Preparation, Characterization and in vitro Release of Chitosan-stavudine Conjugate Nano-prodrug

Chitosan-stavudine （d4T） conjugate with a succinic spacer was synthesized via carbodiimide coupling reaction and structurally characterized. In order to nanosize it for improving its therapeutic properties, the chitosan-5＇-O-succinyl-d4T conjugate was crosslinked with sodium tripolyphosphate （TPP） to obtain the chitosan-d4T conjugate nano-prodrug. The morphologies of chitosan-d4T conjugate nanoparticles were observed by transmission electron microscopy （TEM）, and their zeta potential, particle size, and polydispersity （size distribution） were measured by the dynamic light scattering （DLS） techniques. In vitro drug release studies at pH 1.1 and pH 7.4 indicate that the crosslinked chitosan-d4T conjugate nano-prodrug can prevent the coupled d4T from leaking out before entering the target viral reservoirs and provide a mild sustained release without the burst release. The results reveal that constructing conjugated chitosan nano-prodrugs may be a promising approach for improving the therapy efficacy of drugs in antiviral treatment.

Combination therapy to overcome ferroptosis resistance by biomimetic self-assembly nano-prodrug

Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer.Herein,we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib(Gefi),ferrocene(Fc)and dihydroartemisinin(DHA)for the combined therapy of both ferroptosis and apoptosis.In the tumor microenvironment,this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH.Interestingly,the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc,further executing tumor cell death with concomitant chemotherapy by Gefi.More importantly,this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis,as well as no noticeable side-effects during treatments.This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.

Dynamic crosslinked polymeric nano-prodrugs for highly selective synergistic chemotherapy

To achieve highly selective synergistic chemotherapy attractive for clinical translation,the precise polymeric nano-prodrugs(PPD-NPs)were successfully constructed via the facile crosslinking reaction between p H-sensitive poly(ortho ester)s and reduction-sensitive small molecule synergistic prodrug(Pt(IV)-1).PPD-NPs endowed the defined structure and high drug loading of cisplatin and demethylcantharidin(DMC).Moreover,PPD-NPs exhibited steady long-term storage and circulation via the crosslinked structure,suitable negative potentials and low critical micelle concentration(CMC),improved selective tumour accumulation and cellular internalization via dynamic size transition and surficial amino protonation at tumoural extracellular p H,promoted efficient disintegration and drug release at tumoural intracellular p H/glutathione,and enhanced cytotoxicity via the synergistic effect between cisplatin and DMC with the feed ratio of 1:2,achieving significant tumour suppression while decreasing the side effects.Thus,the dynamic crosslinked polymeric nano-prodrugs exhibit tremendous potential for clinically targeted synergistic cancer therapy.

pH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy

Currently,the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy,owing to its precise structure,high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract,blood circulation and tumor tissues compared to other oral nanomedicines.Herein,this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes,which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters.The precise nano-prodrugs exhibit extraordinarily high drug loading(68.16%),electric neutrality,strong hydrophobicity,and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH.These favorable physicochemical properties can effectively facilitate gastrointestinal absorption,blood circulation stability,tumor accumulation,cellular uptake,and cytotoxicity,therefore achieving high oral relative bioavailability(358.72%)and significant tumor growth inhibition while decreasing side effects.Thus,this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.

纳米聚合物前药的设计合成及其抗乳腺癌的应用

癌症是全球重大的公共卫生问题。根据世界卫生组织国际癌症研究机构发布的全球癌症数据最新统计,女性乳腺癌位列全球第二,占新增病例总数的11.6%。乳腺癌常规治疗手段存在生物利用度低、毒副作用大和易产生耐药性等问题。纳米聚合物前药因其高载药率、低毒副作用、高效靶向性和实时可控性等独特的优势应运而生。总结了纳米聚合物前药的优势及分类,并从设计合成路线、刺激响应途径、主动靶向特性及其抗乳腺癌应用等方面进行了系统介绍,以便研究人员深入了解作用机制,从而进一步优化其设计和应用策略。此外还讨论了纳米聚合物前药在乳腺癌治疗中的前景与挑战,以期为纳米聚合物前药的临床应用提供有益借鉴。

半乳糖高分子纳米前药构建及肝癌治疗

用于肝癌治疗的化疗药物存在水溶性差、全身性毒副作用大、没有病灶靶向性等缺陷.研究制备了三种基于半乳糖骨架的还原响应型纳米前药PGal25D、PGal35D和PGal50D,考察其自组装行为,并以PGal25D为药物载体考察其体外药物释放能力及细胞学水平的肝癌治疗效果.结果表明,三种纳米前药均可形成自组装体,其中PGal25D有良好的粒径、载药能力和稳定性;体外药物释放实验证实PGal25D有良好的还原敏感性;体外细胞毒性结果显示,其对肝癌细胞表现出较好的选择性治疗.

多西他赛棕榈酸酯脂质体的制备及药效和安全性评价

目的:合成一种多西他赛棕榈酸酯(docetaxel palmitate,DTX-PA)前药,将其制备成多西他赛棕榈酸酯脂质体(docetaxel palmitate liposome,DTX-PA-L)纳米给药系统,并对其抑瘤效果和给药安全性进行初步评价。方法:在缚酸剂和脱水剂的作用下,通过一步酯化法合成目标化合物DTX-PA,并采用ESI-MS、1H-NMR与13 C-NMR等技术进行结构鉴定。采用薄膜分散法制备DTX-PA-L,并对其粒径、电位、包封率等进行表征。构建ICR小鼠S 180腹水移植瘤模型,考察DTX-PA-L的抗肿瘤活性,并对给药小鼠进行血常规检测,考察该制剂的血液毒性。结果:本研究成功合成了DTX-PA前药,制备的DTX-PA-L为半透明液体,粒径为(110.66±0.75)nm,zeta电位为(-30.79±1.51)mV,包封率为(95.77±0.35)%。药效学和血常规实验结果表明,与阳性药多西他赛注射液(商品名Taxotere)相比,DTX-PA-L具有显著的增效减毒作用。结论:采用一步酯化法合成,并以薄膜分散法制备的DTX-PA-L纳米给药系统在降低毒性和提高抗肿瘤效果上具有独特的优势,为多西他赛制剂的研制提供了一种新的研究思路。

提升姜黄素疗效的策略及技术研究进展

姜黄素是从姜黄Curcuma longa中提取出的多酚类天然化合物,其医疗价值已被发掘超过30年。低剂量的姜黄素就能在抗肿瘤、抗炎、抗氧化等方面发挥显著的作用,但是由于其水溶性差、生物利用率较低,其临床疗效还有待提升。因此,如何有效提升姜黄素的生物利用度与靶向性,使其更稳定地发挥治疗或保健功能,是目前研究者迫切需要解决的关键问题。通过对近年来姜黄素的相关文献资料进行归纳总结,对姜黄素的体内代谢途径进行概括,并对提高姜黄素疗效的相关策略及技术研究进行综述,为姜黄素的进一步研究和开发提供参考。

小分子自组装纳米递药系统研究进展

生物纳米技术在药物递送领域的应用为高端创新制剂的研发注入了新动力,一系列新型纳米递药系统被相继开发乃至应用于临床。其中,由小分子药物或前药自组装形成的纳米递药系统因具有制备工艺简便、载药量超高和易于实现工业化生产等优势而备受关注,已成为纳米递药系统领域的一个重要分支。本文总结了小分子自组装纳米递药系统的最新研究进展。首先,对小分子前药自组装纳米递药系统进行介绍,包括两亲性、疏水性和二聚体小分子前药自组装纳米递药系统。其次,分别介绍小分子化学药物和小分子生物药物自组装纳米递药系统的最新进展。再者,对小分子杂化共组装纳米递药系统进行总结和分析,包括小分子纯药共组装纳米递药系统、小分子前药共组装纳米递药系统及小分子前药/小分子纯药共组装纳米递药系统。最后,讨论了小分子自组装纳米递药系统的合理设计、应用前景和临床挑战,以期为新一代纳米制剂的设计与构建提供参考。