. Four library members were found to possess moderate cytotoxic activity. Some model compounds were also examined, returning [PtCl2L2] (L = 1-(2-picolyl)-4-phenyl-1H-1,2,3-triazole) as the most potent under this investigation with IC50 of 19.05 microM, comparable to that of cisplatin (IC50 = 16.3 microM).

Synthesis, antiproliferative activity and estrogen receptor α affinity of novel estradiol-linked platinum(II) complex analogs to carboplatin and oxaliplatin. Potential vector complexes to target estrogen-dependent tissues.

In the course of efforts to develop 17ß-estradiol-linked to anticancer agents targeting estrogen-dependent tissue, we identified three estradiol-linked platinum(II) complex analogs to cisplatin (E-CDDP) derivatives namely: VP-128 (1), CD-38 (2) and JMP-39 (3) that exhibit potent in vitro and in vivo (for derivative VP-128) activity along with interaction with the estrogen receptor α (ERα). In this study, we prepared and biologically evaluated two novel classes of estradiol-linked platinum(II) complex analogs to carboplatin (E-CarboP, 1a-3a) and oxaliplatin (E-OxaP, 1b-3b). E-CarboP and E-OxaP were designed and based on the estradiol-linker scaffold of E-CDDP derivatives previously identified. Consequently, we assessed the importance of the nature of platinum(II) salt on the antiproliferative activity on MCF-7 and MDA-MB-231 human mammary carcinoma cell lines together with affinity for the ERα by replacing the dichloroplatinum(II) moiety by a cyclobutane-1,1-dicarboxylateplatinum(II) or an oxalateplatinum(II) moiety. Except for compound 3b which is inactive at the concentration tested, the antiproliferative activity of all compounds on both human mammary carcinomas cell lines are in micromolar range and are more active than carboplatin and oxaliplatin alone but less active that their E-CDDP counterparts (1-3). In addition, E-CarboP derivatives 1a-3a show very low affinity for ERα whereas E-OxaPs 1b and 2b show higher affinity for ERα than their parents E-CDDPs (1-2), suggesting that the nature of the platinum(II) salt involved in the vector complexes is extremely important to both retain significant antiproliferative activity and selectivity for the ERα and possibility to target estrogen-dependent tissues. Finally, E-OxaPs 1b and 2b are potentially promising alternatives vector complexes to target estrogen-dependent tissues.

Platinum anticancer drugs. From serendipity to rational design.

The discovery of cis-platin was serendipitous. In 1965, Rosenberg was looking into the effects of an electric field on the growth of Escherichia coli bacteria. He noticed that bacteria ceased to divide when placed in an electric field but what Rosenberg also observed was a 300-fold increase in the size of the bacteria. He attributed this to the fact that somehow the platinum-conducting plates were inducing cell growth but inhibiting cell division. It was later deduced that the platinum species responsible for this was cis-platin. Rosenberg hypothesized that if cis-platin could inhibit bacterial cell division it could also stop tumor cell growth. This conjecture has proven correct and has led to the introduction of cis-platin in cancer therapy. Indeed, in 1978, six years after clinical trials conducted by the NCI and Bristol-Myers-Squibb, the U.S. Food and Drug Administration (FDA) approved cis-platin under the name of Platinol(®) for treating patients with metastatic testicular or ovarian cancer in combination with other drugs but also for treating bladder cancer. Bristol-Myers Squibb also licensed carboplatin, a second-generation platinum drug with fewer side effects, in 1979. Carboplatin entered the U.S. market as Paraplatin(®) in 1989 for initial treatment of advanced ovarian cancer in established combination with other approved chemotherapeutic agents. Numerous platin derivatives have been further developed with more or less success and the third derivative to be approved in 1994 was oxaliplatin under the name of Eloxatin(®). It was the first platin-based drug to be active against metastatic colorectal cancer in combination with fluorouracil and folinic acid. The two others platin-based drugs to be approved were nedaplatin (Aqupla(®)) in Japan and lobaplatin in China, respectively. More recently, a strategy to overcome resistance due to interaction with thiol-containing molecules led to the synthesis of picoplatin in which one of the amines linked to Pt was replaced by a bulky methyl substituted pyridine allowing the drug more time to reach its target, DNA. On the other hand, efforts which were made to find new orally administered analog led to satraplatin bearing to axial acetate groups. Both drugs are still under clinical trials. An alternatively route to the discovery of new derivatives turns to the development of improved delivery strategies such as liposomes and polymers. Liposomal cis-platin or lipoplatin in under a phase III randomized clinical trial for patients suffering from small cell lung cancer whereas polymer-based drug, Prolindac™ is currently under investigation for pretreated ovarian cancers in up to eight European centers.

Adamantane-platinum conjugate hosted in ß-cyclodextrin: enhancing transport and cytotoxicity by noncovalent modification.

This work reports the synthesis of a complex of a carboplatin analog having tethered adamantane that is encapsulated in the hydrophobic cavity of ß-cyclodextrin (ßCD) and its cytotoxic activity towards human neuroblastoma cells (SK-N-SH). We found that this inclusion complex of ßCD adamantane carboplatin analog exhibited higher cytotoxicity towards SK-N-SH cells than carboplatin itself, and the inclusion complex exhibited a higher binding to plasmid pBR322 deoxyribonucleic acid (DNA) than carboplatin. Confocal fluorescence images of SK-N-SH cells treated with ßCD having an attached fluorescein isothiocyanate (FITC)-tag exhibited fluorescence in the vicinity of the nuclei of the neuroblastoma cells. Direct measurements of the platinum content in SK-N-SH cells using inductively coupled plasma mass spectrometry (ICP-MS) indicated that the uptake rate of carboplatin was about 4 times higher than ßCD adamantane carboplatin analog inclusion complex. When compared to carboplatin, we believe that the higher cytotoxicity of inclusion complex towards SK-N-SH cells is due to its higher DNA binding ability as compared to carboplatin, and more efficient delivery to the nucleus of the cell. This work suggests that the advantage of deliberate noncovalent modification with ßCD through host-guest chemistry may also be broadly applicable to other anticancer agents as well.

Evaluation of in vitro cytotoxicity of 6-benzylaminopurine carboplatin derivatives against human cancer cell lines and primary human hepatocytes.

A series of seven platinum(II) cyclobutane-1,1-dicarboxylato (cbdc) complexes {[Pt(cbdc)(L(n))(2)], 1-7}, derived from carboplatin by a substitution of two NH(3) molecules for two 2,6,9-trisubstituted 6-benzylaminopurine-based N-donor ligands (L(n)), was studied by the MTT assay for their in vitro cytotoxic activity against seven human cancer cell lines, i.e. lung carcinoma (A549), cervix epithelioid carcinoma (HeLa), osteosarcoma (HOS), malignant melanoma (G361), breast adenocarcinoma (MCF7), ovarian carcinoma (A2780) and its cisplatin-resistant analogue (A2780cis), and against two primary cultures of human hepatocytes (LH31 and LH32). The prepared complexes were cytotoxic against several cancer cells, in some cases even more than cisplatin. The best results were achieved for complexes 1 (IC(50)=17.4 ± 2.0 µM) and 2 (IC(50)=14.8 ± 2.1 µΜ) against HOS cells, 1 (IC(50)=15.1 ± 6.8 µM), 2 (IC(50)=13.6 ± 5.2 µM) and 6 (IC(50)=19.0 ± 6.6 µM) against MCF7, 6 (IC(50)=6.4 ± 0.1 µM) against A2780, and 1-6 (IC(50)=15.6 ± 4.0, 12.9 ± 3.7, 15.8 ± 3.8, 16.6 ± 5.5, 22.1 ± 2.5, and 5.6 ± 1.7 µM, respectively) against A2780cis. Viability of human hepatocytes was not declined by the tested complexes up to the concentration of 50 µM (for 1, 3-7) and 20 µM (for 2; caused by lower solubility of this complex).

Comparison of different theory models and basis sets in the calculations of structures and 13C NMR spectra of [Pt(en)(CBDCA-O, O')], an analogue of the antitumor drug carboplatin.

Comparisons of various density functional theory (DFT) methods at different basis sets in predicting the molecular structures and (13)C NMR spectra for [Pt(en)(CBDCA-O, O')], an analogue of the antitumor drug carboplatin, are reported. DFT methods including B3LYP, B3PW91, mPW1PW91, PBE1PBE, BPV86, PBEPBE, and LSDA are examined. Different basis sets including LANL2DZ, SDD, LANL2MB, CEP-4G, CEP-31G, and CEP-121G are also considered. It is remarkable that the LSDA/SDD level is clearly superior to all of the remaining density functional methods in predicting the structure of [Pt(en)(CBDCA-O, O')]. The results also indicate that the B3LYP/SDD level is the best to predict (13)C NMR spectra for [Pt(en)(CBDCA-O, O')] among all DFT methods.