Self-Assembly of a Linear-Dendritic Polymer Containing Cisplatin and Norcantharidin into Raspberry-like Multimicelle Clusters for the Efficient Chemotherapy of Liver Cancer.

Combination chemotherapy has been proved to be an effective strategy in the clinic, and nanoformulations have drawn much attention in the field of drug delivery. However, conventional nanocarriers suffer from shortcomings such as inefficient coloading and undesired molar ratios of the combined drugs, preleakage of cargos during systemic circulation, and lack of cancer-selective drug release. To achieve tumor-specific codelivery of cisplatin (CDDP) and norcantharidin (NCTD) for synergistic treatment of liver cancer, a novel linear-dendritic polymer, termed as G1(PPDC)x, was designed and synthesized, where a prodrug consisting of cisplatin (CDDP) and norcantharidin (NCTD) was conjugated to PEG2000 via ester bonds to fabricate linear polymer-drug conjugates, and the conjugates were subsequently grafted to the terminal hydroxyls of a dendritic polycarbonate core. Benefiting from the hydrogen bond interactions, G1(PPDC)x could spontaneously self-assemble into a unique type of raspberry-like multimicelle clusters in solution (G1(PPDC)x-PMs). G1(PPDC)x-PMs possessed an optimal synergistic ratio of CDDP and NCTD, without obvious premature release or disassembly in biological environments. Intriguingly, upon extravasation into the interstitial tumor tissues, G1(PPDC)x-PMs (132 nm in diameter) could disassemble and reassemble into smaller micelles (40 nm in diameter) in response to the mildly acidic tumor microenvironment, which would enhance the deep tumor penetration and cellular accumulation of drugs. In vivo delivery of G1(PPDC)x-PMs led to a significantly prolonged blood circulation half-life, which is beneficial to achieve sufficient tumor accumulation through the enhanced permeability and retention (EPR) effect. G1(PPDC)x-PMs displayed the best antitumor activity in H22 tumor-bearing mice with a tumor inhibition rate of 78.87%. Meanwhile, G1(PPDC)x-PMs alleviated both myelosuppression toxicities of CDDP and vascular irritation of NCTD. Our results demonstrated that G1(PPDC)x-PMs could serve as an effective drug delivery system for codelivery of CDDP and NCTD to treat liver cancer efficiently.

Exploring the Pivotal Components Influencing the Side Effects Induced by an Analgesic-Antitumor Peptide from Scorpion Venom on Human Voltage-Gated Sodium Channels 1.4 and 1.5 through Computational Simulation.

Voltage-gated sodium channels (VGSCs, or Nav) are important determinants of action potential generation and propagation. Efforts are underway to develop medicines targeting different channel subtypes for the treatment of related channelopathies. However, a high degree of conservation across its nine subtypes could lead to the off-target adverse effects on skeletal and cardiac muscles due to acting on primary skeletal muscle sodium channel Nav1.4 and cardiac muscle sodium channel Nav1.5, respectively. For a long evolutionary process, some peptide toxins from venoms have been found to be highly potent yet selective on ion channel subtypes and, therefore, hold the promising potential to be developed into therapeutic agents. In this research, all-atom molecular dynamic methods were used to elucidate the selective mechanisms of an analgesic-antitumor ß-scorpion toxin (AGAP) with human Nav1.4 and Nav1.5 in order to unravel the primary reason for the production of its adverse reactions on the skeletal and cardiac muscles. Our results suggest that the rational distribution of residues with ring structures near position 38 and positive residues in the C-terminal on AGAP are critical factors to ensure its analgesic efficacy. Moreover, the substitution for residues with benzene is beneficial to reduce its side effects.

[Observation of radiobiological characteristics in a HepG2 cell line with mitochondrial DNA deletion].

OBJECTIVE: To study the radiobiological characteristics of a HepG2 cell line with mitochondrial DNA (mtDNA) deletion. METHODS: HepG2 cells were cultured in a medium containing ethidium bromide, acetylformic acid and uracil. The HepG2 cell line with mtDNA deletion (ρ(0)HepG2 cells) were acquired after 30 subcultures by limited dilution cloning. The cell survival was then observed in the absence of acetylformic acid and uracil, and the total mtDNA deletion in the cells was confirmed by PCR. The radiosensitivity of HepG2 and ρ(0)HepG2 cells was evaluated by exposure to gradient doses of 6 MV X ray irradiation. The cell apoptosis was assessed following a 2 Gy X-ray exposure with Hochest33342 staining, and the invasiveness of ρ(0)HepG2 cells was measured by Transwell assay. RESULTS: HepG2 cells could survive 30 subcultures in the presence of ethidium bromide, and massive cell death occurred after removal of acetylformic acid and uracil from the medium. PCR confirmed total mtDNA deletion from ρ(0)HepG2 cells, whose α/ß value was significantly lower than that of HepG2 cells. ρ(0)Hep-G2 cells showed an obviously lowered cell apoptosis rate following X-ray exposure with enhanced cell invasiveness. CONCLUSION: HepG2 cells can be induced by ethidium bromide into ρ(0)HepG2 cells with an increased radiation resistance, anti-apoptosis ability and cell invasiveness.

Feasibility of computed tomography-guided core needle biopsy in producing state-of-the-art clinical management in Chinese lung cancer.

BACKGROUND: A satisfactory biopsy determines the state-of-the-art management of lung cancer in this era of personalized medicine. This study aimed to investigate the suitability and efficacy of computed tomography (CT)-guided core needle biopsy in clinical management. METHODS: A cohort of 353 patients with clinically suspected lung cancer was enrolled in the study. Patient factors and biopsy variables were recorded. Epidermal growth factor receptor (EGFR) gene mutations and echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement were detected in tumor specimens. Adequacy of biopsic obtainment for clinical trial screening and tissue bank establishment were reviewed. RESULTS: Overall diagnostic accuracy of malignancy achieved 98.5%. The median biopsy time of the cohort was 20 minutes. In patients with non-small cell lung cancer (NSCLC), 99.3% (287/289) were diagnosed as specific histologic subtypes, and two patients (0.7%) were determined as NSCLC not otherwise specified (NOS). EGFR mutations were analyzed in 81.7% (236/289) of patients with NSCLC, and 98.7% (233/236) showed conclusive results. EML4-ALK gene fusion was tested in 43.9% (127/289) of NSCLC patients, and 98.4% (125/127) showed conclusive results: 6.4% (8/125) of those had gene fusion. Ninety-six NSCLC patients participated in clinical trial screening and provided mandatory tumor slides for molecular profiling. Pathological evaluation was fulfilled in 90 patients (93.8%); 99.4% (320/322) of patients with malignancy provided extra tissue for the establishment of a tumor bank. CONCLUSIONS: CT-guided core needle biopsy provided optimal clinical management in this era of translational medicine. The biopsic modality should be prioritized in selected lung cancer patients.