Electrospun nanofibers-mediated on-demand drug release.

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Electrospun Nanofibers-Mediated On-Demand Drug Release Menglin Chen,* Yan-Fang Li, and Flemming Besenbacher degradability. Research to improve the mechanisms of controlled drug delivery has seen much success in recent decades, achieving long-lasting zero-order drug release and ligand-based targeting to reduce issues with short drug half-life and endurance of multiple administrations, along with the improved specificity etc.[2,3] However, many diseases are found to follow aberrant regulatory feedback cycles and rhythms. Therefore, these underlying comprehensive mechanisms should be taken into account to design the ideal pulsatile DDSs with ability to response and synchronize the release profile with the changing physiologic, pathophysiologic conditions aided with externally manipulated environments.[4] Notably, stimuli-sensitive materials have emerged as one of the novel programmable delivery systems in which the release of the encapsulated contents can be readily modulated by various extra- and intracellular biological stimuli (e.g., pH,[5] redox potential,[6] and enzyme[7] as well as external artificial triggers (e.g., light,[8] temperature,[9] magnetic field[10] and ultrasound,[11] either reversibly or non-reversibly)). Many studies have been confined within bottom-up biotechnology such as micelles,[12] polymersomes,[13] and hydrogels.[14,15] The significance of the overall fibrillar and porous nanoscale topography of the extracellular matrix (ECM) in promoting essential cellular processes has led to consideration of delivery vehicles with biomimetic nanofibrous features.[16] An attractive drug delivery vehicle is recently developed using electrospinning techniques, which can in principle achieve uniform dispersion of drug within the polymeric matrix with high loading capacity and minimal drug loss. This versatile topdown technique utilizes high-voltage electric fields to generate continuous nanofibers from virtually any polymers, composites or supramolecules, which entangle in the similar fashion as polymers.[17–25] The possibility of using electrospun matrices as constructs for giving controlled release of a number of drugs, including antibiotics, anticancer drugs, as well as proteins and DNA/RNA have been explored.[26–31] One intriguingly emerging area is to combine the electrospinning techniques with the stimuli-sensitive materials to fabricate stimuli-responsive drug-loaded nanofibers. This Review emphasizes emerging researches that utilize electrospinning to fabricate nanofibrous form of current investigated intelligent materials as drug delivery vehicles, for example, that are

A living system has a complex and accurate regulation system with intelligent sensor-processor-effector components to enable the release of vital bioactive substances on demand at a specific site and time. Stimuli-responsive polymers mimic biological systems in a crude way where an external stimulus results in a change in conformation, solubility, or alternation of the hydrophilic/hydrophobic balance, and consequently release of a bioactive substance. Electrospinning is a straightforward and robust method to produce nanofibers with the potential to incorporate drugs in a simple, rapid, and reproducible process. This feature article emphasizes an emerging area using an electrospinning technique to generate biomimetic nanofibers as drug delivery devices that are responsive to different stimuli, such as temperature, pH, light, and electric/magnetic field for controlled release of therapeutic substances. Although at its infancy, the mimicry of these stimuli-responsive nanofibers to the function of the living systems includes both the fibrous structural feature and bio-regulation function as an on demand drug release depot. The electrospun nanofibers with extracellular matrix morphology intrinsically guide cellular drug uptake, which will be highly desired to translate the promise of drug delivery for the clinical success.

1. Introduction Research on site specific and temporal control of drug delivery system (DDS) is receiving a major impetus towards the development of new improved drug therapies. As is frequently found in the living body, many vital functions are regulated by pulsed or transient release of bioactive substances, at a specific site and time, as a response of a “demand.” Furthermore, numerous bioactive peptides, proteins, and nucleic acids have been recently progressed for use as more effective and sophisticated therapeutic drugs, which are normally metabolized rapidly in the body and can cause undesired cytotoxic side effect with large dose of administration. Therefore, the development of delivery formulations by which drugs are delivered on-demand to the diseased cells is recognized as one of the essential fundamentals to realize the therapeutic specificity and accuracy.[1] The design factors of drug delivery devices include size, surface charge, and chemistry, chemical components, and Dr. M. Chen, Y.-F. Li, Prof. F. Besenbacher Interdisciplinary Nanoscience Center Aarhus University DK-8000, Aarhus, Denmark E-mail: [email protected]

DOI: 10.1002/adhm.201400166

Adv. Healthcare Mater. 2014, DOI: 10.1002/adhm.201400166

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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responsive to certain key environmental factors, such as pH, temperature, light, and electric/magnetic field, to allow on demand pulsatile release of the bioactives in a timely and spatially controlled manner. A small number of stimuli-responsive systems have been incorporated into electrospun nanofibrous delivery vehicles through direct co-electrospinning or post modification via chemical or supramolecular bonds, as crosslinkers or on the polymer backbone. Upon stimulation, volume change or disassembly of delivery vehicles was induced, which consequently lead to the pulsatile release of the drug. After a brief introduction of electrospinning, the on-demand drug delivery mechanisms are first discussed and then a few intriguing applications are addressed.

attention in the field of tissue regeneration because of its ease of generate DDSs through a one-step process, and its resemblance to nanotopographical elements in the ECM of tissues. Drugs can be embedded in the fiber through dissolution or dispersion in the polymer solution liquids to achieve uniform dispersion of drug within the nanofibrous polymeric matrix with high loading capacity. On the other hand, as previously reviewed, the ultrahigh surface to volume ratio of nanofibers would facilitate the stimulus transfer and subsequently speed up the response rate and enable a wide range of applications such as sensors and actuators.[45] It is thus captivating to combine the electrospinning techniques with the stimuli-sensitive materials to develop nanofibrous stimuli-responsive DDSs.

2. Principles of Electrospinning

3. On-Demand Drug Delivery Mechanisms

th

[32]

After first discovered in the late 16 century by William Gilbert In a living body, many vital activities are tightly controlled to that an electric field can affect fluid dynamics, and then reinmaintain health and a normal metabolic balance via a feedback vented in 1900,[33] electrospinning has driven exponentially system called “homeostasis.” A disease generally happens when the body is out of homeostasis. The body needs to act quickly to increased attention as an emerging technology for nanofibers fight the causes and effects of disease to regain its homeostasis, manufabrication since 1990s. Electrohydrodynamics, referring and in many cases this requires a boost of bioactives or drugs. to the dynamics of electrically charged fluids, constitutes the The fast and accurate “on-demand” regulation system in nature basis for electrospinning.[34] When a sufficiently high voltage is is indeed inspiring for modern drug delivery design. A grand applied to a liquid droplet, the liquid becomes charged and the challenge revolves around the understanding of the mechagenerated electrostatic repulsion counteracts the surface tennisms to prepare materials with desired properties. sion resulted a stretched droplet. At a critical point, where the The desired “on demand of a stimulus” function is depended surface tension is overcome, a stream of liquid erupts from the on the materials properties, that derive from their chemistry surface. If the molecular cohesion of the liquid is sufficiently nature and structure, that can change physically or chemically high, stream breakup does not occur (if it does, droplets are in response of the stimulus. Nearly every physical and chemelectrosprayed[35] and a charged liquid jet ejected from the tip ical process occurs with a simultaneous energy change in difof a capillary tube elongates and moves towards a grounded ferent forms such as heat, radiation, and kinetics. Such forms surface). Fast solvent evaporation accompany with further of energy change can thus be applied as stimulus (Figure 1). jet elongation and thining from the whipping process lead to a mat of continuous fibers, range in diameter from several Various specific on-demand stimuli-responsive mechanisms nanometers to micrometers, deposited on the surface. As an have been combined with electrospinning as a means to deliver electrohydrodynamic technique, the electrospun fiber composibioactives primarily in response to the specific stimuli. The tion, morphology, and alignment essentially depend on the applied electrical field, the liquid properties, mainly the ionic strength and the viscosity, and their dynamic interplay at the ambient condition. Along with specific control over fiber components/alignment by manipulation of spinnerets, such as coaxial spinneret, or collectors and electric field, it can also be made high throughput with multi-spinnerets in parallel. A thorough discussion of electrospinning technique and all these methods and materials is beyond the scope of this review. However, these topics have been extensively reviewed by several authors.[36–38] Virtually any polymers,[39–41] some supramolecules that entangle in a similar polymeric fashion,[42–44] and numerous composites allowing flexibility for add-on functionalities, can be electrospun into nanofibers, enabled electrospinning with a broad range of appli- Figure 1. Illustration of the mechanisms of on demand drug delivery upon biological, chemical, cations. Among them, it has attracted intense light, temperature, magnetic, electric field stimuli.

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3.1. Thermosensitive Electrospun Fibers Temperature regulates all types of physical, chemical, or biological reactions. Thermoregulation is the ability of an organism to keep its body temperature by metabolic processes within certain boundaries. Failed thermoregulation leads to diseases and syndromes such as hyperthermia, endocrine system disorders and erythromelalgia. Thermosensitive materials are thus often used for the drug delivery. They usually have a sharp and sensitive temperature response towards either varied body temperatures at the diseased site or resulted by deliberate treatments. Temperature-responsive materials[46,47] are generally prepared from thermal-sensitive polymers, which exhibit a volume phase transition at a certain temperature, due to intra- and intermolecular forces and solvation, for example, hydrogen bonding and hydrophobic interactions.

3.1.1. Thermoresponsive Nanofibers Based on PNIPAM Poly(N-isopropylacrylamide) (PNIPAAm) is one of the most studied temperature-sensitive polymers, as it will exhibit thermalreversible volume phase transition at lower critical solution temperature (LCST). Below the LCST, PNIPAm is hydrophilic due to intermolecular hydrogen bonding between the polymer chains and water molecules. While above the LCST, the hydrogen bonding is replaced by intramolecular hydrogen bonding between C O and N H groups along the PNIPAM chains (Figure 2a), resulting in aggregation of the polymer in water.[31,48,49] Simultaneously as the polymer is not in solution, the water is less ordered and has higher entropy; the process is thus also thermodynamically driven. Consequently, the volume phase transition of the PNIPAm drug carriers between the swelling and deswelling states will affect the release of the encapsulated drugs, either positively or negatively. The former is elaborated as at the deswelling state at the high temperature, the drug is quickly expelled out; the latter is explained as the heterogenerous deswelling of the carriers induced formation of a dense, less permeable surface layer, described as a skin barrier for drug release. 3.1.1.1. Co-Electrospinning of PNIPAM with Another Polymer: A few studies have applied co-electrospinning of a blend of PNIPAM and another polymer and a drug, where the release of the encapsulated drug was negatively affected by elevated temperature. Tang et al.[51] co-electrospun PNIPAm with poly(2acrylamido-2-methylpropanesulfonic acid) (PAMPS), which was added to improve the electrospinnability of PNIPAm. The addition of PAMPS and nifedipine as a hydrophilic drug did not alter the LCST for the hydrophility/hydrophobility switchability of PNIPAm. The nanofibers responded to the environment temperature change, and the drug release was effectively slowed down by increasing the temperature over LCST. Song et al. reported PNIPAm/PEO (poly(ethylene oxide)) blend to co-electrospin into nanofibers, where vitamin B12 (VB12) was encapsulated as a model drug.[52] A decreased release of VB12 at 37 °C, compared with the release at 20 °C, was observed.


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mechanisms of each system with its specific material’s chemical nature are discussed below.

The drug release rates could further be tuned by the changing the composition of PNIPAm and PEO. The decrease of the PNIPAM/PEO (w/w) ratio led to the increase of drug release rate. Lin et al.[53] also reported thermoresponsive nanofibers by co-electrospinning PNIPAAm with hydrophoboic polyurethane (PU) to deliver nifedipine. Less release of nifedipine was found upon heating above LCST. These studies demonstrated negative effect on drug release, indicating the heterogeneity of these blend systems. The swelling–deswelling responses using co-electrospinning of PNIPAM with another polymer are nonreversible, since at temperature below LCST the nanofibers inevitably present insufficient resistance in water to withstand dissolution and thus poor mechanical firmness. 3.1.1.2. NIPAM Copolymers: In response to develop reversible systems, Okuzaki et al.[54] incorporated NIPAm with stearyl acrylate (SA) as a copolymer poly(NIPA-co-SA). Due to the physically crosslinking of long alkyl chains from SA, the prepared electrospun nanofibers mat were stable in water below LCST and could undergo rapid reversible volume phase change. 3.1.1.3. Crosslinked NIPAM Polymer Nanofibers: Instead of applying copolymerization with hydrophobic monomers to increase stability of PNIPAM, Lin et al.[55] reported a facile method to post-chemically crosslink PNIPAm electrospun network with retained thermoresponsibility. A polyhedral oligomeric silsesquioxane (POSS) with eight epoxide groups was used as a crosslinker. The resulted nanofibers mat was stable in both water and organic solutions such as ethanol and acetone. Interestingly, the electrospun fibers mat showed no deformation after being immersed into cold water for 4 weeks. Further data based on the UV–vis transmittance change monitored by spectrophotometer indicated that the sample could undergo swelling– deswelling switching for at least 50 cycles. The improved stability in aqueous solutions provides PNIPAM promising prospects in its thermocontrolled drug release applications. In the study of Kim et al.,[50] thermoswitchable release of fluorescein isothiocyanate (FITC)–dextran was successfully achieved using crosslinked electrospun fibers containing a copolymer of NIPAM and N-hydroxymethylacrylamide (HMAAm), which undergoes self-condensation upon heating. By thermal curing, stable nanofibers were obtained in aqueous solutions both below and above the LCST. The fibers exhibited rapid and reversible swelling and shrinking in several cycles. Upon heating up to 45 °C, FITC–dextran was immediately released by a positive “squeezing” effect, resulting from a rather homogeneous crosslinked system. After the temperature altered to 10 °C, almost no dextran evolved during the cooling process (Figure 2b,c).

3.1.2. Thermoresponsive Nanofibers Based on Polymers with Amphiphilic Balance Pluronic or the PEG–PPG–PEG triblock copolymer is another well-known thermosensitive polymer[56] approved by US Food and Drug Administration (FDA) and has been applied in DDSs as a thermogelling system. The gelation is considered to respond at elevated temperature by a 3D packing of micelles due to the hydrophilic–hydrophobic balance of the amphiphilic molecule.



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Figure 2. a) Hydrogen bonding changes between LCST (Reproduced with permission.[19] Copyright 2010, ACS Publications. b) Release profiles of FITC-dextran from crosslinked PNH 5 (squares) and PNH 10 (circles) in response to cycles of temperature alternation between 10 and 45 °C; c) Schematic of the “on–off” controlled release of dextran (red) from temperatureresponsive NFs. Reproduced with permission.[50] Copyright 2012, IOP Publishing.

Hydrogel nanofiber mats based on thermoresponsive multiblock poly(ester urethane)s comprising poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and poly(ε-caprolactone) (PCL) segments were fabricated by electrospinning by Loh et al.[57] The temperature increase causes the volume of water trapped to be reduced by about half. This is due to the PPG segment in the copolymer becoming more hydrophobic at higher temperatures. The encapsulated protein, bovine serum albumin (BSA), was subsequently expelled together with the water, thus a higher rate of release at 37 °C was observed.

3.2. pH-Sensitive Electrospun Fibers

polymers containing functional groups with the acid dissociation constant pKa close to the physiological/pathophysiological pH can be applied. The pH changes will result in the change of water absorption, swelling ratio, and solubility of the polymers. Chunder et al. reported a pH-responsive nanofiber drug carrier applying co-electrospinning of two weak polyelectrolytes, poly(acrylic acid) (PAA) and poly(allylamine hydrochloride) (PAH).[60] Based on the protonation/deprotonation equilibrium of the two polyelectrolytes, methylene blue (MB), a small cationic model drug, interacted differently with the polymeric drug carriers at different pH, and subsequently its release was found increased with the decrease of pH. Demirci et al.[61] recently synthesized poly(4-vinylbenzoic acid-co-(ar-vinylbenzyl) trimethylammonium chloride) [poly(VBAco-VBTAC), pKa 7.65] via reversible addition–fragmentation chain transfer (RAFT). The electrospun nanofibers were found to be able to reversibly swell–deswell between pH 5.4 and 8.8, due to the protonatin/deprotonation of 4-vinylbenzoic acid (VBA), and change the release profile of ciprofloxacin correspondingly.

3.2.2. pH-Dependent Hydrolysis Kinetics Chemical reactions such as hydrolysis are also kinetically dependent on the pH. Thus polymers containing acid-labile bonds such as acetal or hydrazone groups are susceptible to speed degradation under acidic conditions[62] (Figure 4). Li et al. reported two pH-responsive electrospun fibrous DDSs utilizing acid-labile groups, acetal or ortho ester, in the polymer backbones.[63,64] Both the acetal and ester groups are stable at neutral environment, but would hydrolyze fast in acidic environment. Therefore, the fast hydrolysis in acidic pH value caused

The pH within tissues and cellular compartments varies from acidic to slightly alkaline. For instance, gastrointestinal tract varies from acidic in stomach (pH 2) to more basic in the intestine (pH 5–8); endosome and lysosome are rather acidic (pH 4.5–6.5). pH-triggered DDSs have thus been clinically used in oral drug delivery, and recently widely studied for gene delivery.[58,59] Materials respond to the pH variations undergo mainly two mechanisms. 3.2.1. pH Influences Protonation/Deprotonation Balance Protonation/deprotonation is strongly associated with pH variations (Figure 3) thus

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Figure 3. Protonation–deprotonation equilibrium of a) poly(acrylic acid) and b) chitosan.




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swelling of fibers. Consequently, faster release of the drugs was found from the electrospun scaffold with the increasing of applied electric voltage.

3.4. Light-Sensitive Electrospun Fibers

Figure 4. The hydrolysis of a) acetal and b) hydrazone trigger by acid pH.

the structural deformation of the drug carriers and subsequently speeds up the drug release. In both studies, accelerated release of paracetamol in acidic buffer solutions was observed. Our group has recently reported electrospun nanofibrous poly lactic-co-glycolic acid (PLGA) drug carriers to delivery siRNA in vitro.[20] Enhanced green fluorescence protein (EGFP) gene silencing was chosen as a model system. The pHdependent degradation of the polyester carrier plays an important role in the siRNA delivery. An optimized release profile for prolonged and efficient gene silencing was achieved by a short weak alkaline pretreatment, which modified the degradation profile of PLGA carrier.

3.3. Electric-Field-Responsive Electrospun Fibers Electrical field can trigger redox reactions and in some cases also the process of ionization, which could lead to swelling, shrinking, or bending of the polymeric drug carriers.[65–68] Yun et al. prepared electro-responsive drug carrier by electrospinning of poly(vinyl alcohol)/PAA/multi-walled carbon nanotubes (PVA/PAA/MWCNTs) composites.[69] MWCNTs were used to improve the conductivity of the DDS. As seen in Figure 5, the swelling ratio of the electrospun nanofibers increased with the increasing of electric voltage. This is resulted from the carboxylic acid groups in the polymer were ionized under the applied electric voltages. The ionization of carboxylic acid groups induced the electrostatic repulsion and subsequently led to the

A particularly intriguing possibility is offered by lightresponsive materials allowing remote and accurate operation that can easily be focused into specific areas of therapeutic applications. The photoresponse of these materials is often based on the photoisomerization of constituent molecules that undergoes a large conformational change between two states in response to the absorption of light at two different wavelengths.[70]

3.4.1. Ultraviolet Light Responsive Fibers Typically, trans-cis-isomerization of azobenzene chromophores[71] that gives rise to changes of the dipole moments, polarity, or shape of the molecules has been incorporated into different systems for a wide range of applications.[72–74] These molecules switch from its trans- to cis-form under UV light and switch reversely upon heating or exposing to the light with the wavelength above 400 nm, and thus they have been explored in drug release systems such as micelles and hydrogels.[75–77] Cyclodextrins (CDs) have been extensively studied for over half a century[78] mainly because of their peculiar hosting properties. The truncated cone structure made of glucopyranose units has endowed CDs a unique combination of a hydrophilic outer surface, where the hydroxyl groups are located, and a hydrophobic inner cavity to host various hydrophobic molecules and form water-soluble inclusion complexes (ICs). It is known that azobenzene can efficiently bind to CD in its trans-isomer but not in cis-configuration.[79,80] Based on the unique UV-responsive CD-azo supramolecules, Fu et al.[81] reported a UV-light-triggered drug release system using electrospun nanofibers. The fibers were electrospun from a block copolymer of vinylbenzyl chloride (VBC) and glycidyl methacrylate (GMA) (PVBC-b-PGMA). Azide groups were then introduced on the fiber surfaces to allow further click chemistry with 4-propargyloxyazobenzene (PAB).

Figure 5. a) Effect of electric voltage on the swelling behavior of nanofibers; b) Drug release behavior of nanofibers depending on electric voltage. Reproduced with permission.[69] Copyright 2011, Elsevier.




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Figure 6. a) The synthesis of the CD and 5FU prodrug (R-CD-5FU), and the photoresponsive loading and release of the R-CD-5FU prodrug on the CNFPVBC-b-PGMA-AB surface by host–guest interaction. b) UV response of CD/Azo inclusion complex, R represents 5FU, R′ represents the fiber. c) UV-responsive release profile of the R-CD-5FU prodrug. Reproduced with permission.[81] Copyright 2009, ACS Publications.

Once the fiber surfaces were functionalized with azobenzene groups, 5-Fluorouracil (5FU) conjugated with α-cyclodextrin (α-CD) as an anti-cancer prodrug, was loaded on the fibers by the CD-azobenzene host–guest interaction. As reported, the electrospun nanofibers demonstrated an excellent controlled release of 5FU upon the irradiation of UV light (Figure 6). Upon exposure to UV light, the drugs were released quickly into the solution and reached to the maximum release after 30 min of UV irradiation. Further, the delivery system demonstrated a fast and specific response to the UV stimuli, drug release quickly occurred upon UV irradiation and ceased immediately after stopped exposure. Using this approach, photo-triggered effective and controlled release of a CD prodrug was realized.

3.4.2. Near-Infrared Light Responsive Fibers Considering the quick attenuation of UV in tissues, a suitable alternative light source for biological applications could be nearinfrared (NIR) light, which has a deep penetration depth into tissues and low risk of damage to healthy tissues.[82] NIR lightresponsive materials were usually synthesized by incorporating of photo-sensitive nanostructures that have intense absorptions in the NIR light range.[83–86] In particular, due to the tunable localized surface plasmon resonance (LSPR), gold nanorods (AuNRs) are not only attractive probes for cancer cell imaging, but also nanoscale localized photothermal heat sources.[87] The generated heat can be used to trigger drug release when AuNRs serve as an anticancer-drug carrier. The NIR light-responsive electrospun nanofibers are thus discussed specifically in the application session 4.1 cancer therapy.

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3.5. Multistimuli-Responsive Fibers Zhang et al.[88] prepared temperature and pH dual-responsive poly(methyl methacrylate/N-isopropyl acrylamide/acrylic acid) (P(MMA/NIPAM/AAc)). The fabricated non-woven fibers exhibited reversible and positive temperature controlled release of Rhodamine 610 chloride as a model drug, where faster release was found above LCST. Furthermore, the LCST of the nanofibers could be tuned from 38 to 52 °C by decreasing the ratio of two monomers, NIPAM and MMA, from 7:3 to 5:5. The acrylic acid (AAc) and PAA molecules adjust their conformation due to the protonation/deprotonation equilibrium in aqueous solutions. The obtained nanofibers were found to shrink upon both elevated temperature and decreased pH. The shrinkage pH thresholds could be varied by changing the ratios of NIAPM, MMA, and AAc. At a ratio of 5:10:5 and 4:10:6, the samples shrank at pH 4.4 and 5.6, respectively. The samples at a ratio of 3:10:7 had the shrinkage pH threshold at 6.5, which was very close to the pH value of tumor cells and thus could be used in the targeted treatment of tumors and avoid side effect on the normal tissues.

4. Medical Applications 4.1. Cancer Therapy 4.1.1. pH-Responsive Nanofibers for Cancer Targeted Delivery pH variations within microenvironment of disease-affected tissues have been observed, including tumors, infarctions,




4.1.2. Hyperthermia Nanofibers Augmented with Thermoresponsive Delivery One of the advantages of the electrospun nanofibers scaffold is their resembling with ECM, which intrinsically guide cellular drug uptake. Min et al. reported electrospun poly(N-isopropylacrylamide)-co-polystyrene (PNIPAM-co-PS) nanofibers as biocompatible nanofibers had a synergy of topographic induction to facilitate the cellular accumulation of the anticancer drug daunorubicin inside drug-sensitive and drugresistant leukemia K562 cells.[91] The nanofibers were suggested to affect the activity of P-glycoprotein on the drug-resistant leukemia cell membrane and efficiently prevent the drug efflux from the cells, which provide an approach to improve the efficiency of drug delivery. A hyperthermic condition (up to 42 °C) damages and kills cancer cells, or makes cancer cells more sensitive to the effects of radiation and certain anticancer drugs. The combination of thermoresponsive polymers with a local hyperthermia condition at the solid tumor could be a potential tumor treatment. Both light and magnetic field have been applied as local heat sources. 4.1.2.1. NIR Light as a Heat Source: Combining with thermalsensitive polymers, under NIR light stimulation, AuNR will generate heat and subsequently trigger the volume change transformation of the polymers and result in controlled release of entrapped drugs.[92–94] In this regard, Vyas et al.[95] reported NIR-responsive LCST transitions using electrospun fibrous composites of AuNRs and poly(N-isopropylacrylamide-co-polyethylene glycol acrylate) (PNPA). The obtained material showed controlled release of BSA under the irradiation of NIR light. By combination of the photothermal effect of AuNRs with the thermoresponsibility from PNIPAm, upon NIR exposure, the AuNRs locally heat up PNIPAm, which subsequently experienced an obvious volume decrease and consequently speed up the drug release (Figure 7a–c). After removing NIR exposure, the electrospun nanofibers swelled and drug release deceased immediately (Figure 7d). This study first realized the ability to


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and several other conditions connected with acidosis and alkalosis. Typically, while the pH value of normal tissues and blood is about 7.4, extracellular pH in most tumors is more acidic (pH 5.8–7.2) than normal tissues. The high rate of glycolysis in tumor cells under either aerobic or anaerobic conditions has been considered to be a major reason for the acidity, which may benefit the tumor cells and promote invasiveness (metastasis) by destroying the ECM of the surrounding normal tissues.[89] The use of nanofibrous systems that exhibit acidic pH-mediated structural changes has been suggested to target cancer cell without biological damage to normal cells, as one of the most intriguing examples of disease-responsive drug release systems. Li et al.[90] described the release of an anticancer drug 5-flurouracile from chitosan/PEO elestrospun nanofibrous membranes. The percentage of drug released at pH 5.4 was found higher than that at pH 7.4. This was attributed to the protonation–deprotonation equilibrium of the amine groups in the Chitosan at different pH values.

control drug release from electrospun nanofibers under NIR light stimulation, which holds great clinical promise. 4.1.2.2. Magnetic Hyperthemia: Ferromagnetic or superparamagnetic materials have been used for diagnosis and targeted drug deliver.[96,97] They have also been recognized for pulsatile drug delivery using magnetic field to trigger the mechanical deformation of the drug carriers, and affect the drug release subsequently.[98,99] The motion of the materials is driven and controlled by magnetic field, and the final shape is determined by the balance of the magnetic and elastic interactions. Apart from the magnetic field induced drug carriers deformation, the application of alternating magnetic field can also generate heat and has been recognized for magnetic resonance imaging and hyperthermia cancer therapy. Huang et al.[100] reported an electrospun magnetic hyperthermia nanofiber made of polystyrene and heavily loaded with iron oxide nanoparticles. The magnetic fibers can be repeatedly heated without loss of heating capacity or release of IONPs. Upon functionalization of the fiber surface with collagen, human SKOV-3 ovarian cancer cells attached well to the fibers. Applying an alternating magnetic field during 10 min to the fiber webs killed all fiber-associated cancer cells, showing more efficiency than applying a warm water bath. Combining with thermoresponsive materials, the locally controllable heat will subsequently lead to the conformational change of the drug carrier and controlled release of the drug. A smart hyperthermia nanofiber is described by Kim et al.[99] with simultaneous heat generation and drug release in response to “on–off” switching of alternating magnetic field (AMF) for induction of skin cancer apoptosis (Figure 8). The nanofiber is composed of a chemically crosslinkable temperature-responsive polymer, copolymer of NIPAAm, and N-hydroxymethylacrylamide (HMAAm) (poly(NIPAAm-co-HMAAm)), with an anticancer drug (doxorubicin; DOX) and MNPs. MNPs serve as a source of heat to induces the deswelling of polymer network and trigger drug release, respectively. The 70% of human melanoma cells died in only 5 min application of AMF in the presence of the MNPs and DOX-incorporated nanofibers by double effects of heat and drug.

4.2. HIV Transmission Prevention Ball et al. reported drug-eluting polycaprolactone electrospun fiber mesh for topical drug delivery for human immunodeficiency virus (HIV) prevention. The HIV infection inhibition with physical obstruction of sperm penetration was observed in vitro, which indicates the application may serve as an innovative platform technology for drug delivery to the lower female reproductive tract.[101] A recent feature research by Huang et al.[102] elaborated the potential use of electrospun cellulose acetate phthalate (CAP) fibers to prevent HIV transmission on-demand based on the pH differences between human semen (pH between 7.4 and 8.4) and healthy vaginal flora (pH below 4.5). In their study, electrospun CAP nanofibers were used as the pHresponsive vehicle to delivery anti-viral drugs to prevent HIV. CAP often used as enteric coatings in pharmaceutical industry has a pH-sensitive solubility, which is resistant at acidic fluid, but is dissolved at mild alkaline pHs. The CAP nanofibrous



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Figure 7. a–c) Schematic of proposed release mechanism; d) FITC–BSA cumulative release (µg FITC–BSA per mg polymer). Reproduced with permission.[95] Copyright 2011, IOP Publishing.

mesh can thus be used as vaginal film and be kept stable as long as the environment is acidic, as shown in Figure 9, the drugloaded electrospun CAP fibers adhered on vaginal epithelium, and kept stable in vaginal flora. Once the semen was introduced into the vaginal liquid, the pH increased, leading to the dissolution of CAP and subsequently release of the anti HIV drug.

4.3. Therapeautic Cell Delivery Since bone marrow transplants have been found to be effective, along with some other approved clinical treatments, such as hematopoietic stem cell transplants, cell therapy has been recognized as an important field for the treatment of disease.[103] Especially the potential of stem cells to become and replace almost any of the body’s cells holds the promise of a cure for numerous serious injuries and degenerative diseases.[104] Furthermore, cells either naturally or be programmed to secrete the relevant therapeutic factors that have the capacity to release soluble factors such as cytokines, chemokines, and growth factors, which facilitate angiogenesis, anti-inflammation, and anti-apoptosis.[105] The efficient delivery of the therapeutic cells to the specific disease site is thus desirable. Combining with tissue engineering strategies, cells seeded on a scaffold are delivered in

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a 3D organized manner, which mimics the ECM constructs, which will not only minimize the cellular loss from the traditional injection delivery method, but also improve the integration into the diseased sites. Similar drug delivery concepts are thus applied on the therapeutic cell delivery. Kim et al.[106] recently developed a novel nanofiber enables the facile encapsulation and on-demand release of cells in response to external signals. A copolymer of N-isopropylacrylamide (NIPAAm) with a UV-reactive benzophenone (BP) conjugated co-monomer was synthesized and electrospun into nanofibers. Upon UV crosslinking, the fibers undergo a volume phase transition from a hydrophilic swollen state to a hydrophobic collapsed state when heated to 37 °C. As a consequence, human dermal fibroblasts are squeezed out from the web with excellent viability and proliferation behavior (Figure 10).

5. Conclusions and Perspectives A living system has a complex and accurate regulation system with intelligent sensor-processor-effector components to enable the release of vital bioactive substances on-demand at a specific site and time. Stimuli-responsive polymers mimic biological systems in a crude way where an external stimulus (e.g.,




REVIEWS Figure 8. a) A smart hyperthermia nanofiber system utilizes MNPs and doxorubicin (DOX) dispersed in crosslinked thermoresponsive poly(NIPAAmco-HMAAm) nanofibers. The “on–off” release of DOX was realized by the shrinking-swelling reponse to AMF induced heat. Both the generated heat and released DOX induce apoptosis of cancer cells by hyperthermic and chemotherapeutic effects, respectively. b) “On–off” switchable and reversible heat profile and swelling ratio and DOX release profile. c) In vitro anticancer tests involving human melanoma (COLO 679) cells determined by an MTT assay. The cells were cultured at 37 °C for 2 d. MNPs-nanofiber (red line) or DOX/MNPs-nanofiber (purple line) was then added to the medium and cells were coincubated at 37 °C for another 24 h. AMF was then turned “on” for 5 min to increase the medium temperature to 45 °C at days 3 and 4. Cells were also incubated in the absence of nanofibers with (blue line) and without (black line) free DOX addition at days 3 and 4. Proliferation index = N D/N D = 1, where N D = cell number on day D, N D = 1 = cell number on day 1. Reproduced with permission.[99] Copyright 2013, Wiley-VCH.

change in pH or temperature) results in a change in conformation, solubility, or alternation of the hydrophilic/hydrophobic balance, and consequently release of a bioactive substance. This feature article emphasizes an emerging area using electrospinning technique to generate biomimetic nanofibers as drug delivery devices that are responsive to different stimuli, such as temperature, pH, light, and electric/magnetic field for controlled release of therapeutic substances. Although at its infancy, the mimicry of these stimuli-responsive nanofibers

to the function of the living systems includes both the fibrous structural feature and bio-regulation function as a stimuliresponsive drug depot. Other biological stimuli-responsive systems, such as cellular enzymes in the living systems need to be explored. Kim et al. demonstrated that disulfide bonds could be cleaved by intracellular glutathione (GSH) and the system could be exploited as redox-responsive system for intracellular drug delivery.[107] Disease-specific delivery should also be given

Figure 9. A) Vaginal epithelium covered by a web of electrospun CAP fibers containing the anti-viral drug before contacting with human semen contaminated with HIV. B) Vaginal epithelium covered by a web of electrospun CAP fibers containing the anti-viral drug after contacting with human semen contaminated with HIV. CAP is a cellulose polymer where part of the hydroxyls are esterified with phthalic acid, which is deprotonated and soluble at basic pH. Reproduced with permission.[102] Copyright 2011, Elsevier.




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Figure 10. a) Facile capture and release of cells by using a nanofiber web that transforms from a fibrous to a hydrogel-like structure by wrapping, swelling, and shrinking processes in response to temperature changes. b) Photocrosslinking of poly(NIPAM-BP). c) The percentage of released cells from the web during the heating/cooling processes between 4 and 37.8 °C. This process was repeated for three cycles. d) An MTT assay illustrates the proliferation potential of the released cells after the third cycle (open bar: cells cultured on TCPS, closed bar: released cells from NF webs). Reproduced with permission.[106] Copyright 2012, Wiley-VCH.

special attention. One of the most popular applications of pHsensitive polymers is the fabrication of insulin delivery systems for the treatment of diabetic patients. Delivering insulin strictly requires the right dose at the exact time of need. In a glucose-rich environment, such as the bloodstream after a meal, the oxidation of glucose to gluconic acid catalyzed by glucose oxidase (GluOx) can lower the pH to approximately 5.8. The enzyme glucose oxidase (GluOx) is thus immobilized in different types of pH-sensitive hydrogels for modulated insulin delivery.[108] When the glucose diffuse into the hydrogel, GluOx will oxidize it and lower the pH, which subsequently trigger the pH response of the hydrogel to release the insulin; the release stopped as soon as pH increased. However, there exhibited a lag time in responses; thus nanofibrous hydrogel with ultrahigh surface to volume ratio holds great promise with improved sensitivity. On the other hand, light and magnetic field are especially applicable in the newly emerging area of theranostics, in which diagnostics and therapy are combined into one delivery system, and delivered to the patient in a single, combined dosage form. In this combination, theranostics allows for simultaneous monitoring of disease progression or regression in response to a prescribed therapy. Further work at this direction can apply imaging- based diagnostics to monitor the accumulation of the theranostic substances until significant levels are achieved

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at a known disease site, and then trigger for drug release in response to applied stimuli. All in all, drug release from electrospinning generated nanodelivery systems in response to different stimuli especially diseasespecific signals may be a promising target drug delivery strategy. Further solidification of the evidence for efficacy of the electrospinning method and the resultant stimuli-responsive DDSs requires both in vitro evaluations and in vivo animal studies.

Acknowledgements The authors gratefully acknowledge the Danish Council for Strategic Research for the funding to the ElectroMed Project at the iNANO Center, the Carlsberg Foundation, and the Aarhus University Research Foundation for their financial support. Received: March 26, 2014 Revised: May 6, 2014 Published online:

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