Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
最新号
選択された号の論文の15件中1~15を表示しています
Current Topics - Recent Progress in Drug Delivery System for Cancer Therapy
Current Topics: Reviews
  • Hidemasa Katsumi, Shugo Yamashita, Masaki Morishita, Akira Yamamoto
    2020 年 68 巻 7 号 p. 560-566
    発行日: 2020/07/01
    公開日: 2020/07/01
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    Bone metastases can cause high morbidity and mortality, often developing as they advance, especially in patients with prostate and breast cancers. Most drugs are rarely distributed to the bone and are hence pharmacologically ineffective in treating bone metastases. The development of drug targeting technologies is required for the efficient treatment of bone metastases. To date, numerous bone-targeting ligands, including tetracyclines, bisphosphonates, aspartic acid, and aptamers have been developed and used for bone-targeted delivery of anti-tumor drugs, peptide/protein drugs, nucleic acid drugs, and diagnostic imaging agents. The conjugates of drugs with bone-targeting ligands were first developed in the field of bone drug targeting systems; macromolecular carriers and nanoparticles modified with these bone-targeting ligands have also been developed. Additionally, antibodies to prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2) are used in active targeting bone metastatic prostate cancer and breast cancer, respectively. Some conjugates using antibodies to PSMA and HER2 were developed and used in clinical trials. In this review, recent challenges in the development of bone-targeted delivery systems and strategies for the treatment of bone metastasis have been summarized. Future development of novel drug formulations in order to optimize targeted drug delivery in the treatment of bone metastasis have also been discussed.

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    Editor’s picks

    This paper analyzes and summarizes the development of novel drug formulations in order to optimize targeted drug delivery in the treatment of bone metastasis using bone-targeting ligands and antibodies to metastatic cancer. Metastases of the bone is a common development especially in patients with breast and prostate cancers. However, most drugs are inefficiently distributed to the bone and are hence pharmacologically suboptimal in treating metastases in the bone. This paper could be useful for the development of drug targeting technologies for the treatment of bone metastasis.

  • Koki Ogawa, Naoya Kato, Shigeru Kawakami
    2020 年 68 巻 7 号 p. 567-582
    発行日: 2020/07/01
    公開日: 2020/07/01
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    Because the brain is the most important human organ, many brain disorders can cause severe symptoms. For example, glioma, one type of brain tumor, is progressive and lethal, while neurodegenerative diseases cause severe disability. Nevertheless, medical treatment for brain diseases remains unsatisfactory, and therefore innovative therapies are desired. However, the development of therapies to treat some cerebral diseases is difficult because the blood–brain barrier (BBB) or blood–brain tumor barrier prevents drugs from entering the brain. Hence, drug delivery system (DDS) strategies are required to deliver therapeutic agents to the brain. Recently, brain-targeted DDS have been developed, which increases the quality of therapy for cerebral disorders. This review gives an overview of recent brain-targeting DDS strategies. First, it describes strategies to cross the BBB. This includes BBB-crossing ligand modification or temporal BBB permeabilization. Strategies to avoid the BBB using local administration are also summarized. Intrabrain drug distribution is a crucial factor that directly determines the therapeutic effect, and thus it is important to evaluate drug distribution using optimal methods. We introduce some methods for evaluating drug distribution in the brain. Finally, applications of brain-targeted DDS for the treatment of brain tumors, Alzheimer’s disease, Parkinson’s disease, and stroke are explained.

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    Editor’s picks

    Because brain disorders such as glioma, Alzheimer’s disease and Parkinson’s disease are lethal, or cause severe symptoms, medical treatment is needed. Recently, with the progress of understanding pathology, new therapeutic candidates have been developed. However, there are still unmet medical needs in the medication of brain disorder. This is mainly because most drugs cannot cross blood-brain barrier (BBB). To solve this problem, drug delivery system (DDS) using some approaches (e.g. antibody, nanocarrier, ultrasound irradiation) is being studied for overcoming BBB. In this review, we comprehensively reviewed on the development and therapeutic application of brain-targeted DDS.

  • Yu Ishima, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida
    2020 年 68 巻 7 号 p. 583-588
    発行日: 2020/07/01
    公開日: 2020/07/01
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    A unique phenomenon in solid tumors, the enhanced permeability and retention (EPR) effect is now well known in the development of macromolecular anticancer therapy. However, cancers with low vascular permeability have posed a challenge for these EPR based therapeutic systems. An intrinsic vascular modulator, such as nitric oxide (NO), could augment the endogenous EPR effect. However, the most important aim has been to construct an effective NO delivery system for cancer. Since it is well known that human serum albumin is one of the most important endogenous NO transport proteins in human circulation, for more than a decade we have demonstrated that S-nitrosated human serum albumin dimer (SNO-HSA-Dimer) becomes an enhancer of the EPR effect. Here, we summarize the enhanced effect of SNO-HSA-Dimer on the anticancer effect of macromolecular anticancer drugs such as PEGylated liposomal doxorubicin (Doxil®). In C26-bearing mice with highly permeable vasculature, SNO-HSA-Dimer is able to increase more 3-fold the tumor accumulation of these anticancer drugs, thereby tripling their anticancer effects. Interestingly, the tumor accumulation of Doxil® in B16-bearing mice, which are characterized by a low permeable vasculature, increased more than 6-fold in the presence of SNO-HSA-Dimer, and the improved accumulation of Doxil® led to both increased survival and decreased tumor volume. These results strongly suggest that the more cancer is refractory, the more the SNO-HSA-Dimer could enhance the EPR effect via an endogenous albumin transport (EAT) system. Accordingly, we conclude that the EAT system is promising as a drug delivery system (DDS) strategy for refractory cancer therapy.

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    Editor’s picks

    Passive targeting can be applied to a relatively wide range of cancer types due to the enhanced permeability and retention (EPR) effect that is the basis of its theory. However, recent clinical data indicate that the tumor accumulation is only approximately 10% of the dose, and satisfactory results are most rarely obtained using only EPR effect strategy. In this article, the authors introduce the strategy of enhancing the EPR effect using S-nitrosated human serum albumin dimer (SNO-HSA Dimer) and the DDS strategy utilizing the endogenous albumin transport (EAT) system of tumor cells and its future development.

  • Tomoyuki Okuda, Hirokazu Okamoto
    2020 年 68 巻 7 号 p. 589-602
    発行日: 2020/07/01
    公開日: 2020/07/01
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    Inhaled lung cancer therapy is promising because of direct and noninvasive drug delivery to the lungs with low potential for severe systemic toxicity. Thus chemotherapeutic drugs have been administered clinically by nebulization of solution or suspension formulations, which demonstrated their limited pulmonary absorption and relatively mild systemic toxicity. In all these clinical trials, however, there was no obviously superior anticancer efficacy in lung cancer patients even at the maximum doses of drugs limited by pulmonary toxicity. Therefore methods that deliver both higher anticancer efficacy and lower pulmonary toxicity are strongly desired. In addition to the worldwide availability of pressured metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) to treat local respiratory diseases, recent innovations in medicines and technologies are encouraging next steps toward effective inhaled lung cancer therapy with new therapeutic or drug delivery concepts. These include the discovery of target cells/molecules and drug candidates for novel cancer therapy, the development of high-performance inhalation devices for effective pulmonary drug delivery, and the establishment of manufacturing technologies for functional nanoparticles/microparticles. This review highlights the present situation and future progress of inhaled drugs for lung cancer therapy, including an overview of available inhalation devices, pharmacokinetics, and outcomes in clinical trials so far and some novel formulation strategies based on drug delivery systems to achieve enhanced anticancer efficacy and attenuated pulmonary toxicity.

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    Editor’s picks

    Inhaled lung cancer therapy is promising because of direct and noninvasive drug delivery to the lungs with low potential for severe systemic toxicity. In all clinical trials with nebulization of chemotherapeutic drugs, however, there was no obviously superior anticancer efficacy in lung cancer patients even at the maximum doses of drugs limited by pulmonary toxicity. Thus the addition of further drug delivery functions including sustained release, prolonged retention, and targeting in the lungs has been strongly desired to achieve enhanced anticancer efficacy and attenuated pulmonary toxicity of inhaled chemotherapeutic drugs and other drug candidates.

  • Shintaro Fumoto, Koyo Nishida
    2020 年 68 巻 7 号 p. 603-612
    発行日: 2020/07/01
    公開日: 2020/07/01
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    Cancer treatments have improved significantly during the last decade but are not yet satisfactory. Combination therapy is often administered to improve efficacy and safety. Drug delivery systems can also improve efficacy and safety. To control the spatiotemporal distribution of drugs, nanotechnology involving liposomes, solid lipid nanoparticles, and polymeric micelles has been developed. Co-delivery systems of multiple drugs are a promising approach to combat cancer. Synergistic effects and reduced side effects are expected from the use of co-delivery systems. In this review, we summarize various co-delivery systems for multiple drugs, including small-molecule drugs, nucleic acids, genes, and proteins. Co-delivery of drugs with different properties is relatively difficult, but some researchers have succeeded in developing such co-delivery systems. Environment-responsive carrier designs can control the release of cargos. Although their preparation is more complicated than that of mono-delivery systems, co-delivery systems can simplify clinical procedures and improve patient QOL.

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    Editor’s picks

    Combination therapies using multiple drugs are the effective strategies to treat tumors. Various therapeutic regimens have been developed. Here, co-delivery of multiple drugs to tumor tissues using nanotechnology is theoretically useful to improve the efficacy and safety of the regimens. In this review, the authors summarized the current state of co-delivery systems of multiple drugs, including small-molecular chemotherapeutic drugs, proteins, nucleic acids and gene medicines. Especially, they pointed out the importance of selection of the combination, targeted delivery of multiple drugs, and controlled release of drugs based on environment-responsive mechanisms. Co-delivery systems are the promising approach even for immunotherapy using checkpoint inhibitors.

Communication to the Editor
  • Yefang Zou, Zhuoxian Cao, Jie Wang, Xiaoxue Chen, Yan-qin Chen, Yan Li ...
    2020 年 68 巻 7 号 p. 613-617
    発行日: 2020/07/01
    公開日: 2020/07/01
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    電子付録

    Although anthraquinone derivatives possess significant antitumor activity, most of them also displayed those side effects like cardiotoxicity, mainly owing to their inhibition of topoisomerase II of DNA repair mechanisms. Our raised design strategy by switching therapeutic target from topoisomerase II to histone deacetylase (HDAC) has been applied to the design of anthraquinone derivatives in current study. Consequently, a series of novel HDAC inhibitors with a tricylic diketone of anthraquinone as a cap group have been synthesized. After screening and evaluation, compounds 4b, 4d, 7b and 7d have displayed the comparable inhibition in enzymatic activity and cell proliferation than that of Vorinostat (SAHA). Notably, compound 4b showed certain selectivity of antiproliferative effects on cancer cell lines over non-cancer cell lines.

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