受体靶向多肽载体抗肿瘤药物

常规化疗药物对癌细胞没有选择性,常常会导致严重的副作用。提高这些药物的靶向特异性已成为药物开发的热点方向之一。一些小分子多肽能够靶向作用于特定的受体,因而被用作癌症化疗药物的载体。化疗药物与多肽载体偶联构成新的多肽载体抗肿瘤药物。这些药物具有高特异性、高亲和力和肿瘤渗透力等优点,能够通过细胞表面的特定受体将药物送到靶向癌细胞内,提高抗癌效果、减少副作用和癌细胞的耐药性。多肽载体靶向药物被誉为新一代的靶向特异性的抗肿瘤药物之一。     

多肽修饰脂质体靶向药物递送系统研究进展

目的 介绍近年来多肽修饰脂质体靶向药物递送系统的研究进展。方法 查阅和归纳总结近几年相关文献。结果 阐述了精氨酸-甘氨酸-天冬氨酸(RGD)多肽、丙氨酸-脯氨酸-精氨酸-脯氨酸-甘氨酸(APRPG)多肽、细胞穿透肽(CPP)、血管活性肠肽(VIP)等修饰脂质体的研究进展。多肽修饰的包载药物的脂质体可以增加药物在体内的选择性,减少药物毒副作用,提高药物治疗指数。结论 多肽分子是机体内一类重要的生物活性物质,将其作为导向物以配体-受体特异性结合的方式应用于靶向药物递送系统,具有良好的研究价值和应用前景。     

靶向蛋白-蛋白相互作用的抗肿瘤多肽药物的开发与递送

蛋白-蛋白相互作用(PPI)网络异常是肿瘤发生的重要原因.近年来,多肽药物由于其独特的优势被广泛用于靶向肿瘤相关PPI调节剂的开发,并获得了成功.通过对近几年的相关研究进行综述,从靶向PPI多肽的设计与应用角度总结抗肿瘤药物的最新研究进展,以期为基于靶向PPI的抗肿瘤多肽药物研发提供参考.     

含天冬氨酸-谷氨酸寡肽萘普生前药的合成及骨靶向性研究

目的合成以含有Asp-Glu片段的寡肽为载体的非甾体抗炎前药,并初步研究其骨靶向性。方法使用混合酸酐法制备(Asp-Glu)n-Nap前药,通过HAP法研究其骨靶向性。结果制备得到(Asp-Glu)n-Nap前药,产物经ESI-MS和1HNMR确证。HAP实验显示较好的体外骨靶向性。结论所用方法可行,制备的(Asp-Glu)n-Nap非甾体抗炎前药具有潜在的骨靶向性。     

多肽介导的核酸药物递送系统研究进展

核酸药物作为新型基因治疗药物备受关注,但生物学稳定性差、易被体内核酸酶降解、生物利用度低、靶组织内聚集浓度低等是制约其发展的主要因素。新的药物递送技术的快速发展在一定程度上解决了核酸药物的稳定性及靶向递送问题,极大地推动了核酸药物的研发进展。尤其是多肽蛋白类递送载体,已成为核酸药物递送系统研究领域的热点之一。介绍核酸药物递送载体多肽修饰的两种主要方式——共价缀合和非共价络合,重点综述近年来多肽缀合物和复合物以及多肽修饰的载体在核酸药物递送系统中的应用研究,探讨多肽介导的核酸药物递送系统在应用中存在的问题,为新型核酸药物递送系统研发提供参考。     

小肠寡肽转运蛋白及其在提高药物口服吸收中的应用

小肠上皮细胞刷状缘侧的寡肽转运蛋白(PEPT1)以及侧底膜的寡肽转运蛋白是寡肽转运蛋白(PEPT)的2种亚型,它们在寡肽及拟肽类药物(peptidomimetic drug)肠转运中发挥重要作用。通过前体药物(prodrug)设计将一些吸收差的药物修饰成类似二肽或三肽的结构,在PEPT1的介导下吸收,能够提高这些药物的口服生物利用度,这是非常有意义的。     

多肽在药物靶向运送及疾病治疗中的研究进展

作为非病毒转基因载体骨架组件,功能性多肽在构建转基因载体、载体的核转运和靶向运送等方面发挥着重要作用。本文综述了多肽在药物靶向运送和疾病治疗中的研究进展。     

双膦酸作为骨靶向载体治疗骨质疏松症的研究进展

综述了以双膦酸作为骨靶向载体转运其它药物治疗骨质疏松症的研究进展。骨质疏松症是一种在绝经后妇女中最为常见的疾病。目前使用的药物大部分存在着副作用大的缺点，所以需要研制能选择性作用于骨组织的药物。双膦酸类化合物有较好的趋骨性，可以转运药物作用于骨组织。     

纳米制剂技术在骨靶向给药系统中的应用进展

骨骼是人体的重要组成部分,由骨膜、骨质和骨髓构成.正常骨骼时刻处于骨形成和骨吸收的骨重建动态平衡中,两者相互协调作用,共同维持骨骼的生理功能.如果正常骨重建过程发生病变,就会产生各种骨疾病,如骨质疏松症、畸形性骨炎、骨转移瘤、原发性和继发性骨肿瘤、骨关节炎等.由于骨组织硬度大、渗透性差和生理生化过程特殊,一般给药途径很难使药物转运至病灶部位.药物常须通过全身给药,增加剂量才能在骨组织中达到有效的治疗浓度,这样不仅降低了药物的治疗指数,而且也会对患者的非骨组织或器宫造成较为严重的不良反应.骨靶向给药系统(osteotropic drug delivery system,ODDS)能特异性地将药物转运至骨组织从而减小其在非骨组织的分布与结合[1].     

多肽修饰脂质体靶向药物递送系统研究进展

目的介绍近年来多肽修饰脂质体靶向药物递送系统的研究进展。方法查阅和归纳总结近几年相关文献。结果阐述了精氨酸-甘氨酸-天冬氨酸（RGD）多肽、丙氨酸-脯氨酸-精氨酸-脯氨酸-甘氨酸（APRPG）多肽、细胞穿透肽（CPP）、血管活性肠肽（VIP）等修饰脂质体的研究进展。多肽修饰的包载药物的脂质体可以增加药物在体内的选择性,减少药物毒副作用,提高药物治疗指数。结论多肽分子是机体内一类重要的生物活性物质,将其作为导向物以配体-受体特异性结合的方式应用于靶向药物递送系统,具有良好的研究价值和应用前景。     

Bone-targeting macromolecular therapeutics

Musculoskeletal diseases such as osteoporosis are recognized as major public health problems worldwide. Many novel therapeutic agents have been identified for the treatment of these diseases. However, the majority of them are not specific to hard tissue, resulting significant toxicity. Bone-targeting drug delivery systems based on water-soluble polymers can specifically direct candidate drugs to bone thereby reducing side effects due to non-specific tissue interactions. Incorporation of a targeting moiety, a drug release mechanism, drug selection and optimization of the polymer carrier are all essential elements in the development of bone-targeting macromolecular therapeutics. Successful clinical application of this approach can significantly contribute to the development of treatments for many musculoskeletal diseases.     

Comparative study of (Asp)7-CHOL-modified liposome prepared using pre-insertion and post-insertion methods for bone targeting in vivo

Specific delivery of drugs to bone tissue is very challenging due to the architecture and structure of bone tissue. A seven-repeat sequence of aspartate, a representative bone-targeting oligopeptide, is preferentially used for targeted therapy for bone diseases. In this study, Asp7-cholesterol((Asp)7-CHOL) was synthesized and (Asp)7-CHOL-modified liposome loaded with doxorubicin (DOX) was successfully prepared using both pre-insertion (pre-L) and post-insertion (post-L) methods. The formulation was optimized according to particle size, zeta potential and the drug-loading efficiency of the liposome. In addition, the bone affinity of the (Asp)7-CHOL-modified liposome was evaluated using a hydroxyapatite (HA) absorption method. The results suggested that (Asp)7-CHOL-modified liposome show excellent HA absorption; pre-L showed slightly higher HA binding than post-L. However, post-L had a higher DOX entrapment efficiency than pre-L. In vivo imaging further demonstrated that pre-L showed a higher bone-targeting efficiency than post-L, which was consistent with in vitro results. In all, (Asp)7-CHOL-modified liposome showed excellent bone-targeting activity, suggesting their potential for use as a drug delivery system for bone disease-targeted therapies.     

Targeted drug delivery to bone: pharmacokinetic and pharmacological properties of acidic oligopeptide-tagged drugs

Site-specific drug delivery to bone is considered to be achievable by utilizing acidic amino acid homopeptides. We found that fluorescence-labeled acidic amino acid (L-Asp or L-Glu) homopeptides containing six or more residues bound strongly to hydroxyapatite, which is a major component of bone, and were selectively delivered to and retained in bone after systemic administration. We explored the applicability of this result for drug delivery by conjugation of estradiol and levofloxacin with an L-Asp hexapeptide. We also similarly tagged an enzyme, tissue-nonspecific alkaline phosphatase, to see whether this would improve the efficacy of enzyme replacement therapy. The L-Asp hexapeptide-tagged drugs, including the enzyme, were selectively delivered to bone in comparison with the untagged drugs. It was expected that the ester linkage to the hexapeptide would be susceptible to hydrolysis in situ, releasing the drug or enzyme from the acidic oligopeptide. An in vivo experiment confirmed the efficacy of L-Asp hexapeptide-tagged estradiol and levofloxacin, although there was some loss of bioactivity of estradiol and levofloxacin in vitro, suggesting that the acidic hexapeptide was partly removed by hydrolysis in the body after delivery to bone. The adverse effect of estradiol on the uterus was greatly reduced by conjugation to the hexapeptide. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents. We present some pharmacokinetic and pharmacological properties of the L-Asp hexapeptide-tagged drugs and enzyme.     

Pharmacokinetic and biodistribution studies of a bone-targeting drug delivery system based on N-(2-hydroxypropyl)methacrylamide copolymers

Osteotropicity of novel bone-targeted HPMA copolymer conjugates has been demonstrated previously with bone histomorphometric analysis. The pharmacokinetics and biodistribution of this delivery system were investigated in the current study with healthy young BALB/c mice. The 125I-labeled bone-targeted and control (nontargeted) HPMA copolymers were administered intravenously to mice, and their distribution to different organs and tissues was followed using gamma counter and single photon emission computed tomography (SPECT). Both the invasive and noninvasive data further confirmed that the incorporation of D-aspartic acid octapeptide (D-Asp8) as bone-targeting moiety could favorably deposit the HPMA copolymers to the entire skeleton, especially to the high bone turnover sites. To evaluate the influence of molecular weight, three fractions (Mw of 24, 46, and 96 kDa) of HPMA copolymer-D-Asp8 conjugate were prepared and evaluated. Higher molecular weight of the conjugate enhanced the deposition to bone due to the prolonged half-life in circulation, but it weakened the bone selectivity. A higher content of bone-targeting moiety (D-Asp8) in the conjugate is desirable to achieve superior hard tissue selectivity. Further validation of the bone-targeting efficacy of the conjugates in animal models of osteoporosis and other skeletal diseases is needed in the future.     

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

Introduction: Bisphosphonates (BPs) were introduced 45 years ago as anti-osteoporotic drugs and during the last decade have been utilized as bone-targeting groups in systemic treatment of bone diseases. Very recently, strategies of chemical immobilization of BPs in hydrogels and nanocomposites for bone tissue engineering emerged. These strategies opened new applications of BPs in bone tissue engineering.

Areas covered: Conjugates of BPs to different drug molecules, imaging agents, proteins and polymers are discussed in terms of specific targeting to bone and therapeutic affect induced by the resulting prodrugs in comparison with the parent drugs. Conversion of these conjugates into hydrogel scaffolds is also presented along with the application of the resulting materials for bone tissue engineering.

Expert opinion: Calcium-binding properties of BPs can be successfully extended via different conjugation strategies not only for purposes of bone targeting, but also in supramolecular assembly affording either new nanocarriers or bulk nanocomposite scaffolds. Interaction between carrier-linked BPs and drug molecules should also be considered for the control of release of these molecules and their optimized delivery. Bone-targeting properties of BP-functionalized nanomaterials should correspond to bone adhesive properties of their bulk analogs.     

Bone-targeting dendrimer for the delivery of methotrexate and treatment of bone metastasis

We developed a bone-targeting dendrimer for the delivery of anti-tumour agents and effective treatment of bone metastasis, in which alendronate (ALN), a bone-targeting moiety, is covalently bonded to a polyethylene glycol (PEG)-conjugated polyamidoamine (PAMAM) dendrimer (PEG-PAMAM-ALN). Approximately 7.0 and 21.9% of the administered doses of [¹¹¹In]PAMAM and PEG-PAMAM-ALN accumulated in the bones within 180?min after intravenous injection in mice, respectively. [³H]-labelled methotrexate (MTX) rapidly disappeared from the blood, and bone distribution was found to be only 1.1% of the administered dose at 180?min. In contrast, 21.5% of the administered dose of [³H]MTX-loaded PEG-PAMAM-ALN accumulated in the bones at 180?min after intravenous injection in mice, which was approximately 20-fold higher than that of [³H]MTX. In a bone metastatic tumour mouse model, in which B16-BL6/Luc cells were injected into the left ventricle of female C57BL/6 mice, the growth of metastatic tumour in the bones was significantly inhibited by intravenous injection of MTX-loaded PEG-PAMAM-ALN. These findings indicate that PEG-PAMAM-ALN is a promising bone-targeting carrier for the delivery of anti-tumour agents and treatment of bone metastasis.     

Novel bone-targeted Src tyrosine kinase inhibitor drug discovery

Bone-targeted Src tyrosine kinase (STK) inhibitors have recently been developed for the treatment of osteoporosis and cancer-related bone diseases. The concept of bone targeting derives from bisphosphonates, and from the evolution of such molecules in terms of therapeutic efficacy for the treatment of bone disorders. Interestingly, some of the earliest bisphosphonates were recognized for their ability to inhibit calcium carbonate precipitation (scaling) by virtue of their affinity to chelate calcium. This chelating property was subsequently exploited in the development of bisphosphonate analogs as inhibitors of the bone-resorbing cells known as osteoclasts, giving rise to breakthrough medicines, such as Fosamax (for the treatment of osteoporosis) and Zometa (for the treatment of osteoporosis and bone metastases). Relative to these milestone achievements, there is a tremendous opportunity to explore beyond the limited chemical space (functional group diversity) of such bisphosphonates to design novel bone-targeting moieties, which may be used to develop other classes of promising small-molecule drugs affecting different biological pathways. Here, we review studies focused on bone-targeted inhibitors of STK, a key enzyme in osteoclast-dependent bone resorption. Two strategies are described relative to bone-targeted STK inhibitor drug discovery: (i) the development of novel Src homology (SH)-2 inhibitors incorporating non-hydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and bone-targeting properties, leading to the in vivo-effective lead compound AP-22408; and (ii) the development of novel ATP-based Src kinase inhibitors incorporating bone-targeting moieties, leading to the in vivo-effective lead compound AP-23236. In summary, AP-22408 and AP-23236, which differ mechanistically by virtue of blocking Src-dependent non-catalytic or catalytic activities in osteoclasts, exemplify ARIAD Pharmaceuticals' structure-based design of novel bone-targeted lead compounds, successfully achieving in vivo proof-of-concept and providing the framework for the next-generation molecules that have further advanced, in terms of preclinical studies, for the treatment of osteoporosis and related bone diseases, including osteolytic bone metastases.     

Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation

Chemotherapy in treatment of malignant tumors has many side effects due to the poor physiochemical properties and the toxicity to normal tissues. The dual-targeting drug delivery system combining two high-affinity ligands can target anticancer drug primary to the diseased tissue, then to the tumor, which provides both greater efficacy of treatment and less harm to normal tissues. In this paper, a novel dual-targeting moiety RGD₇ (R-G-D-D-D-D-D-D-D; Nonapeptide for bone cancer combining D₆ peptide as bone target moiety and RGD peptide as tumors target moiety was contracted. A series of bone and/or tumor targeting conjugates have been synthesized in a convergent approach and well characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. The hydroxyapatite (HAP) binding, water solubility, the drug release and the distribution in vivo were evaluated. All the conjugates were water-soluble and able to release the parent drugs in vitro. The bone-targeting property of the dual-targeting delivery system was enhanced from the results of the HAP binding and the distribution in vivo. The experiment for verifying tumor targeting property was underway. These results provided an effective entry to the development of a new dual-targeting delivery system for bone cancer.     

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.