Long­term survival of a patient with advanced lung cancer treated with targeted therapy and anti­PD­1 immunotherapy as multi­line therapy: A case report.

Lung cancer is the most common type of cancer worldwide. Lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), is a common type of lung cancer. In recent years, immunotherapy has become the primary method of treatment for several solid cancers, including NSCLC. In the present study, the case of a patient with NSCLC following left superior lobectomy is reported. Different systemic therapies failed, such as a pemetrexed + carboplatin regimen, paclitaxel liposome + cisplatin and pembrolizumab, and albumin-bound paclitaxel + toripalimab, but long-term survival was achieved following targeted therapy and anti-programmed cell death protein-1 (PD-1) immunotherapy. The patient survived for >4 years following lung cancer progression, which is notably longer than expected for patients with advanced lung cancer. In conclusion, the present case demonstrated the efficacy of targeted therapy and anti-PD-1 immunotherapy for the treatment of advanced lung cancer following the occurrence of drug resistance and progressive disease.

Research progress on the biological basis of Traditional Chinese Medicine syndromes of gastrointestinal cancers.

Gastrointestinal cancers account for 11.6 % of all cancers, and are the second most frequently diagnosed type of cancer worldwide. Traditional Chinese medicine (TCM), together with Western medicine or alone, has unique advantages for the prevention and treatment of cancers, including gastrointestinal cancers. Syndrome differentiation and treatment are basic characteristics of the theoretical system of TCM. TCM syndromes are the result of the differentiation of the syndrome and the basis of treatment. Genomics, transcriptomics, proteomics, metabolomics, intestinal microbiota, and serology, generated around the central law, are used to study the biological basis of TCM syndromes in gastrointestinal cancers. This review summarizes current research on the biological basis of TCM syndrome in gastrointestinal cancers and provides useful references for future research on TCM syndrome in gastrointestinal cancers.

Design, synthesis and biological evaluation of novel dihydroquinolin-4(1H)-one derivatives as novel tubulin polymerization inhibitors.

A series of novel dihydroquinolin-4(1H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four cancer cell lines with IC50 values among 0.003-0.024 µM and tubulin polymerization inhibitory activity (IC50 = 3.06 µM). Further mechanism studies revealed that compound 6t could induce K562 cells apoptosis and arrest at the G2/M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent anticancer properties in vitro and in vivo.

Synthesis and bioevaluation of novel stilbene-based derivatives as tubulin/HDAC dual-target inhibitors with potent antitumor activities in vitro and in vivo.

A series of novel stilbene-based derivatives were designed and synthesized as tubulin/HDAC dual-target inhibitors. Among forty-three target compounds, compound II-19k not only exhibited considerable antiproliferative activity in the hematological cell line K562 with IC50 value of 0.003 µM, but also effectively inhibited the growth of various solid tumor cell lines with IC50 values ranging from 0.005 to 0.036 µM. The mechanism studies demonstrated that II-19k could inhibit microtubules and HDACs at the cellular level, block cell cycle arrest at G2 phase, induce cell apoptosis, and reduce solid tumor cells metastasis. What's more, the vascular disrupting effects of compound II-19k were more pronounced than the combined administration of parent compound 8 and HDAC inhibitor SAHA. The in vivo antitumor assay of II-19k also showed the superiority of dual-target inhibition of tubulin and HDAC. II-19k significantly suppressed the tumor volume and effectively reduced tumor weight by 73.12% without apparent toxicity. Overall, the promising bioactivities of II-19k make it valuable for further development as an antitumor agent.

Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects.

Most vascular disrupting agents (VDAs) fail to prevent the regrowth of blood vessels at the edge of tumors, causing tumor rebound and relapse. Herein, a series of novel multifunctional vascular disrupting agents (VDAs) capable of inhibiting microtubule polymerization and histone deacetylases (HDACs) were designed and synthesized using the tubulin polymerization inhibitor TH-0 as the lead compound. Among them, compound TH-6 exhibited the most potent antiproliferative activity (IC50 = 18-30 nM) against a panel of cancer cell lines. As expected, TH-6 inhibited tubulin assembly and increased the acetylation level of HDAC substrate proteins in HepG2 cells. Further in vivo antitumor assay displayed that TH-6 effectively inhibited tumor growth with no apparent toxicity. More importantly, TH-6 disrupted both the internal and peripheral tumor vasculatures, which contributed to the persistent tumor inhibitory effects after drug withdrawal. Altogether, TH-6 deserves to be further investigated for the new approach to clinical cancer therapy.

Design and synthesis of NAD(P)H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties.

A series of NQO1 selectively activated prodrugs were designed and synthesized by introducing indolequinone moiety to the C-3, C-23 or C-28 position of 23-hydroxybetulinic acid (23-HBA) and its analogues. Among them, the representative compound 32j exhibited significant antiproliferative activities against NQO1-overexpressing HT-29 cells and A549 cells, with IC50 values of 1.87 and 2.36 µM, respectively, which were 20-30-fold more potent than those of parent compound 23-HBA. More importantly, it was demonstrated in the in vivo antitumor experiment that 32j effectively suppressed the tumor volume and largely reduced tumor weight by 72.69% with no apparent toxicity, which was more potent than the positive control 5-fluorouracil. This is the first breakthrough in the improvement of in vivo antitumor activities of 23-HBA derivatives. The further molecular mechanism study revealed that 32j blocked cell cycle arrest at G2/M phase, induced cell apoptosis, depolarized mitochondria and elevated the intracellular ROS levels in a dose-dependent manner. Western blot analysis indicated that 32j induced cell apoptosis by interfering with the expression of apoptosis-related proteins. These findings suggest that compound 32j could be considered as a potent antitumor prodrug candidate which deserves to be further investigated for personalized cancer therapy.

Lipid Perfluorohexane Nanoemulsion Hybrid for MRI-Guided High-Intensity Focused Ultrasound Therapy of Tumors.

Magnetic resonance imaging-guided high-intensity focused ultrasound (MRI-guided HIFU) is a non-invasive strategy of diagnosis and treatment that is applicable in tumor ablation. Here, we prepared a multifunctional nanotheranostic agent (SSPN) by loading perfluorohexane (PFH) and superparamagnetic iron oxides (SPIOs) in silica lipid for MRI-guided HIFU ablation of tumors. PFH was introduced to improve the ablation effect of HIFU and the ultrasound (US) contrast performance. Due to its liquid-to-gas transition characteristic, it is sensitive to temperature. SPIOs were used as an MRI contrast agent. Silica lipid was selected because it is a more stable carrier material compared with normal lipid. Previous studies have shown that SSPNs have good biocompatibility, stability, imaging, and therapeutic effects. Therefore, this system is expected to develop an important therapeutic agent for MRI-guided HIFU therapy against tumors.

Stable cerasomes for simultaneous drug delivery and magnetic resonance imaging.

Magnetic liposomes have been frequently used as nanocarriers for targeted drug delivery and magnetic resonance imaging in recent years. Despite great potentials, their morphological/structural instability in the physiological environment still remains an intractable challenge for clinical applications. In this study, stable hybrid liposomal cerasomes (ie, liposomes partially coated with silica) which can co-encapsulate Fe3O4 nanoparticles and the anticancer drug paclitaxel were developed using thin film hydration method. Compared with the drug loaded liposomes, the paclitaxel-loaded magnetic cerasomes (PLMCs) exhibited much higher storage stability and better sustained release behavior. Cellular uptake study showed that the utilization of an external magnetic field significantly facilitated the internalization of PLMCs into cancer cells, resulting in potentiated drug efficacy of killing tumor cells. The T2 relaxivity (r2) of our PLMCs was much higher than that of free Fe3O4 nanoparticles, suggesting increased sensitivity in T2-weighted imaging. Given its excellent biocompatibility also shown in the study, such dual functional PLMC is potentially a promising nanosystem for effective cancer diagnosis and therapy.

Highly uniform and stable cerasomal microcapsule with good biocompatibility for drug delivery.

Efforts to improve the stability of liposomes have recently led to the development of organic-inorganic liposomal cerasomes. However, the uncontrollable size of cerasomes has greatly limited their biomedical applications. In this study, a novel strategy was introduced to fabricate hybrid liposomal cerasomes with high stability and uniform size. The hybrid lipids were first deposited onto CaCO3 microspheres through electrostatic interactions and self-assembly, and then the CaCO3 core was removed to obtain hollow microcapsules, i.e. the cerasomes. The species of the lipid oligomers was detected by MALDI-TOF-MS, which demonstrates the existence of siloxane network on microcapsules' surface. Anticancer drug doxorubicin hydrochloride (DOX) loaded cerasomal microcapsule (DLCM) exhibited an initial burst release behavior followed by the sustained release and remarkably high stability towards surfactant solubilization and long term storage. The DLCM displayed a pH-dependent and sustained DOX release profile in vitro, which can be well explained using a well established mathematical model. Our results indicate that these novel cerasomal microcapsules have great potential to be applied as drug delivery system in cancer therapy.