Strontium-89 combined with doxorubicin in the treatment of patients with androgen-independent prostate cancer

We investigated the activity of a bone-targeting regimen consisting of strontium-89 and doxorubicin in the treatment of patients with androgen-independent prostate cancer. Three and 22 patients with androgen-independent prostate cancer and bone metastasis received doxorubicin at 15 mg/m² and 20 mg/m², respectively (intravenously by continuous infusion over 24 hours, once per week). All patients received strontium-89 55 μCi/kg, intravenously, every 3 months. Antitumor activity (a prostate specific antigen decrease of ≥75% from baseline) was seen in 32% of evaluable patients. Clinical benefit based on pain relief and performance improvement was achieved in 76% and 40% of patients, respectively. Strontium-89 combined with doxorubicin can be delivered with acceptable toxicities. Strontium-89 combined with doxorubicin is active in the treatment of androgen-independent prostate cancer and may be useful in future studies designed to optimize organ (bone)-specific therapies.     

N-(双膦羧次甲基)-6-(5-氟-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基)-6-氧代-己酰胺的合成及其初步的骨靶向性研究

目的合成N-（双膦羧次甲基）-6（5-氟-2，4-二氧代3，4-二氢-2H-嘧啶-1-基）-6-氧代-己酰胺，并进行初步体外骨靶向性实验。方法以5-氟尿嘧啶为原料，经硅烷化、缩合、氢解3步合成6-（5-氟-2，4-二氧代-3，4-二氢-2H-嘧啶-1-基）-6-氧代-己酸（2），用二氯亚砜氯化后再与含氨基的偕二膦酸酯偶联，最后再用溴代三甲基硅烷特异性解离掉膦酸酯得到目标化合物L，并采用羟磷灰石晶体吸附实验考察目标物的骨靶向性。结果合成了目标物L，并利用^-1H—NMR、IR和MS进行了结构确证。结论体外骨靶向性实验结果显示目标物L有较好的骨靶向性。     

Experiments and synthesis of bone-targeting epirubicin with the water-soluble macromolecular drug delivery systems of oxidized-dextran

Abstract

Epirubicin (EPI) is a broad spectrum antineoplastic drug, commonly used as a chemotherapy method to treat osteosarcoma. However, its application has been limited by many side-effects. Therefore, targeted drug delivery to bone has been the aim of current anti-bone-tumor drug studies. Due to the exceptional affinity of Bisphosphonates (BP) to bone, 1-amino-ethylene-1, 1-dephosphate acid (AEDP) was chosen as the bone targeting moiety for water-soluble macromolecular drug delivery systems of oxidized-dextran (OXD) to transport EPI to bone in this article. The bone targeting drug of AEDP–OXD–EPI was designed for the treatment of malignant bone tumors. The successful conjugation of AEDP–OXD–EPI was confirmed by analysis of FTIR and ¹H-NMR spectra. To study the bone-seeking potential of AEDP–OXD–EPI, an in vitro hydroxyapatite (HAp) binding assay and an in vivo experiment of bone-targeting capacity were established. The effectiveness of AEDP–OXD–EPI was demonstrated by inducing apoptosis and necrosis of MG-63 tumor cell line. The obtained experimental data indicated that AEDP–OXD–EPI is an ideal bone-targeting anti-tumor drug.     

Alendronate-decorated biodegradable polymeric micelles for potential bone-targeted delivery of vancomycin

Osteomyelitis is a bone infection disease which is caused by bacteria or other germs, and could cause serious impact on the health and working capacity of the patients. Alendronate (ALN) can chelate strongly with the calcium ion of hydroxyapatite (HA) which is commonly used to treat osteoporosis. Nanomedicine has attracted a lot of attention in that the nano-sized carrier can deliver drug molecules to specific site of interest with the aid of targeting moiety and achieve sustained release, resulting in improved therapeutic effect and reduced side effect. In this study, micelles self-assembled from poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-alendronate (PLGA-PEG-ALN) copolymer were prepared for bone-targeted delivery of vancomycin (Van). The chemical structure of PLGA-PEG-ALN was confirmed by proton nuclear magnetic resonance (¹H-NMR) spectroscopy. The formation of the nanoparticles was characterized by dynamic light scattering, transmission electronic microscopy as well as the critical micelle concentration measurement. Release profiles from the micelles revealed that the conjugation of ALN to the surface of micelle did not pose adverse effect on the drug-loading capacity and release behaviors. The cytotoxicity of Van-loaded PLGA-PEG-ALN micelles as well as the blank micelles was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay toward rat bone marrow stromal cells (rBMSCs) and human embryonic hepatocytes (L02 cells), and results showed that this Van-loaded micelle possesses appropriate cytotoxicity and is safe in the potential treatment of osteomyelitis. The in vitro affinity of PLGA-PEG-ALN micelles to the HA was also confirmed in vitro. The antibacterial effect of Van-loaded PLGA-PEG-ALN micelles was tested against Staphylococcus aureus (SA) which is the main pathogenic bacteria in osteomyelitis, and the results showed that the Van-loaded micelles can effectively inhibit the growth of SA. These results demonstrated that the PLGA-PEG-ALN micelles may be potentially used for the bone targeted delivery of Van.     

Bone site-specific delivery of siRNA

Small interfering RNAs（siRNA） have enormous potential as therapeutics to target and treat various bone disorders such as osteoporosis and cancer bone metastases.However,effective and specific delivery of siRNA therapeutics to bone and bone-specific cells in vivo is very challenging.To realize the full therapeutic potential of siRNA in treating bone disorders,a safe and efficient,tissue- and cell-specific delivery system must be developed.This review focuses on recent advances in bone site-specific delivery of siRNA at the tissue or cellular level.Bone-targeted nanoparticulate siRNA carriers and various bone-targeted moieties such as bisphosphonates,oligopeptides（Asp）₈ and（AspSerSer）₆,and aptamers are highlighted.Incorporation of these bone-seeking targeting moieties into siRNA carriers allows for recognition of different sub-tissue functional domains of bone and also specific cell types residing in bone tissue.It also provides a means for bone-formation surface-,bone-resorption surface-,or osteoblastspecific targeting and transportation of siRNA therapeutics.The discussion mainly focuses on systemic and local bone-specific delivery of siRNA in osteoporosis and bone metastasis preclinical models.     

特异性骨靶向纳米递药系统的优势与临床可应用性

文题释义： 药物靶向性：靶向药物是在目标器官或组织局部形成相对高的浓药物度,减少对非目标器官、组织、细胞的伤害。目前根据靶向目标不同,可分为组织器官水平、细胞水平及亚细胞水平几个层次。根据靶向机制的不同,药物靶向可分为被动靶向、主动靶向、物理靶向等几类,其中的主动靶向即特异性靶向。 纳米药物递送系统：药物递送系统是利用临床医学、药学及材料科学等多学科手段,在恰当的时机将适量的药物递送到正确的位置,从而增加药物的利用效率,提高疗效,降低成本,减少毒副作用。纳米级药物递送系统是指在药剂学中把纳米载体负载治疗药物形成粒径1-1 000 nm纳米粒。因为其纳米级粒径可以使得药物在体内穿过某些生物屏障如血-脑屏障、血-骨髓屏障等,以及利用肿瘤组织的高渗透长滞留效应而达到被动靶向的效果,但其缺乏特异性。背景：在骨相关疾病治疗中特异性主动靶向递药系统非常重要,而纳米技术的发展为其提供了良好的平台,同时为其提供了新的研究思路。 目的：针对以特异性骨靶向递药系统的目前发展及未来前景做一综述。 方法：应用计算机在PubMed、Web of Science和Medline等数据库检索涉及主动骨靶向性递药系统与纳米级递药系统的相关研究,检索关键词为“Bone target therapy,Nanoparticles,Drug delivery system”,检索时间为2014年3月至2019年3月。 结果与结论：靶向基团是特异性骨靶向递药系统的重要组成部分,它决定了递药系统的靶向效率。到目前为止已发现针对于骨组织、破骨细胞、成骨细胞、骨髓间充质干细胞的靶向分子,它们有各自优缺点。目前特异性骨靶向纳米递药系统已在各种骨病领域得到了广泛研究,如转移骨质疏松症、骨髓炎、多发性骨髓瘤、骨肉瘤、骨转移癌等。纳米载体应用的优势为其带来了临床潜力的同时也存在许多挑战,尽管许多基础研究显示出很好的体内结果,但很少有骨靶向基团修饰的纳米递药系统成功地将其转化为临床。 ORCID: 0000-0001-8512-0447(向海滨) 中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

去势抵抗性前列腺癌的治疗进展*

去势抵抗性前列腺癌是一种致死性疾病,进展快,常伴随着转移,预后极差,死亡率接近100% ,患者中位生存时间少于20个月,是前列腺癌治疗的热点和难题,其发生发展机制尚不明确。近些年来涌现出许多治疗去势抵抗性前列腺癌的新方法,包括新型雄激素受体拮抗剂、免疫治疗、紫杉烷类化疗药物、抗血管生成药物、放射性核素、骨靶向药物以及各疗法联合应用等,改善了患者的生存期。本文就去势抵抗性前列腺癌的治疗进展进行综述。