Anti prostate cancer using PEGylated bombesin containing,cabazitaxel loading nano-sized drug delivery system

Context: Prostate cancer (PCa) is the second most-frequently diagnosed cancer in men. Cabazitaxel was approved for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.

Objective: In this study, bombesin (BN), a ligand reported to specifically target GRP overexpressing prostate tumor, was applied for the construction of lipid-polymer hybrid nanoparticles (LPNs), and used for the targeted delivery of cabazitaxel (CAB) to prostate cancer.

Methods: BN-polyethylene glycol-1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (BN-PEG-DSPE) was synthesized. CAB loaded, BN-PEG-DSPE contained LPNs (BN-CAB-LPNs) were prepared. Their particle size, zeta potential and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study of BN-CAB-LPNs was tested in LNCaP human prostatic cancer cell line (LNCaP cells). In vivo anti-tumor efficacy of the carriers was evaluated on mice bearing prostate cancer model.

Results: The optimum BN-CAB-LPNs formulations had a particle size of 184.9?nm and a 26.5?mV positive surface charge. The growth of LNCaP cells in vitro was obviously inhibited. BN-CAB-LPNs also displayed better anti-tumor activity than the other formulations in vivo.

Conclusion: The results demonstrated that BN-CAB-LPNs can sufficiently deliver CAB to the cancer cells and enhance the anti-tumor capacity. Thus, BN-CAB-LPNs can be proved to be a superior nanomedicine which can achieve better therapeutic efficacy of prostate tumor.     

Sequential MR Image‐Guided Local Immune Checkpoint Blockade Cancer Immunotherapy Using Ferumoxytol Capped Ultralarge Pore Mesoporous Silica Carriers after Standard Chemotherapy

Herein, ferumoxytol (Fer) capped antiprogrammed cell death‐ligand 1 (PD‐L1) antibodies (aPD‐L1) loaded ultralarge pore mesoporous silica nanoparticles (Fer‐ICB‐UPMSNPs) are formulated for a sequential magnetic resonance (MR) image guided local immunotherapy after cabazitaxel (Cbz) chemotherapy for the treatment of prostate cancer (PC). The highly porous framework of UPMSNP provides a large capacity for aPD‐L1. Fer capping of the pores extends the period of aPD‐L1 release and provides MR visibility of the aPD‐L1 loaded UPMSNP. As‐chosen Cbz chemotherapy prior to the local immunotherapy induces strong immunogenic cell death, dendritic cell maturation, and upregulation of PD‐L1 of tumor cells. Finally, tumor growth inhibition of sequential MR image‐guided local delivery of Fer‐ICB‐UPMSNPs and a tumor specific adoptive immune reaction are demonstrated in the pretreated Tramp C1 PC mouse model with Cbz chemotherapy. The tumor suppression is superior to those obtained with systemic ICB treatment after Cbz, only Fer‐ICB‐UPMSNP or only Cbz. As a proof‐of concept, MR image‐guided local ICB immunotherapy using Fer‐ICB‐UPMSNPs after chemotherapy suggests a new perspective of translational local immunotherapy for patients who are treated with standard chemotherapies.     

一种卡巴他赛的合成新方法

提出了一种全新的卡巴他赛合成路线.以7-木糖基紫杉烷类化合物为起始原料,经氧化脱木糖基、甲基化、肼解脱侧链得到7,10-二甲基巴卡亭Ⅲ;再与1-叔丁氧羰基-（3R,4S）-4-苯基氮杂环丁烷-2-酮缩合,最后在冰醋酸甲醇溶液中脱除乙氧基乙基（EE）得到卡巴他赛.该合成方法所用起始原料均为紫杉醇提取过程中的废料,成功解决了紫杉醇提取中的废料回收利用问题;并且所用原料价格低廉,反应条件温和,有利于工业化生产.     

卡巴他赛注射液细菌内毒素检查方法的建立

目的：建立卡巴他赛注射液的细菌内毒素检查法（BET法）。方法按中国药典2010年版二部的规定,确定卡巴他赛注射液的细菌内毒素限值,进行BET法的干扰试验,并测定其最大非干扰浓度。结果卡巴他赛注射液对BE哒没有抑制作用,在0．1mg·ml-11及以下浓度时对鲎试剂无干扰作用。结论：卡巴他赛注射液可用BET法进行细菌内毒素检查,用于该制剂的质量控制。     

Rational Design of Tumor Microenvironment‐Activated Micelles for Programed Targeting of Breast Cancer Metastasis

The poor drug delivery to primary and metastatic tumors of breast cancer remains a great challenge for effective antimetastasis therapy. Herein, a tumor microenvironment‐activated cabazitaxel micelles decorated with legumain‐specific melittin (TCM‐legM) are rationally designed for programed targeting of breast cancer metastasis. TCM‐legM is quiescent in blood circulation, but can be specifically activated by the highly expressed legumain in tumor microenvironments to improve their specific targeting and deep penetrating to primary or metastatic tumors. Thereafter, the activated TCM‐legM can be efficiently internalized by cancer cells and motivate the rapid pH‐responsive drug release for antimetastasis therapy. In metastatic 4T1 breast cancer cells, TCM‐legM presents significant inhibition on the proliferation, migration, and invasion activities. In vivo, TCM‐legM can be effectively delivered to both primary and metastatic tumors of breast cancer with deep tumor penetration and efficient cellular internalization, thereby resulting in a notable reduction of tumor growth and producing a 93.4% suppression of lung metastasis. Taken together, the rationally designed TCM‐legM can provide an intelligent drug delivery strategy to enhance the medical performance on treating breast cancer metastasis.     

抗肿瘤药卡巴他赛的合成

合成了微管抑制剂类抗肿瘤药物卡巴他赛,合成路线为：10-脱乙酰巴卡亭Ⅲ（Ⅱ）与甲基化试剂硫酸二甲酯进行甲基化,生成C-7,C-10-二甲基-10-脱乙酰巴卡亭Ⅲ（Ⅲ）;将Ⅲ与（3R,4S）-3-（1-乙氧乙氧基）-2-氧-4-苯基-吖丁啶羧酸叔丁基酯（Ⅳ）进行缩合,生成化合物N-叔丁氧羰基-（2R,3S）-3-苯基-O-（1-乙氧基乙基）异丝氨酸-7,10-二甲基-10-脱乙酰巴卡亭Ⅲ-13-酯（V）;V通过酸性条件脱去1-乙氧基乙基得到目标化合物,总收率（基于Ⅱ）约30％,纯度99.36％.该合成方法耗时短、步骤少,易于工业化应用.