Simple construction and manipulation of low‐molecular‐weight supramolecular nanogels, based on the introduction of multiple hydrogen bonding interactions, with the desired physical properties to achieve effective and safe delivery of drugs for cancer therapy remain highly challenging. Herein, a novel supramolecular oligomer cytosine (Cy)‐polypropylene glycol containing self‐complementary multiple hydrogen‐bonded Cy moieties is developed, which undergoes spontaneous self‐assembly to form nanosized particles in an aqueous environment. Phase transitions and scattering studies confirm that the supramolecular nanogels can be readily tailored to obtain the desired phase‐transition temperature and temperature‐induced release of the anticancer drug doxorubicin (DOX). The resulting nanogels exhibit an extremely high load carrying capacity (up to 24.8%) and drug‐entrapment stability, making the loading processes highly efficient. Importantly, in vitro cytotoxicity assays indicate that DOX‐loaded nanogels possess excellent biosafety for drug delivery applications under physiological conditions. When the environmental temperature is increased to 40 °C, DOX‐loaded nanogels trigger rapid DOX release and exert cytotoxic effects, significantly reducing the dose required compared to free DOX. Given its simplicity, low cost, high reliability, and efficiency, this newly developed temperature‐responsive nanocarrier has highly promising potential for controlled release drug delivery systems.
Previously synthesized amphiphilic diblock copolymers with pendant dendron moieties have been investigated for their potential use as drug carriers to improve the delivery of an anticancer drug to human breast cancer cells. Diblock copolymer (P71D3)‐based micelles effectively encapsulate the doxorubicin (DOX) with a high drug‐loading capacity (≈95%, 104 DOX molecules per micelle), which is approximately double the amount of drug loaded into the diblock copolymer (P296D1) vesicles. DOX released from the resultant P71D3/DOX micelles is approximately 1.3‐fold more abundant, at a tumoral acidic pH of 5.5 compared with a pH of 7.4. The P71D3/DOX micelles also enhance drug potency in breast cancer MDA‐MB‐231 cells due to their higher intracellular uptake, by approximately twofold, compared with the vesicular nanocarrier, and free DOX. Micellar nanocarriers are taken up by lysosomes via energy‐dependent processes, followed by the release of DOX into the cytoplasm and subsequent translocation into the nucleus, where it exert its cytotoxic effect.
The design of drug delivery systems capable of efficiently delivering poorly soluble drugs to target sites still remains a major challenge. Such materials require several different functionalities; typically, these materials should be biodegradable and nontoxic, nonimmunogenic, responsive to their environment, and soluble in aqueous solution while retaining the ability to solubilize hydrophobic drugs. Here, a polypeptide‐polymer hybrid of elastin‐like polypeptides (ELPs) and poly(2‐oxazoline)s (POx) is reported. This paper describes the chemical synthesis, physical characteristics, and drug loading potential of these novel hybrid macromolecules. A novel method is introduced for terminal functionalization of POx with protected maleimide moieties. Following recovery of the maleimide group via a retro Diels–Alder reaction, the consecutive Michael addition of thiol‐functionalized ELPs yields the desired protein‐polymer conjugate. These conjugates form nanoparticles in aqueous solution capable of solubilizing the anti‐cancer drug paclitaxel with up to 8 wt% loading.
With diabetes mellitus becoming an important public health concern, insulin‐delivery systems are attracting increasing interest from both scientific and technological researchers. This feature article covers the present state‐of‐the‐art glucose‐responsive insulin‐delivery system (denoted as GRIDS), based on responsive polymer materials, a promising system for self‐regulated insulin delivery. Three types of GRIDS are discussed, based on different fundamental mechanisms of glucose‐recognition, with: a) glucose enzyme, b) glucose binding protein, and c) synthetic boronic acid as the glucose‐sensitive component. At the end, a personal perspective on the major issues yet to be worked out in future research is provided. 相似文献
A series of pH‐triggered charge‐reversal polyurethane copolymers (PS‐PUs) containing methoxyl‐poly(ethylene glycol) (mPEG), carboxylic acid groups, and piperazine groups is presented in this work. The obtained PS‐PUs copolymers can form into stable micelles at pH 7.4, which response to a narrow pH change (5.5–7.5) and show a tunable pH‐triggered charge‐reversal property. Doxorubicin (DOX) is encapsulated into the PS‐PU micelles as a model drug. The drug release of DOX‐loaded PS‐PU micelles shows an obviously stepped‐up with reducing the pH. Meanwhile, it is found that the charge‐reversal property can improve the cellular uptake behavior and intracellular drug release in both HeLa cells and MCF‐7 cells. Additionally, the time‐dependent cytotoxicity of the DOX‐loaded PS‐PU micelles is confirmed by MTT assay. Attributed to the tunable charge‐reversal property through changing the molar ratio of piperazine/carboxyl, the PS‐PU micelles will be a potential candidate as an intelligent drug delivery system in future studies.
Novel biodegradable polymers with specific properties, structures, and tailorable designs or modifications are in great demand. Poly(phosphoester)s with good biocompatibility and degradability, as well as other adjustable properties have been studied widely because of their potential in biomedical applications. To meet more versatile and diverse biomedical applications, a novel multiarm star‐shaped phosphorester triblock copolymer poly(amido amine)‐block‐poly(2‐butynyl phospholane)‐block‐poly(2‐methoxy phospholane) (PAMAM‐PBYP‐PMP) is synthesized via organo‐catalyzed sequential ring‐opening polymerization. Supramolecular micelles with good architectural stability are self‐assembled into uniform spherical morphology in aqueous solution. Doxorubicin (DOX) can be encapsulated into the micelles with efficient loading capacity. A slow and sustained release in the environment of simulated intracellular lysosome (pH 5.0 with phosphodiesterase I) is observed. In addition, the copolymers and DOX‐loaded supramolecular micelles exhibit low cell‐toxicity and excellent anticancer activity toward HeLa cells. As a consequence, this multiarm star‐shaped PAMAM‐PBYP‐PMP has great potential in drug delivery system for tumor treatment.
Complementary nucleobase‐functionalized polymeric micelles, a combination of adenine‐thymine (A‐U) base pairs and a blend of hydrophilic–hydrophobic polymer pairs, can be used to construct 3D supramolecular polymer networks; these micelles exhibit excellent self‐assembly ability in aqueous solution, rapid pH‐responsiveness, high drug loading capacity, and triggerable drug release. In this study, a multi‐uracil functionalized poly(ε‐caprolactone) (U‐PCL) and adenine end‐capped difunctional oligomeric poly(ethylene glycol) (BA‐PEG) are successfully developed and show high affinity and specific recognition in solution owing to dynamically reversible A‐U‐induced formation of physical cross‐links. The U‐PCL/BA‐PEG blend system produces supramolecular micelles that can be readily adjusted to provide the desired critical micellization concentration, particle size, and stability. Importantly, in vitro release studies show that doxorubicin (DOX)‐loaded micelles exhibit excellent DOX‐encapsulated stability under physiological conditions. When the pH value of the solution is reduced from 7.4 to 5.0, DOX‐loaded micelles can be rapidly triggered to release encapsulated DOX, suggesting these polymeric micelles represent promising candidate pH‐responsive nanocarriers for controlled‐release drug delivery and pharmaceutical applications.
For efficient treatment of multidrug‐resistance (MDR) breast cancer cells, design of biocompatible mixed micelles with diverse functional moieties and superior stability is needed for targeted delivery of chemical drugs. In this study, polypropylene glycol (PPG)‐grafted hyaluronic acid (HA) copolymers (PPG‐g‐HA) are used to make mixed micelles with different amounts of pluronic L61, named PPG‐g‐HA/L61 micelles. Optimized PPG‐g‐HA/L61 micelles with 3% pluronic L61 exhibit great stability in aqueous solution, superior biocompatibility, and significantly increased uptake into MCF‐7 MDR cells via HA–CD44‐specific interactions when compared to free doxorubicin (DOX) and other types of micelles. In addition, DOX in PPG‐g‐HA/L61 micelles with 3% pluronic L61 have toxicity in MCF‐7 MDR cells but significantly lower toxicity in fibroblast L929 cells compared to free DOX. Thus, PPG‐g‐HA/L61 micelles with 3% pluronic L61 content can be a promising nanocarrier to overcome MDR and release DOX in a hyaluronidase‐sensitive manner without any toxicity to normal cells.
Highly efficient functionalization and cross‐linking of polypeptides is achieved via tyrosine‐triazolinedione (TAD) conjugation chemistry. The feasibility of the reaction is demonstrated by the reaction of 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione (PTAD) with tyrosine containing block copolymer poly(ethylene glycol)‐Tyr4 as well as a statistical copolymer of tyrosine and lysine (poly(Lys40‐st‐Tyr10)) prepared form N‐carboxyanhydride polymerization. Selective reaction of PTAD with the tyrosine units is obtained and verified by size exclusion chromatography and NMR spectroscopy. Moreover, two monofunctional and two difunctional TAD molecules are synthesized. It is found that their stability in the aqueous reaction media significantly varied. Under optimized reaction conditions selective functionalization and cross‐linking, yielding polypeptide hydrogels, can be achieved. TAD‐mediated conjugation can offer an interesting addition in the toolbox of selective (click‐like) polypeptide conjugation methodologies as it does not require functional non‐natural amino acids.
To compare the chemotherapeutic efficacy determined by extra‐ and intracellular drug release strategies, poly(ortho ester amide)‐based drug carriers (POEAd‐C) with well‐defined main‐chain lengths, are successfully constructed by a facile method. POEAd‐C3‐doxorubicin (DOX) can be rapidly dissolved to release drug at tumoral extracellular pH (6.5–7.2), while POEAd‐C6‐DOX can rapidly release drug following gradual swelling at intracellular pH (5.0–6.0). In vitro cytotoxicity shows that POEAd‐C3‐DOX exhibits more toxic effect on tumor cells than POEAd‐C6‐DOX at extracellular pH, but POEAd‐C6‐DOX has stronger tumor penetration and inhibition in vitro and in vivo tumor models. So, POEAd‐C6‐DOX with the intracellular drug release strategy has stronger overall chemotherapeutic efficacy than POEAd‐C3‐DOX with extracellular drug release strategy. It is envisioned that these poly(ortho ester amides) can have great potential as drug carriers for efficient chemotherapy with further optimization.
A novel PEGylation polypeptide, poly(ethylene glycol)‐b‐poly(l ‐lysine)‐b‐poly(l ‐cysteine) (PEG‐PLL‐PCys) triblock copolymer is synthesized via the sequential ring‐opening polymerization of amino acid N‐carboxyanhydrides initiated by methoxypolyethylene glycol amine (mPEG‐NH2, M w is 2 kDa). Subsequently, the obtained polypeptide is partially conjugated with fluorocarbon chains via disulfide exchange reaction. PLL segment can condense plasmid DNA through an electrostatic force to form a complex core, PEG segment surrounding the complex like a corona can prevent the complex from precipitation and reduce the adsorption of serum, while PCys segment with fluorocarbon can enhance the cellular uptake and the stability of the formed polyplex micelles in physiological conditions. Experiment results exhibit that the fluorinated polypeptides have low cytotoxicity and good gene transfection efficiency even in the presence of 50% fetal bovine serum.
Stimuli‐sensitive polymeric vesicles or polymersomes as self‐assembled colloidal nanocarriers have received paramount importance for their integral role as delivery system for therapeutics and biotherapeutics. This work describes spontaneous polymersome formation at pH 7, as evidenced by surface tension, steady state fluorescence, dynamic light scattering, and microscopic studies, by three hydrophilic random cationic copolymers synthesized using N ,N‐(dimethylamino)ethyl methacrylate (DMAEM) and methoxy poly(ethylene glycol) monomethacrylate in different mole ratios. The results suggest that methoxy poly(ethylene glycol) chains constitute the bilayer membrane of the polymersomes and DMAEM projects toward water constituting the positively charged surface. The polymersomes have been observed to release their encapsulated guest at acidic pH as a result of transformation into polymeric micelles. All these highly biocompatible cationic polymers show successful gene transfection ability as nonviral vector on human cell line with different potential. Thus these polymers prove their utility as a potential delivery system for hydrophilic model drug as well as genetic material.
d ‐Fructose modified poly(ε‐caprolactone)‐polyethylene glycol (PCL‐PEG‐Fru) diblock amphiphile is synthesized via Cu(I)‐catalyzed click chemistry, which self‐assembles with D‐α‐tocopheryl polyethylene glycol 1000 succinate (TPGS) into PCL‐PEG‐Fru/TPGS mixed micelles (PPF MM). It has been proven that glucose transporter (GLUT)5 is overexpressed in MCF‐7 cells other than L929 cells. In this study, PPF MM exhibit a significantly higher uptake efficiency than fructose‐free PCL‐PEG‐N3/TPGS mixed micelles in both 2D MCF‐7 cells and 3D tumor spheroids. Also, the presence of free d ‐fructose competitively inhibits the internalization of PPF MM in MCF‐7 cells other than L929 cells. PPF MM show selective tumor accumulation in MCF‐7 breast tumor bearing mice xenografts. Taken together, PPF MM represent a promising nanoscale carrier system to achieve GLUT5‐mediated cell specific delivery in cancer therapy.
The high affinity of GLUT5 transporter for d ‐fructose in breast cancer cells has been discussed intensely. In this contribution, high molar mass linear poly(ethylene imine) (LPEI) is functionalized with d ‐fructose moieties to combine the selectivity for the GLUT5 transporter with the delivery potential of PEI for genetic material. The four‐step synthesis of a thiol‐group bearing d ‐fructose enables the decoration of a cationic polymer backbone with d ‐fructose via thiol‐ene photoaddition. The functionalization of LPEI is confirmed by 2D NMR techniques, elemental analysis, and size exclusion chromatography. Importantly, a d ‐fructose decoration of 16% renders the polymers water‐soluble and eliminates the cytotoxicity of PEI in noncancer L929 cells, accompanied by a reduced unspecific cellular uptake of the genetic material. In contrast, the cytotoxicity as well as the cell specific uptake is increased for triple negative MDA‐MB‐231 breast cancer cells. Therefore, the introduction of d ‐fructose shows superior potential for cell targeting, which can be assumed to be GLUT5 dependent.
A new method is developed to prepare silk hydrogels and silk‐pectin hydrogels via dialysis against methanol to obtain hydrogels with high concentrations of silk fibroin. The relationship between the mechanical and biological properties and the structure of the silk‐pectin hydrogels is subsequently evaluated. The present results suggest that pectin associates with silk molecules when the silk concentration exceeds 15 wt%, suggesting that a silk concentration of over 15 wt% is critical to construct interacting silk‐pectin networks. The silk‐pectin hydrogel reported here is composed of a heterogeneous network, which is different from fiber‐reinforced, interpenetrated networks and double‐network hydrogels, as well as high‐stiffness hydrogels (elastic modulus of 4.7 ± 0.9 MPa, elastic stress limit of 3.9 ± 0.1 MPa, and elastic strain limit of 48.4 ± 0.5%) with regard to biocompatibility and biodegradability. 相似文献
Electrospun poly‐l ‐lactic acid (PLLA) nanofiber mats carrying surface amine groups, previously introduced by nitrogen atmospheric pressure nonequilibrium plasma, are embedded into aqueous solutions of oligomeric acrylamide‐end capped AGMA1, a biocompatible polyamidoamine with arg‐gly‐asp (RGD)‐reminiscent repeating units. The resultant mixture is finally cured giving PLLA‐AGMA1 hydrogel composites that absorb large amounts of water and, in the swollen state, are translucent, soft, and pliable, yet as strong as the parent PLLA mat. They do not split apart from each other when swollen in water and remain highly flexible and resistant, since the hydrogel portion is covalently grafted onto the PLLA nanofibers via the addition reaction of the surface amine groups to a part of the terminal acrylic double bonds of AGMA1 oligomers. Preliminary tested as scaffolds, the composites prove capable of maintaining short‐term undifferentiated cultures of human pluripotent stem cells in feeder‐free conditions.
Affinity‐based cell separation is label‐free and highly specific, but it is difficult to efficiently and gently release affinity‐captured cells due to the multivalent nature of cell‐material interactions. To address this challenge, we have developed a platform composed of a capture substrate and a cell‐releasing molecular trigger. The capture substrate is functionalized with a cell‐capture antibody and a coiled‐coil A . The cell‐releasing molecular trigger B ‐PEG (polyethylene glycol), a conjugate of a coiled‐coil B and polyethylene glycol, can drive efficient and gentle release of the captured cells, because A / B heterodimerization brings B ‐PEG to the substrate and PEG chains adopt extended conformations and break nearby multivalent antibody‐biomarker interactions. No enzymes or excessive shear stress are involved, and the released cells have neither external molecules attached nor endogenous cell‐surface molecules cleaved, which is critical for the viability, phenotype, and function of sensitive cells.
To enhance drug cellular uptake, a biodegradable terpolymer is synthesized using taurine, N,N‐Bis (acryloyl) cystamine, and dodecylamine as raw materials by Michael addition terpolymerization. The terpolymer is transformed to zwitterionic nanoparticles (NPs) through self‐assembly. The surface charge of the NPs is convertible from negative at pH 7.4 to positive at pH 6.5, which endows the NPs’ excellent nonfouling feature in bloodstream and effective uptake in tumor cells. The NPs display varied morphologies from solid micelles to polymersomes and nanorods depending on molar ratios of the structural units involved. The NPs can be biodegraded in l ‐glutathione (GSH) solution due to the split of disulfide bonds in main chains of the terpolymers. The NPs demonstrate good pH/reducing responsiveness in drug delivery and can be potentially used as anticancer drug vehicles for enhancement of cellular uptake of anticancer drug.
Poly(2‐alkenyl‐2‐oxazoline)s are promising functional polymers for a variety of biomedical applications, such as drug delivery systems, peptide conjugates, or gene delivery. In this study, poly(2‐isopropenyl‐2‐oxazoline) (PIPOx) is prepared through free‐radical polymerization initiated with azobisisobutyronitrile. Reactive 2‐oxazoline units in the side chain support an addition reaction with different compounds containing a carboxylic group, which facilitates the preparation of polymers labeled with two different fluorescent dyes. The cytotoxicities of 2‐oxazoline monomers, PIPOx, and fluorescently labeled PIPOx are evaluated in vitro using an 3‐(4,5‐Dimethyldiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay and ex vivo using a cell proliferation assay with adenosine triphosphate bioluminescence. The cell uptake of labeled PIPOx is used to determine the colocalization of PIPOx with cell organelles that are part of the endocytic pathway. For the first time, it is shown that poly(2‐isopropenyl‐2‐oxazoline) is a biocompatible material and is suitable for biomedical applications; further, its immunomodulative properties are evaluated.
New macromolecules such as dendrimers are increasingly needed to drive breakthroughs in diverse areas, for example, healthcare. Here, the authors report hybrid antimicrobial dendrimers synthesized by functionalizing organometallic dendrimers with quaternary ammonium groups or 2‐mercaptobenzothiazole. The functionalization tunes the glass transition temperature and antimicrobial activities of the dendrimers. Electron paramagnetic resonance spectroscopy reveals that the dendrimers form free radicals, which have significant implications for catalysis and biology. In vitro antimicrobial assays indicate that the dendrimers are potent antimicrobial agents with activity against multidrug‐resistant pathogens such as methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecium as well as other microorganisms. The functionalization increases the activity, especially in the quaternary ammonium group‐functionalized dendrimers. Importantly, the activities are selective because human epidermal keratinocytes cells and BJ fibroblast cells exposed to the dendrimers are viable after 24 h.
下载免费PDF全文