From oral formulations to drug-eluting implants:using 3D and 4D printing to develop drug delivery systems and personalized medicine

Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.

Nanotechnology-based delivery systems to overcome drug resistance in cancer

Cancer nanomedicine is defined as the application of nanotechnology and nanomaterials for the formulation of cancer therapeutics that can overcome the impediments and restrictions of traditional chemotherapeutics.Multidrug resistance(MDR)in cancer cells can be defined as a decrease or abrogation in the efficacy of anticancer drugs that have different molecular structures and mechanisms of action and is one of the primary causes of therapeutic failure.There have been successes in the development of cancer nanomedicine to overcome MDR;however,relatively few of these formulations have been approved by the United States Food and Drug Administration for the treatment of cancer.This is primarily due to the paucity of knowledge about nanotechnology and the fundamental biology of cancer cells.Here,we discuss the advances,types of nanomedicines,and the challenges regarding the translation of in vitro to in vivo results and their relevance to effective therapies.

Advances of nanotechnology applied to cancer stem cells

Cancer stem cells(CSCs)are a small proportion of the cells that exist in cancer tissues.They are considered to be the culprit of tumor genesis,development,drug resistance,metastasis and recurrence because of their self-renewal,proliferation,and differentiation potential.The elimination of CSCs is thus the key to cure cancer,and targeting CSCs provides a new method for tumor treatment.Due to the advantages of controlled sustained release,targeting and high biocompatibility,a variety of nanomaterials are used in the diagnosis and treatments targeting CSCs and promote the recognition and removal of tumor cells and CSCs.This article mainly reviews the research progress of nanotechnology in sorting CSCs and nanodrug delivery systems targeting CSCs.Furthermore,we identify the problems and future research directions of nanotechnology in CSC therapy.We hope that this review will provide guidance for the design of nanotechnology as a drug carrier so that it can be used in clinic for cancer therapy as soon as possible.

Film-Forming Systems in Topically Administered Pharmaceutical Formulations

The skin is the most extensive and outermost organ in the body and can be greatly exploited both from the point of view of alternative routes of systemic drug delivery and treatment of dermatological diseases. Because of its main function as a barrier against harmful external agents, it also becomes a barrier to drug administration, but there are strategies to reduce this limitation of this promising route of administration. The development of polymer-based film-forming formulations is extensively studied for this purpose, since the formation of a film on the skin increases the contact time of the drug, for this being characterized as a controlled release reservoir system. There are a multitude of possible polymers to compose these formulations and their choice must be made according to the purpose of each application. This work, therefore, aims to study the state of the art of film forming systems for topical application of pharmaceutical formulations.

Overcoming multidrug resistance(MDR) in cancer by nanotechnology

The emerging nanotechnology-based drug delivery holds tremendous potential to deliver chemotherapeutic drugs for treatment of multidrug resistance(MDR) cancer.This drug delivery system could improve the pharmacokinetic behavior of antitumor drugs,deliver chemotherapeutic drugs to target sites,control release of drugs,and reduce the systemic toxicity of drugs in MDR cancer.This review addresses the use of nanotechnology to overcome MDR classified on the bases of the fundamental mechanisms of MDR and various approaches to deliver drugs for treatment of MDR cancer.

Nanotechnological Contribution to Drug Delivery System: A Reappraisal

With the emergence of Nanotechnology, there has been remarkable improvement in the field of drug delivery system over the past decade. Nanotechnology in drug delivery system is an upcoming field and significant research has been conducted in this regard. It has been able to overcome some limitations encountered with the traditional routine drug delivery systems and hence emerged as an effective alternative. This article reviews nanotechnology based different types of drug delivery systems and their therapeutic applications.

基于纳米技术的药物递送系统在肝细胞癌治疗中的研究进展

原发性肝癌是消化系统最常见的恶性肿瘤之一,其中肝细胞癌(HCC)占90%以上。早期HCC以手术切除为主,且预后较好,然而因HCC起病隐匿,绝大多数患者确诊时已进展至中晚期,手术治疗效果较差,而非手术治疗方式因为普遍存在不良反应大,肿瘤选择性低等问题,疗效也不理想,所以目前中晚期HCC治疗仍是临床工作的难点。纳米粒(NP)尺寸小、比表面积大,具有多种独特的理化性质,成为输送药物、基因及细胞活性因子等治疗剂的潜在载体。纳米递送系统以NP为载体,通过功能化修饰,从时间、空间及剂量上调控药物、基因及细胞活性因子等在体内的代谢及转化,在HCC治疗中展现出巨大的潜力。本文主要介绍了几种常见纳米递送系统,包括有机纳米载体、无机纳米载体、外泌体等在HCC治疗中的现状和优势,总结了基于NP的纳米载体治疗HCC的机制,为新型纳米递送系统的研发提供参考。

纳米技术在骨质疏松症治疗中的研究进展

目的 总结纳米技术在骨质疏松症治疗中的研究进展,展望其在临床上的应用前景。方法 应用计算机检索Pubmed、中国期刊全文数据库(CNKI)中2006-2023年的相关文献。在标题、摘要、关键词中以“nano, osteoporosis, bone marrow mesenchymal stem cells(BMMSCs),treatment”或“纳米,骨质疏松,骨髓间充质干细胞,治疗”为检索词进行检索。选择与纳米技术治疗骨质疏松症密切相关的文章,优先选择时间最近且发表于权威杂志的文章。结果 对筛选到的文献进行精选得到34篇文献进行综述。结论 纳米技术由于其高靶向性、高利用率和低不良反应的特性,在骨质疏松症的治疗研究中备受关注。目前常用的纳米技术包括药物纳米化和纳米载药两大类。但目前纳米技术尚未在临床上应用于骨质疏松症的治疗,仍有许多问题待解决。

纳米药物递送系统在眼后段疾病中的研究进展

眼部复杂的给药屏障使得传统眼用制剂难以经眼表到达眼后段病变组织。因此,玻璃体腔注射药物在眼后段疾病中得到广泛应用,这种侵入性的给药途径存在药物半衰期短、需反复注射、并发症多等缺陷。当前,纳米制剂新型眼部药物递送系统,因其能克服眼部给药屏障、增强药物渗透性、提高药物生物利用度,使得药物高效递送至眼后段成为可能。但有关纳米递送药物所使用的载体材料相对繁杂,同时各项研究结论亦存在较大差异,不利于后期相关药物的研发。因此,文章以眼部给药的主要生理屏障为研究基础,重点概述了各类常见纳米药物递送系统在眼后段疾病中的应用,并探讨了其在眼后段疾病中的研究进展,以期为眼后段疾病的治疗提供更加安全、高效的治疗策略。

人造外泌体治疗心肌梗死:应用现状及前景

背景:心肌梗死是目前最严重的心血管疾病之一,现有的临床治疗方案如溶栓治疗、经皮冠状动脉介入治疗和冠状动脉旁路移植术均无法完全恢复缺血造成的心肌损伤。干细胞来源的外泌体治疗心肌梗死是近年来的研究热点,但天然来源的外泌体产量少,获取难度大、耗时长、归巢效果不佳等限制了其临床应用。在这种情况下,构建人造外泌体作为天然外泌体的替代品已成为解决上述问题的有效策略。目的:阐述人造外泌体在治疗心肌梗死中的研究现状,将其分为半人造和全人造两种设计模式,就两种模式的研究进展及存在的问题展开讨论,最后对其在未来的临床应用做出评价和展望。方法:以“人造外泌体,心肌梗死,工程化”为中文检索词,以“artificial exosome,hybrid exosome,myocardial infarction,nanoparticle,drug delivery system”为英文检索词,检索PubMed和中国知网数据库的相关文献。检索时限重点为2017年1月至2022年12月,同时纳入部分经典远期文献。通过阅读文题和摘要进行初步筛选;排除重复性研究、低质量期刊及内容不相关的文献,最后纳入73篇文献进行综述。结果与结论:(1)通过半人造改造外泌体的方式,不论是靶向肽段的修饰、生物膜的杂交或是磁力物质的辅助,均改善了传统的外泌体疗法靶向性不足、驻留率低、易被网状内皮系统所清除等缺陷,提高了传统外泌体治疗心肌梗死的效率,但是这些改造策略存在修饰效率不明确、医学伦理以及生物毒性等方面的问题。(2)全人造仿生外泌体相对于外泌体的改造,其设计自由度较高,可以解决天然来源外泌体提取存储难度高、规模化生产局限等问题,然而全人造外泌体的改造策略目前仍缺少可靠的临床前数据支持与生物安全性的检测,尚未形成规模化生产所需的标准化流程,因此在应用到临床以前,作为替代天然外泌体的人造外泌体方案仍需要科研人员进行持续深入研究。

Fighting type 2 diabetes: Formulation strategies for peptide-based therapeutics

Diabetes mellitus is a major health problem with increasing prevalence at a global level.The discovery of insulin in the early 1900 s represented a major breakthrough in diabetes management,with further milestones being subsequently achieved with the identification of glucagon-like peptide-1(GLP-1)and the introduction of GLP-1 receptor agonists(GLP-1 RAs)in clinical practice.Moreover,the subcutaneous delivery of biotherapeutics is a well-established route of administration generally preferred over the intravenous route due to better patient compliance and prolonged drug absorption.However,current subcutaneous formulations of GLP-1 RAs present pharmacokinetic problems that lead to adverse reactions and treatment discontinuation.In this review,we discuss the current challenges of subcutaneous administration of peptide-based therapeutics and provide an overview of the formulations available for the different routes of administration with improved bioavailability and reduced frequency of administration.

纳米药物递释系统在胃癌治疗中的研究进展

胃癌是最常见的消化道肿瘤之一,发病率居第五位,死亡率居第三位。手术依然是唯一可能治愈胃癌的方法,然而,即便接受根治性切除,绝大多数患者仍然出现肿瘤复发,5年生存率仅为30%。辅助化疗在胃癌术后治疗中起主导作用,化疗虽然可以进一步提高胃癌患者生存,但其副反应发生率高、且需全身多次反复给药。针对传统化疗存在的弊端,开发缓释化疗制剂成为肿瘤治疗领域的热点,其中纳米药物递释系统在缓释化疗方面具有明显的优势。本文对胃癌治疗中纳米药物递释系统的研究进展进行综述。

纳米农药的分类及研究现状

随着纳米技术在交叉学科领域的深入发展,该技术在植物保护领域也取得了突破性进展,为实现农药减施增效、绿色防控目标提供了新途径。梳理了目前主要的纳米农药剂型、纳米载药系统的特点,及其制剂在实际应用中的效果,总结了纳米农药发展中存在的问题,以期为今后纳米农药的研究、使用和推广提供参考。

pH酸敏感性马来酸酰胺键的研究进展

与传统治疗方式相比,纳米药物给药系统具有较好的生物相容性、靶向性、控制或持续药物释放等优点,很大程度上提高了患者的依从性;显著增强渗透滞留(EPR)效应并降低药物的毒副作用。由于人体微环境存在pH差异,pH敏感性化学键作为刺激响应因子,在纳米药物给药系统中得到广泛研究,其中马来酸酰胺衍生物因其有趣的特性和潜力而受到关注。详细介绍了pH敏感性马来酸酰胺键酸触变机理,及其化学键断裂和质子化作用控释机制,并围绕马来酸酰胺键化学结构优势及其在纳米载药体系中的应用研究展开分析论述。

Controlled drug delivery systems： the next 30 years

The drag delivery scientists need to reexamine the advances made during the past 60 years, analyze our current abilities, and design the future technologies that will propel us to achieve the next level of drug delivery technologies. History shows that the first generation （1G） of drag delivery research during 1950-1980 was quite productive, while the second generation （2G） technologies developed during 1980 2010 were not as prolific. The ultimate goal of drug delivery research is to develop clinically useful formulations to treat various diseases. Effective drug delivery systems can be developed by overcoming formulation barriers and/or biological barriers. The engineering approach has a limit in solving the problem, if biological difficulties are not clearly identified and understood. The third generation （3G） drug delivery systems will have to focus on understanding the biological barriers so that they can be overcome by engineering manipulation of the drug delivery systems. Advances in the next 30 years will be most accelerated by starting open dialogues without any preconceived ideas on drug delivery technologies. The new generation of drug delivery scientists needs to be aware of the successes and limitations of the existing technologies to design the new technologies for meaningful advances in the future.

Nano-formulations for transdermal drug delivery:A review

Transdermal drug delivery refers to a means of delivering drugs through the surface of the skin for local or systemic treatment. The drug functions after absorption through the skin into the systemic circulation via capillary action at a certain rate. Use of traditional physical and chemical enhancers to improve the transdermal permeation rate by increasing drug solubility, diffusion coefficient, and reservoir effect is not feasible owing to the toxic side effects of the overuse of chemical penetration enhancers. Nanoformulations generally vary in size and range from 10 nm to 100 nm. The smaller particle size leads to increased drug permeability, stability, retention, and targeting, making nano-formulations suitable for transdermal drug delivery. The different applications of nano-formulations(vesicles or nanoparticles and nanoemulsions) have been widely studied. Here, the classification, characteristics, transdermal mechanism, and application of the most popular nano-formulations in transdermal drug delivery system are reviewed.

茄尼醇及其衍生物在纳米载药系统中的应用研究

大多数用于药物输送的传统纳米载药系统是由缺乏治疗活性的惰性载体材料制成,大量的药物载体物质可能会在体内引起外源性生物毒性和相关的代谢问题,而使用多功能智能给药系统可以减少对药物载体的需求与其潜在毒性之间的冲突。为此,已开发出一系列具有生物活性的“治疗载体”。茄尼醇因其丰富的药理活性和生物相容性而备受关注,本文详细介绍了茄尼醇及其衍生物的生理活性,并围绕茄尼醇及其衍生物化学结构优势、在纳米载药体系中的应用研究展开分析论述。

载有匹伐他汀的纳米涂层支架的研究

目的探讨新型载有他汀药物的纳米涂层支架的有效性及安全性。方法选用生物可吸收性高分子聚合物聚乳酸-羧基乙酸共聚体(PLGA)为原料制作纳米粒子,并用自行研发的阳离子电镀涂层技术将载有荧光标记物异硫氰酸荧光素(FITC)的PLGA纳米粒子均匀涂层于支架表面。先在体外培养人冠状动脉平滑肌细胞及人脐带静脉内皮细胞,比较研究他汀类药物、雷帕霉素和紫杉醇对平滑肌细胞和内皮细胞增殖能力的影响。同时,选择猪作为实验动物行冠状动脉支架植入术,观察载有他汀的纳米涂层支架对内膜增生及内皮再生的影响。结果体外实验发现,在24 h内FITC从纳米粒子内释放出约40%,在30 d后完全释放。FITC纳米粒子56 d以后从涂层支架完全释放。与其他他汀类药物相比,匹伐他汀对平滑肌细胞增殖有明显的抑制作用(P<0.001),并对内皮细胞再生有促进作用(p<0.05)。尽管雷帕霉素和紫杉醇也都能抑制平滑肌细胞的增殖,但匹伐他汀可在最低浓度(0.01μmol/L)即可达到抑制效果(P<0.05)。匹伐他汀纳米粒子涂层支架组与非药物涂层支架组相比内膜增生明显减少(P<0.01)。与雷帕霉素支架组相比,匹伐他汀纳米粒子涂层支架组的内膜增生程度相近(P>0.05),且炎症、纤维沉积及内皮再生延迟作用均明显减少(P值均<0.01)。结论成功开发载有匹伐他汀纳米粒子涂层支架,初步结果显示该支架既可抑制支架内再狭窄,也可减少支架内血栓形成。