The Research on Intelligent Controlled DDS of Polymer Carrier

The intelligent controlled drug delivery systems (DDS) are a series of the preparations including microcapsules or nanocapsules composed of intelligent polymers and medication. The properties of preparations can change with the external stimuli, such as pH value, temperature,chemical substance, light, electricity and magnetism etc. According to this properties, the DDS can be intelligently controlled. This paper has reviemed research on syntheses and applications of intelligent controlled DDS of polymer carriers.Drug delivery system with pH stimuliThe volume of polymer hydrogel can change with the pH value of external environment. The sensitive polymer hydrogels to pH are often as carriers. The polymer hydrogel carrying medicine is especially suitable for taking orally. In order to protect medicine from losing activation, we enwrapped medicine into polymer hydrogel with acidic group. In the acidic environment of stomach,the volume of polymer hydrogel contracts because of the hydrogen bond. The medicine in the polymer hydrogel cannot disperse out. When it goes to the intestine of basic environment, the hydrogen bond will be broken, and the medicine can release.Drug delivery system with temperatureTemperature sensitive polymer hydrogel can change its volume with changing of environmental temperature. This kind of polymer hydrogel can be also used as a carrier of medicine. At a low temperature, the polymer chains form hydrogen bond with water to swell to let medicine disperse out from the hydrogel. On the other hand, the hydrogen bond will be broken and polymer chain will lose water to contract with temperature's increasing. And the medicine will not disperse out. For example,the poly(N-isopropylacrylamide)(PNIPAAm) is the hydrogel that is swelled at lower temperature and contracted at higher temperature. PNIPAAm has the lower critical solution temperature(LCST).We can adjust its LCST to control PNIPAAm hydrogel's swelling or contraction to let medicine release or not.Drug delivery system with other stimuliThe polymer carrier drug delivery system can be intelligently controlled with the stimuli of pH value and temperature. In addition, there are still some other stimuli for DDS. For example, DDS with light; DDS with electricity(or electric field); DDS with magnetism(magnetic field); DDS with chemical substance; etc. The characteristic of intelligent polymer carrier is based on P.J.Flory's gel-swelling theory. Intelligent polymer carrier DDS will be widely used in biological and medical fields.     

pH敏感型聚谷氨酸/透明质酸基互穿网络医用水凝胶的制备及表征

生物材料是推动生物医学领域日新月异变化的基石,医用水凝胶作为重要成员,近年来表现出蓬勃发展的态势。文章介绍了一种新型可注射的、以生物相容性方法交联的聚谷氨酸(Poly (γ-glutamic acid), PGA)/透明质酸(Hyaluronic acid, HA)复合水凝胶。研究首先采用EDC/NHS方法合成了酪胺(Tyramine,Ty)接枝聚谷氨酸的PGA-Ty前体大分子及半胱胺(Cysteamine, CA)修饰透明质酸的HA-CA前体大分子。两种前体大分子的结构分别使用核磁和红外进行了确证。得到的两种前体大分子在低浓度双氧水和辣根过氧化物酶(Horseradish Peroxidase, HRP)的共同作用下,于水相中交联得到互穿网络(Interpenetrating Network, IPN)水凝胶。实验对IPN水凝胶样品的系列性能,如平衡含水量、内部形貌、酶降解速率以及力学性能等进行了测试,并选取了盐酸四环素为药物模型对凝胶的体外药物释放行为、体外抗菌效果进行了测评。凝胶材料的细胞毒性及凝胶支架对细胞3D培养的效果证明其生物相容性优异,体外包埋的细胞经72h培养,未表现出明显细胞毒性。系列数据证明,该种水凝胶可以设计成为pH敏感型的药物控释载体材料,并因其良好的生物相容性,也有作为细胞支架、创伤辅料等其它生物医用材料的潜力。     

Influence of pH on the Motion of Catalytic Janus Particles and Tubular Bubble‐Propelled Micromotors

Self‐propelled miniaturized machines harness the chemical potential of their environment for movement. Locomotion of chemically powered micromotors have been hugely dependent on the surroundings. The use of pH to alter the mobility of micromotors is demonstrated in this work through the manipulation of hydrogen peroxide chemistry in different acidity/alkalinity. The sequential addition of sodium hydroxide to increase the pH of the solution led to a consequent increase in activity of micromotors. Meanwhile, addition of hydrochloric acid compromised the structural integrity of the microstructures, culminating in locomotive changes. Such dramatic changes in activity and velocities of the micromotors allow the usage of this behavior for pH detection. This concept was illustrated with Janus silver micromotors and tubular bimetallic Cu/Pt micromotors. Alteration of pH serves as a useful general strategy for increasing hydrogen peroxide decomposition for enhanced oxygen‐bubble propulsion in catalytic micromotors.     

Cargo Transportation and Methylene Blue Degradation by Using Fuel-Powered Micromotors

In the past two decades, micromotors have experienced rapid development, especially in environmental remediation, the biomedical field, and in cargo delivery. In this study micromotors have been synthesized from a variety of materials. Different functional layers and catalytic layers are formed through template electrodeposition (the bottom-up method). At the same time, the article analyzes the influence of hydrogen peroxide concentration, surfactant type and concentration on the speed of the micromotors. Cargo transportation through tubular micromotors has always been a problem that people are eager to solve. In this article, we electrodeposit a layer of Ni in the microtubes, which effectively guides the microtubular motors to complete the cargo transportation. The potential applications of micromotors are also being explored. We added the prepared micromotors to the methylene blue solution to effectively enhance the degradation.     

Chemotaxis‐Guided Hybrid Neutrophil Micromotors for Targeted Drug Transport

Engineering self‐propelled micromotors with good biocompatibility and biodegradability for actively seeking disease sites and targeted drug transport remains a huge challenge. In this study, neutrophils with intrinsic chemotaxis capability were transformed into self‐guided hybrid micromotors by integrating mesoporous silica nanoparticles (MSNs) with high loading capability. To ensure the compatibility of neutrophil cells with drug‐loaded MSNs, bacteria membranes derived from E. coli were coated on MSNs in advance by a camouflaging strategy. The resulting biohybrid micromotors inherited the characteristic chemotaxis capability of native neutrophils and could effectively move along the chemoattractant gradients produced by E. coli . Our studies suggest that this camouflaging approach, which favors the uptake of MSNs into neutrophils without loss of cellular activity and motility, could be used to construct synthetic nanoparticle‐loaded biohybrid micromotors for advanced biomedical applications.     

Surface Charge‐Reversible Tubular Micromotors for Extraction of Nucleic Acids in Microsystems

Extraction of nucleic acids in microsystems is of significance for biomedical applications, but the current extraction methods generally require sophisticated microchannels and external equipment, hindering their practical applications. In this work, we have demonstrated a simple, versatile and efficient approach to extract nucleic acids in microsystems by developing cationic branched polyethyleneimine (PEI)‐functionalized tubular micromotors. The as‐developed tubular micromotors are fabricated by a two‐step process combining the template‐assisted electrodeposition and carbodiimide chemistry, and contain an inner catalytic Pt layer, a middle magnetic Ni layer and an outer cationic PEI layer. They exhibit autonomous bubble‐propelled motion in aqueous hydrogen peroxide solutions, which can be guided by an external magnetic field, and the surface charges can be reversibly modulated by changing the pH value of the solution. Consequently, the as‐developed tubular micromotors can selectively absorb nucleic acids from acidic solutions and desorb them into alkaline solutions, leading to the extraction of nucleic acids with high efficiency without external stirring. Furthermore, they can be operated in a microchannel chip without the aid of a pumping system. Our results indicate that this PEI‐functionalized tubular micromotor platform provides a novel, simple and versatile microsystem nucleic acid extraction technology, holding considerable promise for important practical applications.     

Stabilization and activation of Pluronic micelles for tumor-targeted drug delivery

In order to be used as drug carriers, Pluronic micelles require stabilization to prevent degradation caused by significant dilution accompanying IV injection. This article studies three routes of Pluronic micelle stabilization. The first route was direct radical crosslinking of micelles cores which resulted in micelle stabilization. However, this compromised the drug loading capacity of Pluronic micelles. In the second route, a small concentration of vegetable oil was introduced into diluted Pluronic solutions. This decreased micelle degradation upon dilution while not compromising the drug loading capacity of oil-stabilized micelles. The third route was a novel technique based on polymerization of the temperature-responsive LCST hydrogel in the core of Pluronic micelles. The hydrogel phase was in a swollen state at room temperature, which provided a high drug loading capacity of the system. The hydrogel collapsed at physiological temperatures which locked the core of micelles thus preventing them from fast degradation upon dilution. This new drug delivery system was called Plurogel®. Phase transitions in Plurogel® caused by variations in temperature or concentration were studied by the EPR. The effect of Pluronic concentration in the incubation medium on the intracellular uptake of two anti-cancer drugs was studied. At low Pluronic concentrations, when the drugs were located in the hydrophilic environment, drug uptake was increased, presumably due to the effect of a polymeric surfactant on the permeability of cell membranes. In contrast, when the drugs were encapsulated in the hydrophobic cores of Pluronic micelles, drug uptake by the cells was substantially decreased. This may be advantageous in the prevention of undesired drug interactions with normal cells. Ultrasonication enhanced intracellular drug uptake from dense Pluronic micelles. These findings permitted the formulation of a new concept of a localized drug delivery.     

Nano/Micromotors for Diagnosis and Therapy of Cancer and Infectious Diseases

Micromotors are man-made nano/microscale devices capable of transforming energy into mechanical motion. The accessibility and force offered by micromotors hold great promise to solve complex biomedical challenges. This Review highlights current progress and prospects in the use of nano and micromotors for diagnosis and treatment of infectious diseases and cancer. Motion-based sensing and fluorescence switching detection strategies along with therapeutic approaches based on direct cell capture; killing by direct contact or specific drug delivery to the affected site, will be comprehensively covered. Future challenges to translate the potential of nano/micromotors into practical applications will be described in the conclusions.     

Thermodynamic Studies of Insulin Loading into a Glucose Responsive Hydrogel Based on Chitosan‐polyacrylamide‐polyethylene Glycol

The insulin therapy constitutes the preferred treatment for Diabetes Mellitus (DM). The traditional insulin therapy, which consists of daily subcutaneous insulin injections to control blood glucose level, is not able to regulate the blood glucose level precisely. In this research, to facilitate the diabetic patient life, an intelligent drug delivery system based on a biodegrable biopolymer to control the insulin release, was designed. In this system, chitosan‐polyethylene glycol hydrogel and glucose oxidize play the role of drug carrier and glucose biosensor, respectively. To increase the hydrogel drug loading capacity, hydrogels with different PEG content were synthesized and insulin was loaded by swelling‐diffusion method into them. The loaded hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), High performance liquid chromatography (HPLC), and Thermogravimetric analysis (TGA). Finally, the thermodynamic study for insulin loading process was performed to investigate the stability of the drug in the system.     

A green chemistry approach towards synthesizing hydrogel for sustained ocular delivery of brinzolamide: In vitro and ex vivo evaluation

Brinzolamide is a carbonic anhydrase inhibitor used in the eye drop form for the treatment of glaucoma. It requires frequent dosing to attain therapeutic concentration. Therefore, this study aimed to prepare sustained ocular drug delivery of brinzolamide. The objective of the study was to prepare a hydrogel loaded with a nanostructured lipid carrier (NLC) of brinzolamide. The hydrogel was prepared by a green synthesis approach using genipin as a natural crosslinking agent and polymers such as carboxymethyl chitosan and poloxamer 407. The melt emulsification-ultra sonication method was used to prepare a nanostructured lipid carrier of brinzolamide, which was loaded into a hydrogel using a swelling and loading method. The NLC formulation has shown small particle sizes of 111.20 ?± ?2.15 ?nm, polydispersity index of 0.280 ?± ?0.005 and % entrapment efficiency of 82.16% ?± ?0.14%. The NLC-loaded hydrogels of brinzolamide formulations were studied for swelling properties and showed temperature and pH-responsive swelling behavior. The optimized hydrogel formulation has been studied for in vitro drug release and showed drug release for a longer duration (24 ?h) than marketed eye drops (8 ?h). In an ex vivo study, hydrogel formulations showed transcorneal permeability 4.54 times greater than marketed eye drops. The hydrogel formulation of brinzolamide produced by the green synthesis method has shown sustained-release properties with no sign of ocular irritation. Hence, the hydrogel of brinzolamide-loaded NLC would be the potential drug delivery approach in the near future for sustained ocular drug delivery in glaucoma management.     

Investigation of a novel thermogelling hydrogel for a versatility of drugs delivery

The P(CL-PDO)-PEG-(P(CL-PDO)(PECP) copolymer hydrogel is an attractive thermogelling material for practical applications due to the fast dissolution of the copolymer in water and good stability of the resultant sol solution that is beneficial for guest matter mixing. In this paper, the degradation properties and drug release behavior of the hydrogel loaded with various types of drugs were evaluated. The integrity of the PECP hydrogel could preserve for 2?weeks and became viscous liquid after degradation time of 21?weeks. With the degradation time, both the molecular weight and weight loss of the hydrogel decreased gradually. NMR analysis of the degraded products indicated that the chain breaking of the copolymer mainly occurred within the sequence structures of PDO-PDO or PDO-PCL, implying the acceleration effect of PDO unit to the degradation of hydrogel. Three distinct types of drugs including small molecular hydrophobic, small molecular hydrophilic and hydrophilic macromolecular drugs were loaded into the PECP hydrogel to evaluate their release profiles. The result showed that the releasing periods for macromolecular protein or hydrophobic drug were extended to more than one month. Since these two types of drugs are loaded within different regions of the hydrogel due to their different hydrophobic/hydrophilic nature, the PECP hydrogel is expected to develop injectable system loaded with a versatility of drugs or guest matter for synergetic effect.     

Photo‐Modulated Therapeutic Protein Release from a Hydrogel Depot Using Visible Light

The use of biomacromolecular therapeutics has revolutionized disease treatment, but frequent injections are required owing to their short half‐life in vivo. Thus there is a need for a drug delivery system that acts as a reservoir and releases the drug remotely “on demand”. Here we demonstrate a simple light‐triggered local drug delivery system through photo‐thermal interactions of polymer‐coated gold nanoparticles (AuNPs) inside an agarose hydrogel as therapeutic depot. Localized temperature increase induced by the visible light exposure caused reversible softening of the hydrogel matrix to release the pre‐loaded therapeutics. The release profile can be adjusted by AuNPs and agarose concentrations, light intensity and exposure time. Importantly, the biological activity of the released bevacizumab was highly retained. In this study we demonstrate the potential application of this facile AuNPs/hydrogel system for ocular therapeutics delivery through its versatility to release multiple biologics, compatibility to ocular cells and spatiotemporal control using visible light.     

Characterization of a Multi-responsive Magnetic Graphene Oxide Nanocomposite Hydrogel and Its Application for DOX Delivery

Nanocomposite hydrogels are one of the most important types of biomaterials which can be used in many different applications such as drug delivery and tissue engineering.Incorporation of nanoparticles within a hydrogel matrix can provide unique characteristics like remote stimulate and improved mechanical strength.In this study,the synthesis of graphene oxide and graphene oxide nanocomposite hydrogel has been studied.Nanocomposite hydrogel was synthesized using carboxymethyl cellulose as a natural base,acrylic acid as a comonomer,graphene oxide as a filler,ammonium persulfate as an initiator,and iron nanoparticles as a crosslinking agent.The effect of reaction variables such as the iron nanoparticles,graphene oxide,ammonium persulfate,and acrylic acid were examined to achieve a hydrogel with maximum absorbency.Doxorubicin,an anti-cancer chemotherapy drug,was loaded into this hydrogel and its release behaviors were examined in the phosphate buffer solutions with different pH values.The structure of the graphene oxide and the optimized hydrogel were confirmed by Fourier-transform infrared spectroscopy,Raman spectroscopy,X-ray diffraction,scanning electron microscopy,and atomic force microscopy.     

Methyl methacrylate-co-itaconic acid (MMA-co-IA) hydrogels for controlled drug delivery

In the present work methyl methacrylate-co-itaconic acid (MMA-co-IA) hydrogels were synthesized by free radical copolymerization of methyl methacrylate (MMA) and itaconic acid (IA) using ethylene glycol dimethacrylate (EGDMA) and methylene bisacrylamide (MBAAm) as crosslinkers and benzoyl peroxide as initiator. Selected samples were loaded with model drug lactulose. For the lactulose release, the effect of pH, monomeric compositions, degree of crosslinking were investigated. The release of lactulose was studied for 8 h period in USP phosphate buffer solutions of varying pH 1.2, 5.5, 6.5 and 7.0. The drug release data were fitted into various kinetics models like the zero order, first order, Higuchi and Peppas. The release kinetics of lactulose from MMA/IA hydrogels was found to be best described by the Peppas model. Results showed that drug release increased by increasing IA content in the hydrogels but the effect of changing of crosslinking ratio on drug release was not significant. The surface morphology of MMA/IA drug loaded hydrogel was studied by SEM which revealed uniform distribution of the drug in the hydrogels. In conclusion, it can be said that lactulose can be successfully incorporated into crosslinked MMA/IA hydrogels and its release can be modulated by changing the mole fraction of the acid component in the gels.     

Preparation and Characterization of a Novel Drug Delivery System: Biodegradable Nanoparticles in Thermosensitive Chitosan/Gelatin Blend Hydrogels

A novel injectable in situ gelling drug delivery system (DDS) consisting of biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) nanoparticles and thermosensitive chitosan/gelatin blend hydrogels was developed for prolonged and sustained controlled drug release. Four different HTCC nanoparticles, prepared based on ionic process of HTCC and oppositely charged molecules such as sodium tripolyphosphate, sodium alginate and carboxymethyl chitosan, were incorporated physically into thermosensitive chitosan/gelatin blend solutions to form the novel DDSs. Resulting DDSs interior morphology was evaluated by scanning electron microscopy. The effect of nanoparticles composition on both the gel process and the gel strength was investigated from which possible hydrogel formation mechanisms were inferred. Finally, bovine serum albumin (BSA), used as a model protein drug, was loaded into four different HTCC nanoparticles to examine and compare the effects of controlled release of these novel DDSs. The results showed that BSA could be sustained and released from these novel DDSs and the release rate was affected by the properties of nanoparticle: the slower BSA release rate was observed from DDS containing nanoparticles with a positive charge than with a negative charge. The described injectable drug delivery systems might have great potential application for local and sustained delivery of protein drugs.     

Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics

The creation of an oral drug delivery platform to administer chemotherapeutic agents effectively can not only increase patient compliance, but also potentially diminish drug toxicity. A microfabricated device offers advantages over conventional drug delivery technology. Here we describe the development of a multi-layered polymeric drug-loaded microfabricated device (microdevice) for the oral delivery of therapeutics, which offers unidirectional release of multiple therapeutics. The imaging and release of therapeutics from the multi-layered device was performed with three different fluorescently labeled albumins. The release of insulin and chemotherapeutic camptothecin was also observed to be released in a controlled manner over the course of 180 min in vitro. Furthermore, asymmetric delivery was shown to concentrate drug at the device/cell interface, wherein 10 times more drug permeated an intestinal epithelial cell monolayer, compared to unprotected drug-loaded hydrogels. The bioactivity of the released chemotherapeutic was shown with cytostasis of colorectal adenocarcinoma cells. Cytostasis of drug loaded hydrogels was significantly higher than control empty hydrogel laden microdevices. Our results conclude that microfabrication of a hydrogel laden microdevice leads to a viable oral delivery platform for chemotherapeutics.     

Pullulan hydrogels improve mesenchymal stem cell delivery into high-oxidative-stress wounds

Cell-based therapies for wound repair are limited by inefficient delivery systems that fail to protect cells from the acute inflammatory environment. Here, a biomimetic hydrogel system is described that is based on the polymer pullulan, a carbohydrate glucan known to exhibit potent antioxidant capabilities. It is shown that pullulan hydrogels are an effective cell delivery system and improve mesenchymal stem cell survival and engraftment in high-oxidative-stress environments. The results suggest that glucan hydrogel systems may prove beneficial for progenitor-cell-based approaches to skin regeneration.     

Modified SBA-15 as the carrier for metoprolol and papaverine: Adsorption and release study

A series of modified SBA-15 materials were applied in drug delivery systems. The internal surface of siliceous hexagonal structure of SBA-15 was modified with different amount of (3-mercaptopropyl)trimethoxysilane (MPTMS) and oxidized in the presence of hydrogen peroxide. The sulfonated material was loaded with metoprolol tartrate or papaverine hydrochloride. Both drugs indicated strong chemical interaction with modified mesoporous surface. The characteristic of the obtained materials was performed with XRD and DRUV-vis spectrometry, themogravimetry and nitrogen adsorption (BET) measurements. The obtained results show that modification of the mesoporous materials leads towards significant decrease of the drug delivery rate.     

Three-dimensional porous HPMA-co-DMAEM hydrogels for biomedical application

The aim of this work is to develop a novel biocompatible drug delivery carrier and tissue engineering scaffold with the ability of controlled drug release and also tissue regeneration. We have synthesized N-(2-hydroxypropyl)methacrylamide and 2-(dimethylamino)ethyl methacrylate copolymer-based hydrogels loaded with doxorubicin and tested in vitro. The manifestation of temperature sensitivity is noted with a sharp decrease or increase in hydrogel optical transparency that happens with the temperature exceeding a critical transition value. The drug release profile exhibited pH-sensitive behavior of the hydrogel. The hydrolytic degradation of gel and in vitro studies of polymer–doxorubicin conjugate and doxorubicin release from hydrogel matrix indicated that hydrogels were stable under acidic conditions (in buffers at pH 4.64 and 6.65). In both drug forms, polymer–doxorubicin conjugate and free doxorubicin could be released from the hydrogel scaffold at a rate depending directly on either the rate of drug diffusion from the hydrogel or rate of hydrogel degradation or at rate controlled by a combination of the both processes. In vitro analysis showed homogenous cell attachment and proliferation on synthesized hydrogel matrix. In vivo implantation demonstrated integration of the gel with the surrounding tissue of mice within 2 weeks and prominent neo-angiogenesis observed in the following weeks. This multifunctional hydrogels can easily overcome biological hurdles in the in vivo conditions where the pH range changes drastically and could attain higher site-specific drug delivery improving the efficacy of the treatment in various therapeutical applications, especially in cancer therapy, and could also be used as tissue engineering scaffold due to its porous interconnected and biocompatible behavior.     

Dual Photo‐ and pH‐Responsive Supramolecular Nanocarriers Based on Water‐Soluble Pillar[6]arene and Different Azobenzene Derivatives for Intracellular Anticancer Drug Delivery

Two novel types of supramolecular nanocarriers fabricated by the amphiphilic host–guest inclusion complex formed from water‐soluble pillar[6]arene ( WP6 ) and azobenzene derivatives G1 or G2 have been developed, in which G1 is structurally similar to G2 but has an extra phenoxy group in its hydrophobic region. Supramolecular micelles can be initially formed by WP6 with G1 , which gradually transform into layered structures with liquid‐crystalline properties, whereas stable supramolecular vesicles are obtained from WP6 and G2 , which exhibit dual photo‐ and pH‐responsiveness. Notably, the resulting WP6 ? G2 vesicles can efficiently encapsulate anticancer drug mitoxantrone (MTZ) to achieve MTZ‐loaded vesicles, which maintain good stability in a simulated normal physiological environment, whereas in an acid environment similar to that of tumor cells or with external UV irradiation, the encapsulated drug is promptly released. More importantly, cytotoxicity assay indicates that such vesicles have good biocompatibility and the MTZ‐loaded vesicles exhibit comparable anticancer activity to free MTZ, especially with additional UV stimulus, whereas its cytotoxicity for normal cells was remarkably reduced. Flow cytometric analysis further confirms that the cancer cell death caused by MTZ‐loaded vesicles is associated with apoptosis. Therefore, the dual pH‐ and UV‐responsive supramolecular vesicles are a potential platform for controlled release and targeted anticancer drug delivery.