New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na₂[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.     

Magnetic resonance imaging measurements of vascular permeability and extracellular volume fraction of breast tumors by dynamic Gd-DTPA-enhanced relaxometry

Vascular permeability (k(ep), min(-1)) and extracellular volume fraction (v(e)) are tissue parameters of great interest to characterize malignant tumor lesions. Indeed, it is well known that tumors with high blood supply better respond to therapy than poorly vascularized tumors, and tumors with large extracellular volume tend to be more malignant than tumors showing lower extracellular volume. Furthermore, the transport of therapeutic agents depends on both extracellular volume fraction and vessel permeability. Thus, before treatment, these tissue parameters may prove useful to evaluate tumor aggressiveness and to predict responsiveness to therapy and variations during cytotoxic therapies could allow to assess treatment efficacy and early modified therapy schedules in case of poor responsiveness. As a consequence, there is a need to develop methods that could be routinely used to determine these tissue parameters. In this work, blood-tissue permeability and extracellular volume fraction information were derived from magnetic resonance imaging dynamic longitudinal relaxation rate (R(1)) mapping obtained after an intravenous bolus injection of Gd-DTPA in a group of 92 female patients with breast lesions, 68 of these being histologically proven to be with carcinoma. For the sake of comparison, 24 benign lesions were studied. The measurement protocol based on two-dimensional gradient echo sequences and a monoexponential plasma kinetic model was that validated in the occasion of previous animal experiments. As a consequence of neoangiogenesis, results showed a higher permeability in malignant than in benign lesions, whereas the extracellular volume fraction value did not allow any discrimination between benign and malignant lesions. The method, which can be easily implemented whatever the imaging system used, could advantageously be used to quantify lesion parameters (k(ep) and v(e)) in routine clinical imaging. Because of its large reproducibility, the method could be useful for intersite comparisons and follow-up studies.     

傅里叶变换红外光谱技术诊断恶性肿瘤的研究进展

恶性肿瘤严重威胁人类的健康和生命,因此其早期诊断显得尤为重要。近年来,傅里叶变换红外光谱技术在诊断恶性肿瘤方面显示出了巨大的潜力。与传统方法相比,该技术在诊断肿瘤方面具有准确、快速、无创、原位、廉价、自动化、可重复、无需预处理、能够在分子水平上早期诊断等显著优势。本文综述了FTIR技术应用于诊断呼吸、消化、泌尿、生殖、神经、皮肤、血液等各系统恶性肿瘤方面的研究进展,并结合国际上临床医学、光谱学和化学计量学的学科发展现状提出了五点展望：扩大样本量,进行多中心研究;与内窥镜、穿刺活检结合,实现术中实时原位诊断并指导活检;进一步实现自动化;找寻更为高效的化学计量学方法;个别指认比较困难的光谱参数的识别尚有待进一步研究证实。随着FTIR技术的进一步发展和完善,它必将成为一种辅助诊断恶性肿瘤的重要方法,甚至可能作为肿瘤的常规筛查手段并应用于其分期分级中。     

女性乳腺肿瘤的傅里叶变换红外光谱鉴别方法的探索

通过75例女性良,恶性乳腺肿瘤及正常乳腺组织的傅里叶变换红外光谱(FTIR)对比研究发现,它们之间存在着明显而规律的光谱差异,这反 映了组织中蛋白质,核酸和脂类等生物分子在不同性质的乳腺肿瘤中的构型与构像及以及相对含量上的差别,研究表明,FTIR可从分子水平上揭示肿瘤组织的特性,能对良,恶性乳腺肿瘤的鉴别提供丰富而可靠的结构信息,极有可能发展成为一种肿瘤鉴别方法.     

Ni-Alginate Hydrogel Microspheres with Sustained Interleukin 2 Release to Boost Cytokine-Based Cancer Immunotherapy

Interleukin 2 (IL2) is the first approved immunotherapeutic agent in cancer treatment. However, high-dose IL2 administrated through intratumoral injection still spreads all over the body, causing serious systemic toxicity. Herein, an injectable nickel-alginate hydrogel microsphere (Ni-ALGMS) to allow effective loading of IL2 and its sustained release after intratumoral administration is reported. In this design, histidine (his)-tagged IL2 is assembled into the Ni-ALGMS via the coordination bonds between his-tag and Ni²⁺. After injecting IL2-loaded Ni-ALGMSs (IL2@Ni-ALGMSs) into the tumor, IL2 slowly releases over long periods, thereby avoiding the risk of cytokine storm happening in IL2 systemic administration. Applying such IL2@Ni-ALGMSs for tumor model treatment can significantly increase the tumor infiltration of T lymphocytes, and effectively inhibit tumor growth, especially in combination with immune checkpoint inhibitors. This study presents a novel IL2 sustained-releasing platform for tumor immunotherapy, which can also be conveniently applied in other cytokines-based immunotherapies.     

Nanoagent-Promoted Mild-Temperature Photothermal Therapy for Cancer Treatment

Photothermal therapy (PTT), which utilizes near-infrared light-absorbing agents to ablate tumor, has emerged as a highly promising anticancer strategy and received intensive clinical trials in recent years. Mild-temperature PTT, which circumvents the limitations of conventional PTT (e.g., thermoresistance and adverse effects), is emerging and shows great potential in the forthcoming clinical applications. However, mild-temperature PTT without adjuvant therapy is not able to completely eradicate tumors because its therapeutic efficacy is dramatically impaired by its inferior heat intensity. As a result, strategies capable of enhancing the anticancer efficacy of mild-temperature PTT are urgently necessitated, which mainly rely on on-demand fabrication of functionalized nanoagents. In this review, the strategies of nanoagent-promoted mild-temperature PTT are highlighted. Furthermore, challenges and opportunities in this field are rationally proposed, and hopefully people can be encouraged by this promising anticancer therapy.     

Pyridinium-Substituted Tetraphenylethylenes Functionalized with Alkyl Chains as Autophagy Modulators for Cancer Therapy

Tuning autophagy in a controlled manner could facilitate cancer therapy but it remains challenging. Pyridinium-substituted tetraphenylethylene salts (PTPE 1 — 3 ), able to target mitochondria and disrupt autophagy after forming complexes with albumin, are reported. Mitochondrion affinity and autophagy-inducing activity are improved by prolonging the length of alkyl chains in PTPE 1 – 3 . PTPE 1 – 3 demonstrate proautophagic activity and a mitophagy blockage effect. Failure of autophagosome–lysosome fusion in downstream autophagy flux results in cancer cell death. Moreover, fast formation of complexes of PTPE 1 – 3 with albumin in blood can facilitate biomimetic delivery and deep tumor penetration. Efficient tumor accumulation and effective tumor suppression are successfully demonstrated with in vitro and in vivo studies. PTPE 1 – 3 salts exhibit dual functionality: they target and image mitochondria because of aggregation-induced emission effects and they are promising for cancer therapy.     

Pyridinium‐Substituted Tetraphenylethylenes Functionalized with Alkyl Chains as Autophagy Modulators for Cancer Therapy

Tuning autophagy in a controlled manner could facilitate cancer therapy but it remains challenging. Pyridinium‐substituted tetraphenylethylene salts (PTPE 1 — 3 ), able to target mitochondria and disrupt autophagy after forming complexes with albumin, are reported. Mitochondrion affinity and autophagy‐inducing activity are improved by prolonging the length of alkyl chains in PTPE 1 – 3 . PTPE 1 – 3 demonstrate proautophagic activity and a mitophagy blockage effect. Failure of autophagosome–lysosome fusion in downstream autophagy flux results in cancer cell death. Moreover, fast formation of complexes of PTPE 1 – 3 with albumin in blood can facilitate biomimetic delivery and deep tumor penetration. Efficient tumor accumulation and effective tumor suppression are successfully demonstrated with in vitro and in vivo studies. PTPE 1 – 3 salts exhibit dual functionality: they target and image mitochondria because of aggregation‐induced emission effects and they are promising for cancer therapy.     

Proteomic analysis of pancreatic ductal carcinoma cells treated with 5-aza-2'-deoxycytidine

A pancreatic adenocarcinoma cell line (PaCa44), which contains, among other alterations, a methylated p16 promoter, was treated with a chemoterapeutic agent, 5-aza-2'-deoxycytidine (DAC), in order to evaluate the effect of this drug on cell growth and protein expression. Cell proliferation was strongly inhibited by a 24 h DAC treatment and this inhibition lasted for at least 10 days. Master maps of control and treated PaCa44 cells were generated by analysis with the PDQuest software. The comparison between such maps showed up- and downregulation of 45 polypeptide chains, of which 32 were downregulated and 13 upregulated, out of a total of 700 spots detected by a medium-sensitivity stain, micellar Coomassie Brilliant Blue. Fingerprinting by mass spectrometry analysis enabled the identification of 36 of these spots. Among the major changes in DAC-treated cells: cofilin and profilin 1 are silenced; coactosin, peptidyl-propyl cis-trans isomerase A and cystatin B are decreased by 22, 16- and 15-fold, respectively; stress-70 protein, superoxide dismutase and protein disulfide isomerase A3 are increased by 13-, 11-, and 5-fold, respectively. The significance of some of these major changes is discussed.