Nanogels as Pharmaceutical Carriers: Finite Networks of Infinite Capabilities

Nanogels are swollen nanosized networks composed of hydrophilic or amphiphilic polymer chains. They are developed as carriers for the transport of drugs, and can be designed to spontaneously incorporate biologically active molecules through formation of salt bonds, hydrogen bonds, or hydrophobic interactions. Polyelectrolyte nanogels can readily incorporate oppositely charged low‐molecular‐mass drugs and biomacromolecules such as oligo‐ and polynucleotides (siRNA, DNA) as well as proteins. The guest molecules interact electrostatically with the ionic polymer chains of the gel and become bound within the finite nanogel. Multiple chemical functionalities can be employed in the nanogels to introduce imaging labels and to allow targeted drug delivery. The latter can be achieved, for example, with degradable or cleavable cross‐links. Recent studies suggest that nanogels have a very promising future in biomedical applications.     

Biohybrid nanogels

Biohybrid nanogels are crosslinked colloidal networks that consist of biological and synthetic polymers as building blocks. Such polymer colloidal particles attracted much attention in recent years mainly due to their outstanding properties and huge application potential that by far overcome classical nanogels or microgels prepared from water-soluble synthetic polymers. In this report, we review recent developments on the synthesis and properties of biohybrid nanogels. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3044–3057     

Novel Designed Polyisobutylene-Based Biopolymers: Synthesis,Characterization, and Biological Testing of Amphiphilic Chameleon Networks

After a very brief introduction into the impact of living polymerization on preparative polymer chemistry and a look into the dearth of de novo polymer synthesis research for novel biopolymers, this presentation will focus on a new class of synthetic biopolymers: amphiphilic chame- leon networks, i.e., biocomponent networks comprising random strands of hydrophobic and hydrophilic polymers, for blood contact application and mainly for use as narrow diameter (<4 mm) vascular grafts. First, the precision syntheses of amphiphilic networks will be outlined. Subse-quently the surface and bulk characterization of these novel molecular composites by a battery of physicochemical methods will be highlighted. Finally, representative results of biological in-vitro and in-vivo testing will be summarized. We propose that for bio-or hemocompatibility to arise, it may be necessary to employ “smart” amphiphilic surfaces capable of rapid reversible hydrophobic/hydrophilic reorganization so as to present the most favorable lowest energy surface conformation to the medium. It appears that these surfaces are smooth, flexible, and of very low modulus, and that the bulk of these materials have cocontinuous phase-separated microarchitectures with random microdomains in the 10–100 A diameter range. Contemporary macromolecular engineering can deliver materials exhibiting this combination of characteristics.     

Amphiphilic hydrogel nanoparticles. Preparation, characterization, and preliminary assessment as new colloidal drug carriers

Inverse emulsion photopolymerization of acrylated poly(ethylene glycol)-bl-poly(propylene glycol)-bl-poly(ethylene glycol) and poly(ethylene glycol) was successfully employed to prepare stable, cross-linked, amphiphilic nanoparticles. Even at low emulsifier concentrations (2%) and high water-to-hexane weight ratios (35/65), the stability of the inverse emulsion allowed for the formation of well-defined colloidal material. Inverse emulsion characteristics and polymerization conditions could be controlled to vary the size of the nanoparticles between 50 and 500 nm. The presence of hydrophobic nanodomains within these otherwise hydrophilic nanoparticles was verified by using pyrene as a microenvironmentally sensitive probe. The hydrophobic poly(propylene glycol)-rich domains appear to be suitable for incorporation of hydrophobic drugs, encapsulating Doxorubicin up to 9.8% (w/w). We believe that the complex nano-architecture of these materials makes them a potentially interesting colloidal drug delivery carrier system and that the method should be useful for a number of amphiphilic macromolecular precursors.     

Inverting structures: from micelles via emulsions to internally self-assembled water and oil continuous nanocarriers

Fluid-like colloidal structures are key components in nature's own functional materials and important for various applications. For instance, self-assembled structures are formed spontaneously by amphiphilic molecules in solvent, tailored by directional noncovalent intermolecular forces. These structures form the framework of cells defining their geometry and microenvironments for chemical reactions, for maintaining concentration gradients, and for nutrient exchange. Knowledge on the mechanisms at play that underlie the self-assembly of amphiphilic molecules into nanostructures in aqueous and nonaqueous solvents and their dispersion into particles can have direct implications for the rational design of new advanced and nature-inspired materials. These colloidal materials could help to deliver drug molecules and nutrients in a tailored manner to the body, or act as sustainable solvents for chemical or biotechnological processes. This contribution summarizes the recent progress in understanding the self-assembly structure formation in polar and nonpolar solvents and discusses the advances in hierarchically organized systems. Furthermore, it discusses challenges in the characterization of structure and dynamics in these biomimetic materials and highlights selected applications in the fields of drug delivery, food, and biotechnology.     

具有疏水核/亲水壳的双亲胶体粒子的制备

制备了具有疏水性聚苯乙烯核/亲水性聚丙烯酰胺壳的双亲粒子.疏水核通过超浓乳液聚合制备,亲水壳层通过过氧化羟基异丙苯和硫酸亚铁的界面引发制备.控制条件可得到网孔(半包覆)、褶皱(全包覆)两种形态的壳层.壳层孔的存在使得核层聚合物能够与外界接触.粒子的双亲性通过吸水吸油率进行表征.     

Synthesis, surface modifications, and size-sorting of mixed nickel-zinc ferrite colloidal magnetic nanoparticles

We report on the spontaneous covalent growth of monomolecular adlayers on mixed nickel-zinc nanoferrite colloidal suspensions (ferrofluids). Synthesized nanoparticles were subjected to surface modification by means of acid chloride chemistry, leading to the formation of covalent bonds between the hydroxy groups at the nanoparticle surface and the acid chloride molecules. This procedure can be easily tailored to allow for the formation of adlayers containing both hydrophobic and hydrophilic regions stacked at predetermined distances from the magnetic core, and also providing the nanoferrites with functional carboxy groups capable of further modifications with, for example, drug molecules. Here, fluorophore aminopyrene molecules were bound to such modified nanoferrites through amide bonds. We also used the same chemistry to modify the surface with covalently bound long-chain palmitoyl moieties, and for comparison we also modified the nanoferrite surface by simple adsorption of oleic acid. Both procedures made the surface highly hydrophobic. These hydrophobic colloids were subsequently spread on an aqueous surface to form Langmuir monolayers with different characteristics. Moreover, since uniformity of size is crucial in a number of applications, we propose an efficient way of sorting the magnetic nanoparticles by size in their colloidal suspension. The suspension is centrifuged at increasing rotational speed and the fractions are collected after each run. The mean size of nanoferrite in each fraction was measured by the powder X-ray diffraction (PXRD) technique.     

Amphiphilic poly(D,L-lactic acid)/poly(ethylene glycol)/poly(D,L-lactic acid) nanogels for controlled release of hydrophobic drugs

Photocrosslinked nanogels with a hydrophobic core and hydrophilic shell are successfully fabricated with the goal of obtaining a biocompatible and biodegradable drug carrier for hydrophobic anticancer drugs. These nanogels are composed of amphiphilic triblock copolymers, poly(D,L-lactic acid)/poly(ethylene glycol)/poly(D,L-lactic acid) (PLA-PEG-PLA), with acrylated groups at the end of the PLA segments. The copolymers are synthesized by ring-opening polymerization and possess a low CMC (49.6 mg x L(-1)), which easily helps to form micelles by self-assembly. The acrylated end groups allow the micelles to be photocrosslinked by ultraviolet irradiation, which turn the micelles into nanogels. These nanogels exhibit excellent stability as a suspension in aqueous media at ambient temperature as compared to the micelles. Moreover, the size of the nanogels is easily manipulated in a range of 150 to 250 nm by changing the concentration of crosslinkers, e.g., ethylene glycol dimethacrylate, and ultraviolet light irradiation time. The nanogels achieve a high encapsulation efficiency and offer a steady and long-term release mechanism for the hydrophobic anticancer drug, CPT. It shows that these nanogels are useful for a hydrophobic anticancer drug-carrier system. [pictures: see text] Formation of the PLA-PEG-PLA nanogels.     

Rational Design and Development of Polymeric Nanogels as Protein Carriers

Proteins have gained significant attention as potential therapeutic agents owing to their high specificity and reduced toxicity. Nevertheless, their clinical utility is hindered by inherent challenges associated with stability during storage and after in vivo administration. To overcome these limitations, polymeric nanogels (NGs) have emerged as promising carriers. These colloidal systems are capable of efficient encapsulation and stabilization of protein cargoes while improving their bioavailability and targeted delivery. The design of such delivery systems requires a comprehensive understanding of how the synthesis and formulation processes affect the final performance of the protein. This review highlights critical aspects involved in the development of NGs for protein delivery, with specific emphasis on loading strategies and evaluation techniques. For example, factors influencing loading efficiency and release kinetics are discussed, along with strategies to optimize protein encapsulation through protein-carrier interactions to achieve the desired therapeutic outcomes. The discussion is based on recent literature examples and aims to provide valuable insights for researchers working toward the advancement of protein-based therapeutics.     

Preparation of polymer nanoparticles by self-assembling of amphiphilic poly-<Emphasis Type="Italic">N</Emphasis>-vinylpyrrolidone derivatives in aqueous media

Amphiphilic N-vinylpyrrolidone polymers were prepared by a new one-step procedure consisting in radical polymerization of the monomer in the presence of long-chain monobasic saturated carboxylic acid chlorides as chain-transfer and chain-terminating agents. The behavior of the new amphiphilic polymers differing in the structure of the hydrophilic and hydrophobic moieties in aqueous media was studied. The synthesized polymers at definite concentrations undergo spontaneous aggregation with the formation of spherical nanosized micellar particles consisting of a hydrophobic core and a hydrophilic shell. The main characteristics of the polymer nanoparticles formed were determined, and the possibility of using them as promising carriers for the delivery of biologically active compounds and drugs was revealed.     

pH敏感性两亲聚合物网络PAA—l—PTHF的研究

以具有良好柔性和生物相容性的聚四氢呋喃（ＰＴＨＦ）为疏水链段,具有ｐＨ敏感性的聚丙烯酸（ＰＡＡ）为亲水链段,通过ＰＴＨＦ双端基大分子单体与丙烯酸自由基共聚,首次合成了聚丙烯酸－ｌ－聚四氢呋喃（ＰＡＡ－ｌ－ＰＴＨＦ）两亲聚合物网络,并对网络的结构、组成以及交联点密度进行了表征。两亲聚合物网络溶胀行为研究表明,ＰＡＡ－ｌ－ＰＴＨＦ既能在水中溶胀又能在有机溶剂中溶胀,在水中的溶胀度随网络亲水链段ＰＡＡ含     

Biodegradable nanogels prepared by self-assembly of poly(L-lactide)-grafted dextran: entrapment and release of proteins

We showed previously that poly(L-lactide)-grafted dextran could form biodegradable nanogels in water. In this paper, various properties of Dex-g-PLLA nanogels were compared with Dex-Chol (dextran-cholesterol conjugate) nanogels to investigate the effects of hydrophobic units. Dex-g-PLLA nanogels exhibited significantly lower CAC and higher colloidal stability, indicating a strong tendency to form nanogels. We prepared lysozyme-loaded Dex-g-PLLA nanogels, and they exhibited a sustained release of lysozyme for 1 week without denaturation in PBS at 37 degrees C. The Dex-g-PLLA nanogels therefore have great potential as a delivery vehicle for therapeutic protein.     

Synthesis and molecular recognition of pyrenophanes with polycationic or amphiphilic functionalities: artificial plate-shaped cavitant incorporating arenes and nucleotides in water

Water-soluble pyrenophanes possessing polycationic or amphiphilic side chains have been developed as synthetic host molecules to investigate hydrophobic and/or pi-stacking interactions. By utilizing omega-acetalic alkyl side chains to retain solubility and versatility, water-soluble macrocyclic pyrenophanes could be easily obtained by Stille coupling, followed by conversion of the acetal groups to hydrophilic substituents. Among the pyrenophanes synthesized, hexaammonium-, bis(diazoniacrown)-, and tetrakis[octa(oxyethylene)]-derived ones showed enough solubility in pure water. The former two cationic pyrenophanes strongly recognized anionic arenes including nucleotides, while the latter neutral one associated with monopyrenyl guests regardless of their electric natures. The strength of recognition for nucleotides by bis(diazoniacrown)pyrenophane depended on the number of phosphate moieties, decreasing in the following order: triphosphate > diphosphate approximately monophosphate.     

A new design for light-breakable polymer micelles

A new and general design strategy is presented for amphiphilic block copolymers whose micellar aggregates can be dissociated by light. A diblock copolymer composed of hydrophilic poly(ethylene oxide) (PEO) and a hydrophobic polymethacrylate bearing pyrene pendant groups (PPy) was synthesized using ATRP. Upon UV light irradiation of polymer micellar solutions, the photosolvolysis of pyrene moieties results in their detachment from the polymer and converts the hydrophobic PPy block into hydrophilic poly(methacrylic acid). This effect leads to complete dissociation of polymer micelles.     

Amphiphilic Metallopolymers for Photoswitchable Supramolecular Hydrogels

A series of amphiphilic metallopolymers is described that features zinc(II) bis‐terpyridine coordination nodes as well as a backbone with hydrophobic azoaryl moieties and hydrophilic phenylene‐ethynylene units decorated with PEG brushes. Using such metallopolymers at very low concentration, stable, photo‐responsive and self‐healing hydrogels are obtained. UV irradiation of the gel allows modulation of the degree of hydrophobic π‐π interactions between photoisomerizable azoaryl units and a polarity switch that overall induces a fast gel‐to‐sol transition. Finally, the material phase can be readily and fully restored to the thermodynamically stable state either thermally or photochemically by using visible light. The presented strategy can be further generalized towards modular supramolecular metallopolymers for injectable gels in drug delivery and bio‐engineering applications.     

Zwitterionic Moieties from the Huisgen Reaction: A Case Study with Amphiphilic Dendritic Assemblies

Supramolecular nano‐assemblies that reduce nonspecific interactions with biological macromolecules, such as proteins, are of great importance for various biological applications. Recently, zwitterionic materials have been shown to reduce nonspecific interactions with biomolecules, owing both to their charge neutrality and their ability to form a strong hydration layer around zwitterions via electrostatic interactions. Here, new triazole‐based zwitterionic moieties are presented that are incorporated as the hydrophilic functionalities in facially amphiphilic dendrons. The amphiphilic zwitterionic dendrons spontaneously self‐assemble in aqueous solutions forming micelle‐type aggregates, which were confirmed by DLS, TEM, and fluorescence techniques. The structural and functional characteristics of the zwitterionic dendrons are also compared with the corresponding charge‐neutral PEG‐based dendrons and anionic carboxylate‐based dendrons. Surface‐charge measurements, temperature sensitivity and evaluation of interactions of these assemblies with proteins form the bases for these comparisons.     

Mitigation of Inflammatory Immune Responses with Hydrophilic Nanoparticles

While hydrophobic nanoparticles (NPs) have been long recognized to boost the immune activation, whether hydrophilic NPs modulate an immune system challenged by immune stimulators and how their hydrophilic properties may affect the immune response is still unclear. To answer this question, three polymers, poly(ethylene glycol) (PEG), poly(sulfobetaine) (PSB) and poly(carboxybetaine) (PCB), which are commonly considered hydrophilic, are studied in this work. For comparison, nanogels with uniform size and homogeneous surface functionalities were made from these polymers. Peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) and an LPS‐induced lung inflammation murine model were used to investigate the influence of nanogels on the immune system. Results show that the treatment of hydrophilic nanogels attenuated the immune responses elicited by LPS both in vitro and in vivo. Moreover, we found that PCB nanogels, which have the strongest hydration and the lowest non‐specific protein binding, manifested the best performance in alleviating the immune activation, followed by PSB and PEG nanogels. This reveals that the immunomodulatory effect of hydrophilic materials is closely related to their hydration characteristics and their ability to resist non‐specific binding in complex media.     

Drug-loaded and superparamagnetic iron oxide nanoparticle surface-embedded amphiphilic block copolymer micelles for integrated chemotherapeutic drug delivery and MR imaging

We report on the fabrication of organic/inorganic hybrid micelles of amphiphilic block copolymers physically encapsulated with hydrophobic drugs within micellar cores and stably embedded with superparamagnetic iron oxide (SPIO) nanoparticles within hydrophilic coronas, which possess integrated functions of chemotherapeutic drug delivery and magnetic resonance (MR) imaging contrast enhancement. Poly(ε-caprolactone)-b-poly(glycerol monomethacrylate), PCL-b-PGMA, and PCL-b-P(OEGMA-co-FA) amphiphilic block copolymers were synthesized at first by combining ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP), and post- modification techniques, where OEGMA and FA are oligo(ethylene glycol) monomethyl ether methacrylate and folic acid-bearing moieties, respectively. A model hydrophobic anticancer drug, paclitaxel (PTX), and 4 nm SPIO nanoparticles were then loaded into micellar cores and hydrophilic coronas, respectively, of mixed micelles fabricated from PCL-b-PGMA and PCL-b-P(OEGMA-co-FA) diblock copolymers by taking advantage of the hydrophobicity of micellar cores and strong affinity between 1,2-diol moieties in PGMA and Fe atoms at the surface of SPIO nanoparticles. The controlled and sustained release of PTX from hybrid micelles was achieved, exhibiting a cumulative release of ~61% encapsulated drugs (loading content, 8.5 w/w%) over ~130 h. Compared to that of surfactant-stabilized single SPIO nanoparticles (r(2) = 28.3 s(-1) mM(-1) Fe), the clustering of SPIO nanoparticles within micellar coronas led to considerably enhanced T(2) relaxivity (r(2) = 121.1 s(-1) mM(-1) Fe), suggesting that hybrid micelles can serve as a T(2)-weighted MR imaging contrast enhancer with improved performance. Moreover, preliminary experiments of in vivo MR imaging were also conducted. These results indicate that amphiphilic block copolymer micelles surface embedded with SPIO nanoparticles at the hydrophilic corona can act as a new generation of nanoplatform integrating targeted drug delivery, controlled release, and disease diagnostic functions.     

Tuning amphiphilicity/temperature‐induced self‐assembly and in‐situ disulfide crosslinking of reduction‐responsive block copolymers

New poly(ethylene oxide)‐based block copolymers (ssBCs) with a random copolymer block consisting of a reduction‐responsive disulfide‐labeled methacrylate (HMssEt) and a thermoresponsive di(ethylene glycol)‐containing methacrylate (MEO₂MA) units were synthesized. The ratio of HMssEt/MEO₂MA units in the random P(MEO₂MA‐co‐HMssEt) copolymer block enables the characteristics of well‐defined ssBCs to be amphiphilic or thermoresponsive and double hydrophilic. Their amphiphilicity or temperature‐induced self‐assembly results in nanoaggregates with hydrophobic cores having different densities of pendant disulfide linkages. The effect of disulfide crosslinking density on morphological variation of disulfide‐crosslinked nanogels is investigated. In response to reductive reactions, the partial cleavage of pendant disulfide linkages in the hydrophobic cores converts the physically associated aggregates to disulfide‐crosslinked nanogels. The occurrence of in‐situ disulfide crosslinks provides colloidal stability upon dilution. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2057–2067