Tumor vascular heterogeneity and the impact of subtumoral nanoemulsion biodistribution.

Aim: Investigate the heterogeneous tumor tissue organization and examine how this condition can interfere with the passive delivery of a lipid nanoemulsion in two breast cancer preclinical models (4T1 and Ehrlich). Materials & methods: The authors used in vivo image techniques to follow the nanoemulsion biodistribution and microtomography, as well as traditional histopathology and electron microscopy to evaluate the tumor structural characteristics. Results & conclusion: Lipid nanoemulsion was delivered to the tumor, vascular organization depends upon the subtumoral localization and this heterogeneous organization promotes a nanoemulsion biodistribution to the highly vascular peripherical region. Also, the results are presented with a comprehensive mathematical model, describing the differential biodistribution in two different breast cancer models, the 4T1 and Ehrlich models.

Combined paclitaxel-doxorubicin liposomal results in positive prognosis with infiltrating lymphocytes in lung metastasis.

Aim: To investigate the effect of liposomes containing the classical cytotoxic drugs paclitaxel and doxorubicin (Lipo-Pacli/Dox), against a metastatic breast cancer model. We also investigated if Lipo-Pacli/Dox was capable of reverting the tolerogenic environment of metastatic lesions. Materials & methods: Immunogenic cell death induction by the Pacli/Dox combination was assessed in vitro. Antitumor activity and in vivo safety of Lipo-Pacli/Dox were evaluated using a 4T1 breast cancer mouse model Results: Lipo-Pacli/Dox, with a size of 189 nm and zeta potential of -5.01 mV, promoted immune system activation and partially controlled the progression of pulmonary metastasis. Conclusion: Lipo-Pacli/Dox was useful to control both primary tumor and lung metastasis in breast cancer (4T1) mice model. Additionally, Lipo-Pacli/Dox acts as an immunological modulator for this metastatic breast cancer model.

Photodynamic therapy in superficial basal cell carcinoma treatment.

Basal cell cancer (BCC) is an epithelial neoplasm that arises from basal cells, which constitute the lower layer of the epidermis. Global statistics have shown the progressive increase in the incidence of skin cancer in several countries. The cumulative exposure to solar radiation (ultraviolet B) in the first two decades of life represents the critical risk for the disease. Preclinical and clinical trials have shown photodynamic therapy (PDT) as a promising innovation for treatment of skin cancers, especially to the non-melanoma group. The authors reviewed trials with photodynamic therapy in superficial basal cell carcinoma with different photosensitizers to better evaluate how PDT modifies the natural history of sBCC. We conclude trials should not assess only the immediate efficacy but the main goal of long-term effectiveness of the protocols in order to generate best evidence for clinical practice.

Selol nanocapsules with a poly(methyl vinyl ether-co-maleic anhydride) shell conjugated to doxorubicin for combinatorial chemotherapy against murine breast adenocarcinoma in vivo.

Nanocapsules containing selol and doxorubicin (NCS-DOX) with an oily core of selol and a shell of poly(methyl vinyl ether-co-maleic anhydride) covalently conjugated to doxorubicin were developed in a previous work. In this study, these nanocapsules showed a similar antitumour effect in comparison to the free doxorubicin (DOX) treatment, but showed no evident DOX-related cardiotoxicity, as evidenced by serum creatine kinase-MB (CK-MB) activity. The histopathological analysis showed that the free DOX treatment induced more intense morphological damage to myocardial tissues in comparison to NCS-DOX treatment. Animals treated with free DOX presented important muscle fibre degradation and animals treated with NCS-DOX, heart tissue did not present signals of muscle fibre degeneration. These results indicate that the cardiotoxicity related to DOX is reduced when this drug is carried by the NCS-DOX. Noteworthy, biodistribution analyses showed that NCS-DOX accumulated more intensely in tumours than the free DOX. Thus, this study reinforces the importance of the development of nanocapsules as drug carriers for the treatment of cancer.

An updated overview on the development of new photosensitizers for anticancer photodynamic therapy.

Photodynamic therapy (PDT), based on the photoactivation of photosensitizers (PSs), has become a well-studied therapy for cancer. Photofrin®, belonging to the first generation of PS, is still widely used for the treatment of different kinds of cancers; however, it has several drawbacks that significantly limit its general clinical use. Consequently, there has been extensive research on the design of PS molecules with optimized pharmaceutical properties, with aiming of overcoming the disadvantages of traditional PS, such as poor chemical purity, long half-life, excessive accumulation into the skin, and low attenuation coefficients. The rational design of novel PS with desirable properties has attracted considerable research in the pharmaceutical field. This review presents an overview on the classical photosensitizers and the most significant recent advances in the development of PS with regard to their potential application in oncology.

Identification of a novel small-molecule Keap1-Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy.

A new Keap1-Nrf2 protein-protein interaction (PPI) inhibitor ZJ01 was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. ZJ01 could in vitro trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, ZJ01 suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 in H9c2 cardiac cells. Moreover, in an in vivo mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, ZJ01 demonstrated a cytoprotective effect, upregulated Nrf2 protein nuclear accumulation, and remarkably suppressed the abovementioned cytokine levels in cardiomyocytes. The results presented herein provided a novel chemotype for the development of direct Keap1-Nrf2 PPI inhibitors and suggested that compound ZJ01 is a promising drug lead for septic cardiomyopathy treatment. ZJ01 was identified as a new Keap1-Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by in vitro and in vivo experiments.

Self-nanoemulsifying drug-delivery systems improve oral absorption and antischistosomal activity of epiisopiloturine.

AIM: To develop a self-nanoemulsifying drug-delivery system (SNEDDS) able to improve oral absorption of epiisopiloturine (EPI), and test the antischistosomal activity in a mice model. RESULTS: SNEDDS had a nanoscopic size and was able to enhance EPI bioavailability after oral administration, and SNEDDS-EPI (40 mg.kg-1) improved the in vivo antischistosomal activity of EPI, demonstrating that SNEDDS was able to improve the pharmacokinetics of EPI, and to maintain the pharmacodynamic activity against Schistosoma mansoni in vivo. CONCLUSION: Taken together, these results indicate that SNEDDS-EPI is efficient in reducing worm burden in comparison to treatment with the free version of EPI. [Formula: see text].

Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities.

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC50=2.5µM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50=6.5-36.2µM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy.

Acid-sensitive lipidated doxorubicin prodrug entrapped in nanoemulsion impairs lung tumor metastasis in a breast cancer model.

AIM: To develop an acid-sensitive lipidated, doxorubicin (Dox) prodrug (C16-Dox) to be entrapped in lipid nanoemulsion (NE-C16-Dox) as a nanocarrier to treat breast cancer models (in vitro and in vivo). RESULTS: We report the efficacy of NE-C16-Dox in in vitro experiments, as well as the improved chemotherapeutic index and tumor-control efficacy compared with treatment with free Dox in an in vivo murine 4T1 breast cancer model. In addition, NE-C16-Dox allowed the use of a higher dose of Dox, acceptable biocompatibility and a significant reduction in lung metastasis. CONCLUSION: Taken together, these results indicate that NE-C16-Dox is promising for breast cancer treatment, thus creating possibilities to translate these nanotechnology concepts to clinical applications.

Nanostructured Systems for the Organelle-specific Delivery of Anticancer Drugs.

Nanotechnology has provided powerful tools to improve the chemotherapy of cancer. Different nanostructures have been developed which deliver the anticancer drugs more selectively to tumor than to healthy tissues. The result has generally been the increase in efficacy and safety of classical anticancer drugs. In recent years, several studies have focused not only on the delivery of anticancer drugs to tumors, but also on delivering the drugs to specific organelles of cancer cells. Endoplasmic reticulum, Golgi apparatus, lysosomes, mitochondria, and nucleus have been the targets of different nanostructured drug delivery systems developed with the goal of circumventing drugresistance, increasing drug efficacy, and so on. So far, the results described in the literature show that this strategy may be used to improve chemotherapy outcomes. In this review a discussion is presented on the strategies described in the literature to deliver anticancer drugs to specific organelles of cancer cells by using nanostructures.