Progress in natural polymer engineered biomaterials for transdermal drug delivery systems

The route of a specific drug carrier system is always a significant platform of development that combines the principles of biomedical technology, nanotechnology, and pharmaceutical drug design. Transdermal (TD) drug delivery involves the release of the drug via the stratum corneum of the tissue membrane into the sustained release by diffusion across the epidermal layer. This method (often known as topical drug delivery) has increased noteworthy research enthusiasm in the course of recent decades due to its relatively simpler and non-invasive administration. Over the past few decades, considerable advancement was achieved in TD delivery and a number of drugs are now successfully reported. In this review, we focus on the progress regarding applications of important biopolymers described for the TD drug release applications and related aspects. Three mostly reported plant and animal-derived polymers (such as natural rubber, chitosan, and cellulose for the development of TD carrier system) were extensively analyzed. The general principle of TD drug delivery, advantages, and limitations of the works reported were also discussed.     

Luminescent porous silica fibers as drug carriers

Luminescent and porous silica fibers have been successfully prepared by using the electrospinning process. The obtained multifunctional silica fibers, which possess a porous structure and display blue luminescence, can serve as a drug delivery host carrier, using ibuprofen (IBU) as a model drug, allowing the investigation of storage/release properties. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FT-IR), N(2) adsorption/desorption, photoluminescence (PL) spectra, and kinetic decay were used to characterize the structural, morphological, and optical properties of the as-obtained samples. The results reveal that the multifunctional silica materials exhibit an irregular porous structure, and display a fiberlike morphology with dimensions of several hundred nanometers in width and several millimeters in length. The obtained silica fibers exhibit an intense broad bluish emission, which might be attributed to impurities and/or defects in the silica fibers. The IBU-loaded silica fiber system shows blue luminescence under UV irradiation and controlled release behavior for IBU. In addition, the emission intensities of silica fibers in the drug carrier system vary with the released amount of IBU, thus allowing the drug release to be easily tracked and monitored by the change of the luminescence intensity.     

基于环糊精的智能刺激响应型药物载体

智能药物载体凭借其独特的刺激-响应机制控制药物的释放速度和转运部位,已成为当前化学与药学领域的研究热点之一。由于具有提高药物在体内的生物利用度和降低其毒副作用等优点,智能药物载体将在未来的临床治疗中起到越来越重要的作用。近年来,环糊精作为药物载体材料的研究取得了巨大进步,其在药物控释的时间、空间和剂量上更为准确。环糊精具有大环结构,可自组装、易于功能化、天然无毒且价格低廉,已被广泛应用于构筑智能药物载体。凭借其自组装、分子识别和动态可逆性能力,环糊精可以同其他生物相容性材料构筑具有不同性能的智能药物载体。这种载体可在外界刺激下做出相关理化性质改变的反馈调节,包括通过内源性刺激(pH值、氧化还原物质和酶浓度等)和外源性刺激(温度、光、磁场、超声和电压等),进而控制药物的释放。本文综述了面向不同刺激因素的基于环糊精智能刺激响应型药物载体的作用机理、特点和应用的最新研究进展,并对其发展前景作了进一步的展望。     

Construction of a pH-responsive drug delivery platform based on the hybrid of mesoporous silica and chitosan

Mesoporous silica nanoparticles (MSN) have been widely used for drug delivery due to their large specific surface area and excellent biocompatibility. However, the mesoporous structure of MSN would lead to the inevitable “premature release” of the drugs, and therefore the modification of MSN for controlled delivery seems to be a necessary step. Herein, chitosan (CS) was used for the surface functionalization of MSN via amidation reaction, and the introduced CS could function as a “gatekeeper” and the drug of methotrexate (MTX) might be encapsulated in the mesopores of MSN. As a result, the “premature release” of the encapsulated MTX could be effectively circumvented with the aid of the CS cap. More importantly, the drug delivery from the hybrid of MSN and CS (MSN/CS) can be endowed with pH-sensitivity by the introduction of CS because the amide bonding between CS and MSN is highly pH-sensitive. The cumulative release of MTX from the MSN/CS is more pronounced at pH 5.0 (80.86%) than those at pH 6.8 (40.46%) and pH 7.4 (18.25%).     

pH‐responsive polymer core–shell nanospheres for drug delivery

Stimuli‐responsive polymer nanoparticles are playing an increasingly more important role in drug delivery applications. However, limited knowledge has been accumulated about processes which use stimuli‐responsive polymer nanospheres (matrix nanoparticles whose entire mass is solid) to carry and deliver hydrophobic therapeutics in aqueous solution. In this research, pyrene was selected as a model hydrophobic drug and a pyrene‐loaded core‐shell structured nanosphere named poly(DEAEMA)‐poly(PEGMA) was designed as a drug carrier where DEAEMA and PEGMA represent 2‐(diethylamino)ethyl methacrylate and poly(ethylene glycol) methacrylate, respectively. The pyrene‐loaded core‐shell nanospheres were prepared via an in situ two‐step semibatch emulsion polymerization method. The particle size of the core‐shell nanosphere can be well controlled through adjusting the level of surfactant used in the polymerization where an average particle diameter of below 100 nm was readily achieved. The surfactant was removed via a dialysis operation after polymerization. Egg lecithin vesicles (liposome) were prepared to mimic the membrane of a cell and to receive the released pyrene from the nanosphere carriers. The in vitro release profiles of pyrene toward different pH liposome vesicles were recorded as a function of time at 37 °C. It was found that release of pyrene from the core‐shell polymer matrix can be triggered by a change in the environmental pH. In particular the pyrene‐loaded nanospheres are capable of responding to a narrow window of pH change from pH = 5, 6, to 7 and can achieve a significant pyrene release of above 80% within 90 h. The rate of release increased with a decrease in pH. A first‐order kinetic model was proposed to describe the rate of release with respect to the concentration of pyrene in the polymer matrix. The first‐order rate constant of release k was thus determined as 0.049 h^?1 for pH = 5; 0.043 h^?1 for pH = 6; and 0.035 h^?1 for pH = 7 at 37 °C. The release of pyrene was considered to follow a diffusion‐controlled mechanism. The synthesis and encapsulation process developed herein provides a new approach to prepare smart nanoparticles for efficient delivery of hydrophobic drugs. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4440–4450     

Recent advances in biopolymer based electrospun nanomaterials for drug delivery systems

Drug delivery systems, including liposomes, gels, prodrugs, and so forth, are used to enhance the tissue benefit of a pharmaceutical drug or conventional substance at a specific diseased site with little toxicological impact. Nanotechnology can be a rapidly developing multidisciplinary science that enables the production of polymers at the manometer scale for different medical applications. The use of biopolymers in drug delivery systems provides compatibility, biodegradability and low immunogenicity biologically. Large-scale and smaller-than-expected medication particles can be delivered using biopolymers such as silk fibroins, collagen, gelatine, and others that are easily formed into suspensions. These drug carrier systems are functional at improving drug delivery and can be used in intranasal, transdermal, dental, and ocular delivery systems. This study discusses the latest developments in drug delivery methods based on nanomaterials, mainly using biopolymers like proteins and polysaccharides.     

Designing responsive microgels for drug delivery applications

Microgels based on thermally responsive polymers have been widely investigated in the context of controlled release applications, with increasing recent interest on developing a clearer understanding of what physical, chemical, and biological parameters must be considered to rationally design a microgel to deliver a specific drug at a specific rate in a specific physiological context. In this contribution, we outline these key design parameters associated with engineering responsive microgels for drug delivery and discuss several recent examples of how these principles have been applied to the synthesis of microgels or microgel-based composites. Overall, we suggest that in vivo assessment of these materials is essential to bridge the existing gap between the fascinating properties observed in the lab and the practical use of microgels in the clinic. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3027–3043     

A multifunctional nanocarrier based on nanogated mesoporous silica for enhanced tumor-specific uptake and intracellular delivery

A multifunctional drug delivery system based on MCM-41-type mesoporous silica nanoparticles is described that behaves as if nanogates were covalently attached to the outlets of the mesopores through a highly acid-sensitive benzoic-imine linker. Tumor-specific uptake and intracellular delivery results from the pH-dependent progressive hydrolysis of the benzoic-imine linkage that starts at tumor extracellular pH = 6.8 and increases with decreasing pH. The cleavage of the benzoic-imine bond leads to the removal of the polypseudorotaxane caps and subsequent release of the payload drugs at tumor sites. At the same time, the carrier surface becomes positively charged, which further facilitates cellular uptake of the nanocarriers, thus offering a tremendous potential for targeted tumor therapy.     

Two sides to supramolecular drug delivery systems

Although still in its infancy, there is a rapidly increasing interest in the development of supramolecular drug delivery systems (SDDSs). As chemists, the most challenging task ahead of us is to narrow the gap between SDDSs development in the lab, and clinical drug carriers. Only then will we achieve our ultimate goal of the successful translation of SDDSs to life saving medicines.     

Synthesis of hierarchical sieve-like mesoporous silica nanoparticle aggregates via centrifugal method for drug delivery system

A facile approach towards the scaled-up synthesis of a novel hierarchical sieve-like structure of mesoporous silica nanoparticle aggregates (hsMSNA) with high drug encapsulation efficiency and sustained release behaviors acting as a drug delivery system in the field of nanomedicine.     

Construction of Smart Stimuli-Responsive DNA Nanostructures for Biomedical Applications

DNA nanostructures have recently attracted increasing interest in biological and biomedical applications by virtue of their unique properties, such as structural programmability, multi-functionality, stimuli-responsive behaviors, and excellent biocompatibility. In particular, the intelligent responsiveness of smart DNA nanostructures to specific stimuli has facilitated their extensive development in the field of high-performance biosensing and controllable drug delivery. This minireview begins with different self-assembly strategies for the construction of various DNA nanostructures, followed by the introduction of a variety of stimuli-responsive functional DNA nanostructures for assembling metastable soft materials and for facilitating amplified biosensing. The recent achievements of smart DNA nanostructures for controllable drug delivery are highlighted. Finally, the current challenges and possible developments of this promising research are discussed in the fields of intelligent nanomedicine.     

Controlled drug delivery systems based on calixarenes

Recent advances on calixarene-based drug delivery systems in the form of inclusion complexes, amphiphilic self-assembly nanocarriers including micelles, hydrogels, vesicles and liposomes, and supramolecular nanovalves on mesoporous silicas, were reviewed and discussed.     

Doxorubicin delivery by polymer nanocarrier based on N-methylglucamine resorcinarene

ABSTRACT

Herein we describe a simple method for the synthesis of polymer nanocarrier for the doxorubicin delivery. The nanocarrier consists of N-methyl-glucamine resorcinarenes that are covalently bound to phenylboronic acid. The nanocarrier is stable at normal pH but is hydrolysed at pH below 6. It demonstrates low cytotoxicity and haemolytic activity. Doxorubicin was successfully loaded into the nanocarriers cavity and its release occurs at pH. Flow cytometry data showed that the carrier improves the penetration of doxorubicin into M-Hela cancer cell lines. The encapsulated doxorubicin demonstrates higher cytotoxicity towards the cancer cells.     

Near infra-red light responsive carbon nanotubes@mesoporous silica for photothermia and drug delivery to cancer cells

Among smart activable nanomaterials used for nanomedicine applications, carbon-based nanocomposites are well known to ensure phototherapy while their use for controlled drug delivery is still rarely investigated. In this work, original hybrid mesoporous silica (MS)–coated carbon nanotubes (CNTs) nanoplatforms have been designed to provide phototherapy combined with drug release mediated by NIR laser excitation. The responsive CNT@MS are chemically modified with original isobutyramide (IBAM) grafts acting as non-covalent binders, which ensure a very high drug loading capacity (≥to 80 wt%) of the antitumor drug doxorubicin (DOX) as well as the final adsorption of a human serum albumin (HSA) shell as biocompatible interface and drug gate-keeping. The drug is demonstrated to unbind from the nanocomposite only upon photothermal excitation and to release in the solution. Such smart platforms are further shown to deliver drug upon several pulsatile NIR excitations with controlled temperature profiles. Regarding antitumor action, we demonstrate here that the NIR light induced photothermic effect from the nanocomposites is the main effect accounting for cancer cell toxicity and that DOX delivery mediated by the NIR light brings an additional toxicity allowing a synergistic effect to efficiently kill tumor cells. Finally, when our nanocomposites are embedded within a hydrogel mimicking extracellular matrix, the resulting smart responsive scaffolds efficiently release DOX upon NIR light to the cells localized above the composite hydrogel. These results demonstrate that such nanocomposites are highly promising as new components of implantable antitumor scaffolds that are able to respond to external stimuli in time and location for a better disease management.     

Smart Pellets for Controlled Delivery of 5-Fluorouracil

This work aimed to develop a new one-pot and readily scaled-up formulation capable of retaining 5-fluorouracil and prolonging its release to obtain a site-specific medication delivery for the potential treatment of colorectal cancer. Six polymer-based formulations were successfully produced using a thermal bulk polymerization method and loaded with 5-fluorouracil, which is a chemotherapeutic agent used in the treatment of colorectal carcinoma. The pellets produced were characterized by measuring the glass transition temperature, tensile strength, Young’s modulus, and tensile elongation at break. Studies on in vitro swelling and release were carried out in phosphate-buffered saline to evaluate the behaviour of the developed system. The Young’s modulus, glass transition temperature, and tensile strength all increased significantly as the crosslinker concentration increased, but the fracture strain value reduced significantly. The in vitro swelling profile of the produced formulations was significantly reduced by increasing crosslinking density. Less than 27% cumulative drug release was achieved for all formulations after 5 h of starting the release study. The highest cumulative drug release reached after 24 h was 69%. The developed drug delivery system demonstrated the ability to delay the release of 5-fluorouracil in upper gastrointestinal tract-mimicking conditions, while permitting its release in a controlled way afterward, which makes it promising for the potential delivery of 5-fluorouracil to the colon.     

普鲁兰多糖在药物释放系统中的应用

本综述重点介绍了近年来普鲁兰多糖作为药物释放系统载体材料的研究进展及其在药物释放系统中的应用情况。     

Effect of mesopores on solidification of sirolimus self-microemulsifying drug delivery system

The mesoporous silica materials had a high loading efficiency of sirolimus-SMEDDS. The length of the mesopores played a more important role than the pore diameter in drug dissolution and in vivo absorption.     

pH and Reduction Dual-Responsive Nanogels as Smart Nanocarriers to Resist Doxorubicin Aggregation

The use of smart nanocarriers that can modulate therapeutic release aided by biological cues can prevent undesirable cytotoxicity caused by the premature release of cytotoxic drugs during nanocarrier circulation. In this report, degradable nanocarriers based on pH/reduction dual-responsive nanogels were synthesized to encapsulate doxorubicin hydrochloride (DOX) and specifically boost the release of DOX in conditions characteristic of the cancer microenvironment. Nanogels containing anionic monomer 2-carboxyethyl acrylate (CEA) and N,N′-bis(acryloyl)cystamine (CBA) as a degradable crosslinker have been successfully synthesized via photoinitiated free radical polymerization. The loading process was conducted after polymerization by taking advantage of the electrostatic interaction between the negatively charged nanogels and the positively charged DOX. In this case, a high drug loading capacity (DLC) of up to 27.89% was achieved. The entrapment of DOX into a nanogel network could prevent DOX from aggregating in biological media at DOX concentrations up to ~160 µg/mL. Anionic nanogels had an average hydrodynamic diameter (d_H) of around 90 nm with a negative zeta (ζ) potential of around −25 mV, making them suitable for targeting cancer tissue via the enhanced permeation effect. DOX-loaded nanogels formed a stable dispersion in different biological media, including serum-enriched cell media. In the presence of glutathione (GSH) and reduced pH, drug release was enhanced, which proves dual responsivity. An in vitro study using the HCT 116 colon cancer cell line demonstrated the enhanced cytotoxic effect of the NG-CBA/DOX-1 nanogel compared to free DOX. Taken together, pH/reduction dual-responsive nanogels show promise as drug delivery systems for anticancer therapy.