Current Cancer Drug Targets - Volume 19, Issue 4, 2019

Background: Cancer metastasis has emerged as a major public health threat that causes majority of cancer fatalities. Traditional chemotherapeutics have been effective in the past but suffer from low therapeutic efficiency and harmful side-effects. Recently, it has been reported ursolic acid (UA), one of the naturally abundant pentacyclic triterpenes, possesses a wide range of biological activities including anti-inflammatory, anti-atherosclerotic, and anti-cancer properties. More importantly, UA has the features of low toxicity, liver protection and the potential of anti-cancer metastasis. Objective: This article aimed at reviewing the great potential of UA used as a candidate drug in the field of cancer therapy relating to suppression of tumor initiation, progression and metastasis. Methods: Selective searches were conducted in Pubmed, Google Scholar and Web of Science using the keywords and subheadings from database inception to December 2017. Systemic reviews are summarized here. Results: UA has exhibited chemopreventive and therapeutic effects of cancer mainly through inducing apoptosis, inhibiting cell proliferation, preventing tumor angiogenesis and metastatic. UA nanoformulations could enhance the solubility and bioavailability of UA as well as exhibit better inhibitory effect on tumor growth and metastasis. Conclusion: The information presented in this article can provide useful references for further studies on making UA a promising anti-cancer drug, especially as a prophylactic metastatic agent for clinical applications.

Background: Effective cancer therapy is still a great challenge for modern medical research due to the complex underlying mechanisms of tumorigenesis and tumor metastasis, and the limitations commonly associated with currently used cancer therapeutic options. Nanotechnology has been implemented in cancer therapeutics with immense potential for improving cancer treatment. Objective: Through information about the recent advances regarding cancer hallmarks, we could comprehensively understand the pharmacological effects and explore the mechanisms of the interaction between the nanomaterials, which could provide opportunities to develop mechanism-based nanomedicine to treat human cancers. Methods: We collected related information and data from articles. Results: In this review, we discussed the characteristics of cancer including tumor angiogenesis, abnormalities in tumor blood vessels, uncontrolled cell proliferation markers, multidrug resistance, tumor metastasis, cancer cell metabolism, and tumor immune system that provide opportunities and challenges for nanomedicine to be directed to specific cancer cells and portray the progress that has been accomplished in application of nanotechnology for cancer treatment. Conclusion: The information presented in this review can provide useful references for further studies on developing effective nanomedicine for the treatment of cancer.

Background: One of the main reasons for most of the anticancer drugs to fail in the late preclinical testing and early clinical trials is the differences in drug effects observed from animals and patients, and the challenge has been to find a balance to reduce the inherent differences from species. Objective: Predicting safe starting doses and dosing schedules for human clinical trials is the main purpose of toxicological studies of anticancer drugs. Methods: Relevant information and data were assimilated from manuscripts, congress publications, and online sources. Results: We systematically overview the cons and pros of animal models and briefed the ways to determine human clinical starting doses derived from animal toxicological studies for anticancer drugs. Conclusion: This information helps smart select the suitable predictive model for anti-cancer drugs with the different mechanisms and emphasized the pharmaceutical challenges behind and ahead.

Background: With the development of nanotechnology, nanocarrier has widely been applied in such fields as drug delivery, diagnostic and medical imaging and engineering in recent years. Among all of the available nanocarriers, mesoporous silica nanoparticles (MSNs) have become a hot issue because of their unique properties, such as large surface area and voidage, tunable drug loading capacity and release kinetics, good biosafety and easily modified surface. Objective: We described the most recent progress in silica-assisted drug delivery and biomedical applications according to different types of Cargo in order to allow researchers to quickly learn about the advance in this field. Methods: Information has been collected from the recently published literature available mainly through Title or Abstract search in SpringerLink and PubMed database. Special emphasis is on the literature available during 2008-2017. Results: In this review, the major research advances of MSNs on the drug delivery and biomedical applications were summarized. The significant advantages of MSNs have also been listed. It was found that the several significant challenges need to be addressed and investigated to further advance the applications of these structurally defined nanomaterials. Conclusion: Through approaching this review, the researchers can be aware of many new synthetic methods, smart designs proposed in the recent year and remaining questions of MSNs at present.

Background: Highly Active Metastasis Preventing Therapy (HAMPT) is a quardruple drug combination consisting of mifepristone, aspirin, lysine and doxycycline. Objective: Based on our previous study, here, we further proved that HAMPT could effectively and safely prevent colon cancer metastasis. Methods: It was specifically designed for synergistically controlling key cancer metastatic pathways. The dose of HAMPT was designed at lower than the pharmaceutically-recommended dose, and thus the sub-healthy cancer survivors may take HAMPT safely and for a long time for metastasis chemoprevention. Results: HAMPT within its effective concentration range (1-50 μg/mL) showed no cytotoxicity to colon cancer cells HT-29 and CT-26, but significantly inhibited adhesion and invasion of these colon cancer cell lines to human umbilical vascular endothelial cells (HUVECs), and to Matrigel. HAMPT exhibits a good adhesion inhibited ratio, suggesting that it functions primarily by inhibiting adhesion of the cancer cells to HUVECs, rather than killing the cancer cells. At low concentrations, HAMPT also inhibited cancer cell migration. Flow cytometry analysis revealed that HAMPT had no significant effect on cell cycle, but inhibited IL-1β-induced expression of both E-selectin of HUVECs and Sialyl-Lewis X of HT-29. The in vivo experiment showed that HAMPT suppressed metastasis of CT-26 cells to mouse lungs in a dose-dependent manner. In the mouse model, HAMPT showed advantages in preventing metastasis over other combinations. Conclusion: The present study demonstrated that HAMPT is a novel quadruple drug combination that can safely and effectively prevent cancer metastasis.

Background: Oral administrations of microparticles (MPs) and nanoparticles (NPs) have been widely employed as therapeutic approaches for the treatment of ulcerative colitis (UC). However, no previous study has comparatively investigated the therapeutic efficacies of MPs and NPs. Methods: In this study, curcumin (CUR)-loaded MPs (CUR-MPs) and CUR-loaded NPs (CUR-NPs) were prepared using a single water-in-oil emulsion solvent evaporation technique. Their therapeutic outcomes against UC were further comparatively studied. Results: The resultant spherical MPs and NPs exhibited slightly negative zeta-potential with average particle diameters of approximately 1.7 μm and 270 nm, respectively. It was found that NPs exhibited a much higher CUR release rate than MPs within the same period of investigation. In vivo experiments demonstrated that oral administration of CUR-MPs and CUR-NPs reduced the symptoms of inflammation in a UC mouse model induced by dextran sulfate sodium. Importantly, CUR-NPs showed much better therapeutic outcomes in alleviating UC compared with CUR-MPs. Conclusion: NPs can improve the anti-inflammatory activity of CUR by enhancing the drug release and cellular uptake efficiency, in comparison with MPs. Thus, they could be exploited as a promising oral drug delivery system for effective UC treatment.

Objective: To improve solubility and to reduce aggregation, ZnPcC4 was conjugated to a third-generation poly-amidoamine dendrimer with amino end group (G3-PAMAM-NH2), which acts as a novel photodynamic therapy (PDT) drug carrier system. Methods: The phthalocyanines were synthesized by construction reaction. The nano drug was obtained from the conjugation of ZnPcC4 to G3-PAMAM-NH2, using EDC and NHS as coupling agents. The ZnPcC4@G3-PAMAM-NH2 conjugation was characterized by UV-Vis and MS. The 1O2 quantum yield of ZnPcC4@G3-PAMAM-NH2 in water was measured by the chemiluminescence method. The in vitro PDT responses of the studied photosensitizers were studied in hepatocellular carcinoma cell line HepG2 by MTT assay. Results: At ZnPcC4/G3-PAMAM-NH2 raw ratio of 100/1, the ZnPcC4 conjugate had improved solubility and reduced aggregation tendency in aqueous solution. At this optimum molar ratio, ZnPcC4- G3-PAMAM-NH2 inhibited HepG2 cells, with a half-maximal inhibitory concentration of 1.67 μg/mL upon infrared light exposure. The controls, including dark conditions, or media as well as G3-PAMAM-NH2 exposure, exhibited no inhibitory response. Conclusion: The conjugation of phthalocyanine photosensitizer ZnPcC4 to poly-amidoamine dendrimer G3-PAMAM-NH2 improved the PDT outcomes, in which the optimized binding ratio of ZnPcC4 to G3-PAMAM-NH2 was 6:1.

Background: The lethality of prostate cancer is mainly due to metastasis. Inhibition of metastasis is expected to be a promising approach for prostate cancer therapy. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway is reported to be closely involved in cell growth, migration, etc. Objective: The study investigated the antimetastatic activities of pan-PI3K inhibitor ZSTK474 on DU145 cells. Methods: 1. The In vitro effect of ZSTK474 on the migration, invasion and adhesion of DU145 cells was determined with Transwell migration assay and wound healing assay, Tranwell invasion assay and adhesion assay, respectively. 2. In vitro effect of ZSTK474 on the signal proteins in DU145 cells was determined with Western blot analysis and ELISA. 3. Moreover, the In vivo antimetastatic effect of ZSTK474 was evaluated with MicroCT and histology analysis. Results: ZSTK474 potently attenuated the capability of migration, invasion and adhesion of DU145 cells, negatively regulated Girdin, Integrinβ1 and matrix metalloproteinases (MMPs). In addition, the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), which are known to be related to angiogenesis and metastasis, was also inhibited. Oral administration of ZSTK474 (200 mg/kg) ameliorated in vivo bone metastasis of DU145 cells, with improved bone structure and bone mineral density (BMD). Tissue staining indicated a reduction in metastatic DU145 cells and osteoclasts in the bones of ZSTK474-treated mice, compared with the non-treated group. Conclusion: Our result demonstrated the antimetastatic activity of ZSTK474 on prostate cancer DU145 cells, suggesting the potential application in prostate cancer patients.

Background: MicroRNA (miRNA) therapy, which was widely considered to treat a series of cancer, has been confronted with numerous obstacles to being delivered into target cells because of its easy biodegradation and instability. Methods: In this research, we successfully constructed 11-mercaptoundecanoic acid modified gold nanocages (AuNCs)/polyethyleneimine (PEI)/miRNA/hyaluronic acid (HA) complexes (abbreviated as AuNCs/PEI/miRNA/HA) using a layer-by-layer method for target-specific intracellular delivery of miRNA by HA receptor mediated endocytosis. Results: The results of UV spectra, hydrodynamic diameter and zeta potential analyses confirmed the formation of AuNCs/PEI/ miRNA/HA complex with its average particle size of ca. 153 nm and surface charge of ca. -9.43 mV. Next, we evaluated the antitumor effect of the nanocomplex mediated by the combination of gene therapy and photothermal therapy (PTT) against hepatocellular carcinoma (HCC) in vitro. Conclusion: Our experimental results indicated that the AuNCs/PEI/miRNA/HA complex effectively delivered miRNA to the target cells and its antitumor effect was significantly enhanced by the combination of gene therapy and photothermal therapy. In addition, anti-miR-181b could promote Bel-7402 cell arrest in S phase and improve TIMP-3 mRNA expression. All these results suggested that AuNCs/PEI/miRNA/HA gene delivery system with combination of gene therapy and photothermal therapy might be exploited for HCC treatment.

Background: Improving poorly soluble drugs into druggability was a major problem faced by pharmaceutists. Nanosuspension can improve the druggability of insoluble drugs by improving the solubility, chemical stability and reducing the use of additives, which provided a new approach for the development and application of the insoluble drugs formulation. Paclitaxel (PTX) is a well-known BCS class IV drug with poor solubility and permeability. Also, many studies have proved that paclitaxel is a substrate of the membrane-bound drug efflux pump P-glycoprotein (P-gp), therefore it often shows limited efficacy against the resistant tumors and oral absorption or uptake. Objective: To manufacture an enhanced-penetration PTX nanosuspension (PTX-Nanos), and evaluate the physicochemical property, pharmacokinetics and tissue distribution in vivo and cytotoxic effect in vitro. Methods: PTX-Nanos were prepared by microprecipitation-high pressure homogenization, with a good biocompatibility amphiphilic block copolymer poly(L-phenylalanine)-b-poly(L-aspartic acid) (PPA-PAA) as stabilizer. Results: The PTX-Nanos had a sustained-dissolution manner and could effectively reduce plasma peak concentration and extend plasma circulating time as compared to PTX injection, markedly passively targeting the MPS-related organs, such as liver and spleen. This unique property might enhance treatment of cancer in these tissues and reduce the side effects in other normal tissues. Moreover, the hybrid stabilizers could enhance penetration of PTX in PTX-Nanos to multidrug resistance cells. Conclusion: To sum up, our results showed that the optimal formula could improve the solubility of PTX and the stability of the product. The PTX-Nanos developed in this research would be a promising delivery platform in cancer treatment.