A pH-Responsive Zwitterionic Polyurethane Prodrug as Drug Delivery System for Enhanced Cancer Therapy

Numerous nanocarriers with excellent biocompatibilities have been used to improve cancer therapy. However, nonspecific protein adsorption of nanocarriers may block the modified nanoparticles in tumor cells, which would lead to inefficient cellular internalization. To address this issue, pH-responsive polyurethane prodrug micelles with a zwitterionic segment were designed and prepared. The micelle consisted of a zwitterionic segment as the hydrophilic shell and the drug Adriamycin (DOX) as the hydrophobic inner core. As a pH-responsive antitumor drug delivery system, the prodrug micelles showed high stability in a physiological environment and continuously released the drug under acidic conditions. In addition, the pure polyurethane carrier was demonstrated to be virtually non-cytotoxic by cytotoxicity studies, while the prodrug micelles were more efficient in killing tumor cells compared to PEG-PLGA@DOX. Furthermore, the DOX cellular uptake efficiency of prodrug micelles was proved to be obviously higher than the control group by both flow cytometry and fluorescence microscopy. This is mainly due to the modification of a zwitterionic segment with PU. The simple design of zwitterionic prodrug micelles provides a new strategy for designing novel antitumor drug delivery systems with enhanced cellular uptake rates.     

葡萄糖敏感苯硼酸基高分子纳米药物传输体系

近年来,智能葡萄糖敏感自调式药物传递系统备受关注。这种智能药物释放系统能够模拟胰腺分泌胰岛素的生理模式而精准调控药物释放并控制血糖水平,在糖尿病治疗中具有良好的应用前景。其中,苯硼酸(PBA)功能化的葡萄糖敏感高分子纳米载体成为近年来的研究热点之一。该类材料具有体系稳定、可长期储存、可逆的葡萄糖敏感性能等优势。根据响应因素不同,葡萄糖敏感药物传递系统可分为pH响应、温度响应和光响应等类型。本文重点介绍了基于PBA的葡萄糖敏感高分子纳米药物载体的发展过程、性能和应用,并对该领域的发展前景进行了展望。     

Electrostatic self-assembly of PEG copolymers onto porous silica nanoparticles

A critical requirement toward the clinical use of nanocarriers in drug delivery applications is the development of optimal biointerfacial engineering procedures designed to resist biologically nonspecific adsorption events. Minimization of opsonization increases blood residence time and improves the ability to target solid tumors. We report the electrostatic self-assembly of polyethyleneimine-polyethylene glycol (PEI-PEG) copolymers onto porous silica nanoparticles. PEI-PEG copolymers were synthesized and their adsorption by self-assembly onto silica surfaces were investigated to achieve a better understanding of structure-activity relationships. Quartz-crystal microbalance (QCM) study confirmed the rapid and stable adsorption of the copolymers onto silica-coated QCM sensors driven by strong electrostatic interactions. XPS and FT-IR spectroscopy were used to analyze the coated surfaces, which indicated the presence of dense PEG layers on the silica nanoparticles. Dynamic light scattering was used to optimize the coating procedure. Monodisperse dispersions of the PEGylated nanoparticles were obtained in high yields and the thin PEG layers provided excellent colloidal stability. In vitro protein adsorption tests using 5% serum demonstrated the ability of the self-assembled copolymer layers to resist biologically nonspecific fouling and to prevent aggregation of the nanoparticles in physiological environments. These results demonstrate that the electrostatic self-assembly of PEG copolymers onto silica nanoparticles used as drug nanocarriers is a robust and efficient procedure, providing excellent control of their biointerfacial properties.     

Phosphonylation Controls the Protein Corona of Multifunctional Polyglycerol‐Modified Nanocarriers

Nanocarriers are a platform for modern drug delivery. In contact with blood, proteins adsorb to nanocarriers, altering their behavior in vivo. To reduce unspecific protein adsorption and unspecific cellular uptake, nanocarriers are modified with hydrophilic polymers like poly(ethylene glycol) (PEG). However, with PEG the attachment of further functional structures such as targeting units is limited. A method to introduce multifunctionality via polyglycerol (PG) while maintaining the hydrophilicity of PEG is introduced. Different amounts of negatively charged phosphonate groups (up to 29 mol%) are attached to the multifunctional PGs (M_n 2–4 kg mol^?1, Ð < 1.36) by post‐modification. PGs are used in the miniemulsion/solvent evaporation procedure to prepare model nanocarriers. Their behavior in human blood plasma is investigated to determine the influence of the negative charges on the protein adsorption. The protein corona of PGylated nanocarriers is similar to PEGylated analogs (on same nanocarriers), but the protein pattern could be gradually altered by the integration of phosphonates. This is the first report on the gradual increase of negative charges on nanocarriers and intriguingly up to a certain amount of phosphonate groups per nanocarrier the protein pattern remains relatively unchanged, which is important for the future design of nanocarriers.     

Self-Assembling Drug Formulations with Tunable Permeability and Biodegradability

This review focuses on key topics in the field of drug delivery related to the design of nanocarriers answering the biomedicine criteria, including biocompatibility, biodegradability, low toxicity, and the ability to overcome biological barriers. For these reasons, much attention is paid to the amphiphile-based carriers composed of natural building blocks, lipids, and their structural analogues and synthetic surfactants that are capable of self-assembly with the formation of a variety of supramolecular aggregates. The latter are dynamic structures that can be used as nanocontainers for hydrophobic drugs to increase their solubility and bioavailability. In this section, biodegradable cationic surfactants bearing cleavable fragments are discussed, with ester- and carbamate-containing analogs, as well as amino acid derivatives received special attention. Drug delivery through the biological barriers is a challenging task, which is highlighted by the example of transdermal method of drug administration. In this paper, nonionic surfactants are primarily discussed, including their application for the fabrication of nanocarriers, their surfactant-skin interactions, the mechanisms of modulating their permeability, and the factors controlling drug encapsulation, release, and targeted delivery. Different types of nanocarriers are covered, including niosomes, transfersomes, invasomes and chitosomes, with their morphological specificity, beneficial characteristics and limitations discussed.     

原位探测防污高分子材料与液体界面的分子结构

Marine organisms such as plants, algae or small animals can adhere to surfaces of materials that are submerged in ocean. The accumulation of these organisms on surfaces is a marine biofouling process that has considerable adverse effects. Marine biofouling on ship hulls can cause severe fuel consumption increase. Investigations on antifouling polymers are therefore becoming important research topics for marine vessel operations. Antifouling polymers can be applied as coating layers on the ship hull, protecting it against the settlement and growth of sea organisms. Polyethylene glycol (PEG) is a hydrophilic polymer that can effectively resist the accumulation of marine organisms. PEG-based antifouling coatings have therefore been extensively researched and developed. However, the inferior stability of PEG makes it subject to degradation, rendering it ineffective for long-term services. Zwitterionic polymers have also emerged as promising antifouling materials in recent years. These polymers consist of both positively charged and negatively charged functional groups. Various zwitterionic polymers have been demonstrated to exhibit exceptional antifouling properties. Previously, surface characterizations of zwitterionic polymers have revealed that strong surface hydration is critical for their antifouling properties. In addition to these hydrophilic polymers, amphiphilic materials have also been developed as potential antifouling coatings. Both hydrophobic and hydrophilic functional groups are incorporated into the backbones or sidechains of these polymers. It has been demonstrated that the antifouling performance can be enhanced by precisely controlling the sequence of the hydrophobic-hydrophilic functionalities. Since biofouling generally occurs at the outer surface of the coatings, the antifouling properties of these coatings are closely related to their surface characteristics in water. Therefore, understanding of the surface molecular structures of antifouling materials is imperative for their future developments. In this review, we will summarize our recent advancements of antifouling material surface analysis using sum frequency generation (SFG) vibrational spectroscopy. SFG is a surface-sensitive technique which can provide molecular information of water and polymer structures at interfaces in situ in real time. The antifouling polymers we will review include zwitterionic polymer brushes, mixed charged polymers, and amphiphilic polypeptoids. Interfacial hydration studies of these polymers by SFG will be presented. The salt effect on antifouling polymer surface hydration will also be discussed. In addition, the interactions between antifouling materials and protein molecules as well as algae will be reviewed. The above research clearly established strong correlations between strong surface hydration and good antifouling properties. It also demonstrated that SFG is a powerful technique to provide molecular level understanding of polymer antifouling mechanisms.     

Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature

Thermally sensitive polymeric nanocarriers were developed to optimize the release profile of encapsulated compounds to improve treatment efficiency. However, when referring to thermally sensitive polymeric nanocarriers, this usually means systems fabricated from lower critical solution temperature (LCST) polymers, which have been intensively studied. To extend the field of thermally sensitive polymeric nanocarriers, we for the first time fabricated a polymeric drug delivery system having an upper critical solution temperature (UCST) of 43 °C based on an amphiphilic polymer poly(AAm‐co‐AN)‐g‐PEG. The resulting polymeric micelles could effectively encapsulate doxorubicin and exhibited thermally sensitive drug release both in vitro and in vivo. A drastically improved anticancer efficiency (IC₅₀ decreased from 4.6 to 1.6 μg mL^?1, tumor inhibition rate increased from 55.6 % to 92.8 %) was observed. These results suggest that UCST‐based drug delivery can be an alternative to thermally sensitive LCST‐based drug delivery systems for an enhanced antitumor efficiency.     

Dendrimers and miktoarm polymers based multivalent nanocarriers for efficient and targeted drug delivery

The delivery of biologically active agents to the desired site in the body and intracellular organelles is still a big challenge despite efforts made for more than five decades. With the elaboration of synthetic methodologies to branched and hyperbranched macromolecules such as miktoarm stars and dendrimers, the focus has shifted to nanocarriers able to release and direct drug molecules to a desired location in a controlled manner. We present here recent developments in the field of targeted drug delivery with a focus on two specific macromolecular nanocarriers, dendrimers and miktoarm stars, and provide examples of these nanocarriers tested in different biological systems. A particular attraction of miktoarm stars is their versatility in achieving superior drug loading within their self-assembled structures. Advantages of dendrimers over linear polymers are that the former provide a platform for development of multivalent and multifunctional nanoconjugates, in addition to their ability to accommodate a large number of molecules inside, or at their surfaces.     

Recent Progress in Transdermal Nanocarriers and Their Surface Modifications

Transdermal drug delivery system (TDDS) is an attractive method for drug delivery with convenient application, less first-pass effect, and fewer systemic side effects. Among all generations of TDDS, transdermal nanocarriers show the greatest clinical potential because of their non-invasive properties and high drug delivery efficiency. However, it is still difficult to design optimal transdermal nanocarriers to overcome the skin barrier, control drug release, and achieve targeting. Hence, surface modification becomes a promising strategy to optimize and functionalize the transdermal nanocarriers with enhanced penetration efficiency, controlled drug release profile, and targeting drug delivery. Therefore, this review summarizes the developed transdermal nanocarriers with their transdermal mechanism, and focuses on the surface modification strategies via their different functions.     

合成高分子基温敏水凝胶在眼病治疗中的研究进展

由于眼部存在角膜/结膜屏障、血-房水屏障和血-视网膜屏障等,有效的眼部给药依然面临巨大挑战.近年来,温敏水凝胶在眼部给药领域受到了广泛关注.在室温下,温敏水凝胶材料呈液态,便于以局部滴加或玻璃体内注射的方式给药;当与眼部接触升温并超过其临界成胶温度时,能以物理交联的方式快速凝胶化,从而实现原位缓释给药,提高药物生物利用度.在众多温敏水凝胶材料中,合成高分子具有材料和功能多样化等优势,其中较常见的为泊洛沙姆、聚乙二醇/聚酯和聚(N-异丙基丙烯酰胺).本综述首先介绍了以上3类合成高分子基温敏水凝胶材料的制备方法和成胶特性.然后,围绕眼部给药存在的难点,探讨这些温敏水凝胶在治疗角膜病、干眼症、青光眼和眼部炎症等各种眼病中的相关研究进展.最后,我们比较了这3种水凝胶在使用性能上的优缺点,并对未来眼科温敏水凝胶的材料设计提出了设想和展望.     

Integrated Antimicrobial and Nonfouling Zwitterionic Polymers

Zwitterionic polymers are generally viewed as a new class of nonfouling materials. Unlike their poly(ethylene glycol) (PEG) counterparts, zwitterionic polymers have a broader chemical diversity and greater freedom for molecular design. In this Minireview, we highlight recent microbiological applications of zwitterionic polymers and their derivatives, with an emphasis on several unique molecular strategies to integrate antimicrobial and nonfouling properties. We will also discuss our insights into the bacterial nonfouling performance of zwitterionic polymers and one example of engineering zwitterionic polymer derivatives for antimicrobial wound‐dressing applications.     

Controlling the Stealth Effect of Nanocarriers through Understanding the Protein Corona

The past decade has seen a significant increase in interest in the use of polymeric nanocarriers in medical applications. In particular, when used as drug vectors in targeted delivery, nanocarriers could overcome many obstacles for drug therapy. Nevertheless, their application is still impeded by the complex composition of the blood proteins covering the particle surface, termed the protein corona. The protein corona complicates any prediction of cell interactions, biodistribution, and toxicity. In particular, the unspecific uptake of nanocarriers is a major obstacle in clinical studies. This Minireview provides an overview of what we currently know about the characteristics of the protein corona of nanocarriers, with a focus on surface functionalization that reduces unspecific uptake (the stealth effect). The ongoing improvement of nanocarriers to allow them to meet all the requirements necessary for successful application, including targeted delivery and stealth, are further discussed.     

Advances in lipid carriers for drug delivery to the gastrointestinal tract

Lipid-based formulations have re-emerged as oral drug delivery systems. Advances in the techniques to evaluate the in vivo fate of the formulations, together with an improved knowledge of the gastrointestinal processes/barriers to the evolving lipid-based systems, could explain, at least partially, this revival. In addition, the use of lipid-based formulations is no longer limited to highly lipophilic drugs and has been extended to hydrophilic peptides and macromolecules. Last but not least, (targeted) nanocarriers have been developed exploiting gut physiology toward novel targets in the field. We herein review what we believe have been the major advances in oral drug delivery via lipid-based formulations in recent years, leading to their re-emergence as promising drug delivery systems for future clinical application.     

Novel functional hyperbranched polyether polyols as prospective drug delivery systems

Multifunctional hyperbranched polyether polyols bearing protective poly(ethylene glycol) (PEG) chains with or without the folate targeting ligand at their end have been prepared. Solubilization in these polymers of a fluorescent probe, pyrene, and an anticancer drug, tamoxifen, was physicochemically investigated. It was found that PEG chains attached at the surface of these hyperbranched polymers, in addition to their well-established protective role, enhance the encapsulation efficiency of the polymers. The release of pyrene and tamoxifen observed upon addition of sodium chloride is, in most of the cases, significant only at concentrations exceeding the physiological extracellular concentration. Thus, a significant amount of the probe or drug remains solubilized inside the carriers, which is an encouraging result if the polymers are to be used for drug delivery.     

DNA纳米结构在药物转运载体和智能载药中的应用进展

纳米材料具有荷载效率高、靶向性能好、半衰期较长等优点, 非常适于作为药物转运载体, 可有效提高药物的水溶性、稳定性和疾病治疗效果.目前, 开发具有良好生物相容性、可控靶向释放能力和精确载药位点的理想药物转运载体, 仍是该领域存在的挑战性问题和当前研究的重点.自组装DNA纳米结构是一类具有精确结构、功能多样的纳米生物材料, 具有良好的生物相容性和稳定性、较高的膜渗透性和可控靶向释放能力等优点, 是理想的药物转运载体和智能载药材料.本文总结了DNA纳米结构的发展历程、DNA纳米结构作为药物转运载体的研究现状、动态DNA纳米结构在智能载药中的应用进展, 并对其发展前景进行了展望.     

Multifunctional dendritic polymers in nanomedicine: opportunities and challenges

Nanotechnology has resulted in materials that have greatly improved the effectiveness of drug delivery because of their ability to control matter on the nanoscale. Advanced forms of nanomedicine have been synthesized for better pharmacokinetics to obtain higher efficacy, less systemic toxicity, and better targeting. These criteria have long been the goal in nanomedicine, in particular, for systemic applications in oncological disorders. Now, the "holy grail" in nanomedicine is to design and synthesize new advanced macromolecular nanocarriers and to translate them from lab to clinic. This review describes the current and future perspectives of nanomedicine with particular emphasis on the clinical targets in cancer and inflammation. The advanced forms of liposomes and polyethylene glycol (PEG) based nanocarriers, as well as dendritic polymer conjugates will be discussed with particular attention paid to designs, synthetic strategies, and chemical pathways. In this critical review, we also report on the current status and perspective of dendritic polymer nanoconjugate platforms (e.g. polyamidoamine dendrimers and dendritic polyglycerols) for cellular localization and targeting of specific tissues (192 references).     

Nano‐Star‐Shaped Polymers for Drug Delivery Applications

With the advancement of polymer engineering, complex star‐shaped polymer architectures can be synthesized with ease, bringing about a host of unique properties and applications. The polymer arms can be functionalized with different chemical groups to fine‐tune the response behavior or be endowed with targeting ligands or stimuli responsive moieties to control its physicochemical behavior and self‐organization in solution. Rheological properties of these solutions can be modulated, which also facilitates the control of the diffusion of the drug from these star‐based nanocarriers. However, these star‐shaped polymers designed for drug delivery are still in a very early stage of development. Due to the sheer diversity of macromolecules that can take on the star architectures and the various combinations of functional groups that can be cross‐linked together, there remain many structure–property relationships which have yet to be fully established. This review aims to provide an introductory perspective on the basic synthetic methods of star‐shaped polymers, the properties which can be controlled by the unique architecture, and also recent advances in drug delivery applications related to these star candidates.     

Hydrophilicity Regulates the Stealth Properties of Polyphosphoester‐Coated Nanocarriers

Increasing the plasma half‐life is an important goal in the development of drug carriers, and can be effectively achieved through the attachment of polymers, in particular poly(ethylene glycol) (PEG). While the increased plasma half‐life has been suggested to be a result of decreased overall protein adsorption on the hydrophilic surface in combination with the adsorption of specific proteins, the molecular reasons for the success of PEG and other hydrophilic polymers are still widely unknown. We prepared polyphosphoester‐coated nanocarriers with defined hydrophilicity to control the stealth properties of the polymer shell. We found that the log P value of the copolymer controls the composition of the protein corona and the cell interaction. Upon a significant change in hydrophilicity, the overall amount of blood proteins adsorbed on the nanocarrier remained unchanged, while the protein composition varied. This result underlines the importance of the protein type for the protein corona and cellular uptake.     

Block copolymers at interfaces: Interactions with physiological media

Triblock copolymers (also known as Pluronics or poloxamers) are biocompatible molecules composed of hydrophobic and hydrophilic blocks with different lengths. They have received much attention recently owing to their applicability for targeted delivery of hydrophobic compounds. Their unique molecular structure facilitates the formation of dynamic aggregates which are able to transport lipid soluble compounds. However, these structures can be unstable and tend to solubilize within the blood stream. The use of nanoemulsions as carriers for the lipid soluble compounds appears as a new alternative with improved protection against physiological media. The interfacial behavior of block copolymers is directly related to their peculiar molecular structure and further knowledge could provide a rational use in the design of poloxamer-stabilized nanoemulsions. This review aims to combine the new insights gained recently into the interfacial properties of block copolymers and their performance in nanoemulsions. Direct studies dealing with the interactions with physiological media are also reviewed in order to address issues relating metabolism degradation profiles. A better understanding of the physico-chemical and interfacial properties of block copolymers will allow their manipulation to modulate lipolysis, hence allowing the rational design of nanocarriers with efficient controlled release.