Deaths from lifestyle-related diseases have been decreasing because of the development of medical interventions with clear curative effects. On the other hand, the number of people with cancer is increasing. In Japan, one in every two people will have cancer, and one in three will die from it. Therefore, concern about cancer therapy is on the rise among researchers and the general public. In the past several years, knowledge of proteins that are specifically associated with various types of cancer has expanded rapidly, leading to the development of molecular-targeting drugs that could bring about revolutionary progress in cancer chemotherapy. Moreover, the technology for drug delivery systems (DDS) that carry novel agents to cancer cells efficiently is catching up. Reducing side effects and contributing to patient quality of life are expected of DDS for cancer chemotherapy. Because the technology is evolving almost daily, the newest knowledge should be monitored constantly. Therefore, the latest information on and problems with DDS that contribute to cancer chemotherapy are in presented in this Current Topics section. Six groups of world-leading scientists were invited to contribute papers updating readers on DDS research that could contribute to improved cancer chemotherapy. The first review is "Alteration of tumor microenvironment for improved delivery and intratumor distribution of nanocarriers" by Dr. Tatsuhiro Ishida and Dr. Hiroshi Kiwada (University of Tokushima). They summarized several trials that attempted to manipulate the barriers in the tumor microenvironment which hinder extravasation through the tumor vasculature and penetration of nanocarriers into solid tumors. The second is "Nanoparticle-based passive drug targeting to tumors: Considerations and implications for optimization" by Dr. Ken-ichi Ogawara and coworkers (Faculty of Pharmaceutical Sciences, Okayama University). They introduce their recent findings related to the passive drug targeting strategy for antiangiogenic therapy. "Development of liposomal anticancer drugs" was written by Dr. Kenji Hyodo as a representative of a research group at DDS Research, Eisai Co., Ltd., who addressed the process of liposomal drug product development from various viewpoints. The fourth review is "Recent advances in claudin-targeting technology" by Dr. Shotaro Nagase and coworkers (Osaka University). They describe their studies using the C-terminal fragment of Clostridium perfringens enterotoxin to target and bind claudins and discuss the efficacy of this strategy. Dr. Takuya Iwamoto (Mie University Hospital), in the review titled "Clinical application of drug delivery systems in cancer chemotherapy: Review of the efficacy and side effects of approved drugs," discusses liposomal doxorubicin and nanoparticle albumin-bound (nab)-paclitaxel, which are available clinically, including undesirable side effects. The final topic is "Application of hospital preparations for cancer treatment , and an approach toward their commercialization" by Dr. Kyohei Watanabe and...

Therapeutic efficacy of nanocarriers can be amplified by active targeting and overcoming the extracellular matrix associated barriers of tumors. The aim of the present study was to investigate the effect of oral antifibrotic agent (telmisartan) on tumor uptake and anticancer efficacy of EphA2 receptor targeted liposomes. Docetaxel loaded PEGylated liposomes (DPL) functionalized with nickel chelated phospholipid were prepared using a modified hydration method. DPL were incubated with various concentrations of histidine tagged EphA2 receptor specific peptide (YSA) to optimize particle size, zeta potential, and percentage YSA binding. Cellular uptake studies using various endocytosis blockers revealed that a caveolae dependent pathway was the major route for internalization of YSA anchored liposomes of docetaxel (YDPL) in A549 lung cancer cell line. Hydrodynamic diameter and zeta potential of optimized YDPL were 157.3 ± 11.8 nm and −3.64 mV, respectively. Orthotopic lung tumor xenograft (A549) bearing athymic nude mice treated with oral telmisartan (5 mg/kg) for 2 days showed significantly (p < 0.05) higher uptake of YDPL in tumor tissues compared to healthy tissue. Average lung tumor weight of the YDPL + telmisartan treated group was 4.8-and 3.8-fold lower than that of the DPL and YDPL treated groups (p < 0.05). Substantially lower expression (p < 0.05) of EphA2 receptor protein, proliferating cell nuclear antigen (PCNA), MMP-9, and collagen 1A level with increased E-cadherin and TIMP-1 levels in immunohistochemistry and Western blot analysis of lung tumor samples of the combination group confirmed antifibrotic effect with enhanced anticancer activity. Active targeting and ECM remodeling synergistically contributed to anticancer efficacy of YDPL in orthotopic lung cancer.

Together, our data indicate that Lupeol may orchestrate a bifurcated regulation of neoplastic growth and apoptosis in head and neck cancers and may serve as a promising agent for the management of tumors that have progressed on a platinum-based treatment regimen.

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We have investigated the effects of combination treatment involving ERL (erlotinib) with a glycyrrhetinic acid analog, CDODA-Me in overcoming ERL resistance, providing efforts to improve the oral bioavailability of this treatment using self-nanoemulsifying drug delivery systems (SNEDDS). A Qbd (quality-by-design) approach was used to prepare CDMS (CDODA-SNEDDS, 2 μM), which was characterized using surface response methodology to optimize drug content, particle size, and drug release. CDMS/ERL combinations showed synergism in wild-type and resistant H1975 and HCC827 cell lines with combination index values less than 1. Increased apoptosis, mitochondrial membrane potential depletion, and enhanced intracellular ROS levels were also observed in combination therapy. Western blot analysis showed that combination therapy inhibited phosphorylation of epidermal growth factor receptor (EGFR) (p < 0.01 in all cell lines) and Met receptor tyrosine kinase (MET) (p < 0.01 in all cell lines). In vivo, the relative bioavailability of CDMS increased significantly from 22.13 to 151.76 μg/mL compared to the dosing of oral suspension (dose equivalent). Our results demonstrate that combination therapy involving ERL and CDODA-Me overcomes resistance through dual inhibition of p-EGFR and p-MET leading to the induction of apoptosis, intracellular ROS accumulation, and decreased mitochondrial potential. Furthermore, CDMS improved the oral bioavailability of CDODA-Me.