Drug delivery using Smart Electrospun Fibers

High surface area of nanofibers, room temperature processing condition and ease of loading drug into the fiber matrix has made electrospinning a popular technique for fabricating drug releasing nanofibrous membrane. To further tailor the capability of electrospun membrane, researchers are looking into ways to make the drug loaded membrane responsive to its environmental stimuli for releasing of its load. Selection of materials for electrospinning is based on a few commonly used environmental triggers such as pH, temperature and light.

Temperature responsive

Most polymers especially thermoplastics are responsive to environmental temperature. This in turn will affect the drug release rate from its matrix. Polymers which exhibit changes at temperature close to human body temperature of 37°C is particularly suited for thermos-responsive drug release. Azarbayjani et al (2010) used a mixture of polyvinyl alcohol and poly(N-isopropylacrylamide) (PNIPAM) to control the release of Levothyroxine [3, 5, 3', 5'-tetraiodothyronine], is a synthetic hormone used for the treatment of hypothyroidism and goiter. PNIPAM is a thermally reversible hydrogel with a lower critical solution temperature of 32°C. This material swells below this temperature and shrinks above it. When the material shrinks, drug release is expected to increase. Tran et al (2015) similarly used a combination of PNIPAM and poly(ε-caprolactone) (PCL) to control the release of ibuprofen from the nanofiber matrix. At temperature of 22°C, PNIPAM nanofibers showed a burst release while it demonstrate a gradual release at temperature of 34°C. Release of ibuprofen from PCL is gradual at either temperature. For a composite material with both PCL and PNIPAM, release of ibuprofen is gradual even at 22°C although its release rate is faster than at 34°C. The presence of PCL effectively suppressed the release of ibuprofen at lower temperature. Li et al (2018) used a blend of poly(N-isopropylacrylamide)-b-poly(L-lactide) (PNLA), and poly(L-lactide) (PLLA) to create a thermo-responsive electrospun fibrous membrane for the release of rifampicin, an anti-microbial drug targeted for surgery. The composite membrane showed a higher drug release rates at 40 °C than at 25 °C. PNLA was formed by co-polymerising PNIPAM and PLLA. The thermo-responsive PNIPAM molecular chain would curl up due to intramolecular hydrogen bonds at higher temperatures and this facilitates drug release. Their study showed that increasing the PNIPAM content in the blend increases the drug release with temperature.

Ibuprofen release profiles from a) PNIPAM NFs containing 50 mg Ibuprofen/g NFs; b) PCL NFs containing 50 mg Ibuprofen/g NFs; c) PNIPAM and PCL composite NFs containing 50 mg Ibuprofen/g PNIPAM NFs. (*standard deviation bars were obtained from the measurements of triple diffusion studies. The level of significance was set at a p value of less than 0.05). [Tran et al. Nano Convergence 2015 2:15 doi:10.1186/s40580-015-0047-5. This work is licensed under a Creative Commons Attribution 4.0 International.]

While thermo-responsive polymers may be used to control drug release in response to environmental temperature, another method is to load the polymer matrix with an agent that heats up when a stimulus is activated. Carbon nanotubes (CNTs) have been shown to be an excellent photothermal agent where it converts near-infrared light (NIR) into heat. Cao et al (2020) constructed an electrospun poly (ε-caprolactone)/gelatin/carbon nanotubes (PGC) fiber for localized therapeutic cancer drug delivery. Photoluminescent mesoporous silica nanoparticles (PLMSNs) were used as the drug delivery vehicle and these were adsorbed onto the surface of electrospun PGC fibers by soaking the fibers in PLMSNs solution. The collected PLMSNs assembled fiber composites (PGC-PLMSNs) were found to have a loading efficiency of almost 20% of PLMSNs particles. Under the application of NIR, the PGC-PLMSNs fiber composites were found to heat up in relation with the intensity of NIR irradiation. As the fiber composites heat up, the release rate of PLMSNs particles increases. Within a 12 h period, PGC-PLMSNs without NIR irradiation released less than 15% of PLMSNs. With NIR irradiation, the release of PLMSNs increases to more than 30%. This may be attributed to the weakening of electrostatic interaction between the PLMSNs and PCG fibrous matrix when the PGC matrix is heated. Therefore, the rate of PLMSNs release may be controlled externally through the application of NIR laser. Zhao et al (2023) electrospun fibers made of polycaprolactone (PCL), silver nanoparticles (AgNPs) and black phosphorus (BP), with PCL being the carrier matrix, AgNPs with antibacterial functionality and photothermal BP. When the PCL/AgNPs/BP fibers were irradiated with 808 nm near infra-red (NIR) laser at 0.8 W cm^-2, the temperature was able to increase to about 41 °C in less than 2 min. With the increase in the temperature, the release rate of drugs is expected to increase concurrently. In the absence of NIR, the release of AgNPs was about 62% in 14 days. With application of NIR and an expected temperature of 41 °C, the release rate increased to 89%.

pH responsive

The pH of the media is also a common stimulus for drug release. Biodegradable pH-sensitive polymers containing ortho ester groups such as D,L-lactide have been shown to increase the drug release rate in acidic media [Qi et al 2008]. Yuan et al (2014) constructed a pH responsive polyL-lactide nanofiber containing sodium bicarbonate (NaHCO₃) for faster release of ibuprofen. Their in vivo study showed that nanofibers containing NaHCO₃ resulted in skin scarless healing compared to drug loaded nanofibers without NaHCO₃. By selecting appropriate material, the electrospun fiber matrix may be tailored to withhold drug release until it is in the right pH environment. This is particularly important in orally taken drug delivery system. For drug taken orally but targeted for release in the colon, the carrier have to go through the acidic environment in the stomach before releasing the drugs in the pH neutral colon environment. To achieve this, Yang et al (2018) produced electrospun core-shell fibers with a shellac she'll to protect the drug loaded polyvinylpyrrolidone (PVP) core. As a material, shellac is soluble in neutral condition but insoluble in acid condition. This makes it a suitable protective barrier during passage through the stomach for drug release in pH neutral colon. In vitro drug release study showed that with shellac coating, only 7% of the drugs were lost at the first 2 h in pH 2 media but released all the drugs in neutral media after 10 mins. Without shellac coating, all the drugs were released immediately in acidic condition.

(a) Photograph of a rat model; (b) implantable electrospun fibrous scaffolds; (c) schematic illustration of acid-responsive electrospun fibers; (d) AR-I-PLLA-EF before releasing; (e) AR-I-PLLA-EF after releasing in pH 5.0; (f) the cumulative release curve of drug. Yuan et al (2014) Mediators of Inflammation 2014; 2014: 858045. This work is licensed under a Creative Commons Attribution 3.0 Unported License.

EUDRAGIT® are synthetic polymers containing ratio ranging from two to three methacrylate monomers, such as methacrylic acid, methacrylic acid esters, and dimethylaminoethyl methacrylate with customized solubility in different pH environments. EUDRAGIT® polymers may be electrospun into fibers with drug loaded for release at targeted organ based on their pH. Further mixing of different EUDRAGIT® polymers may be used to alter the rate and amount of drug release. Vlachou et al (2019) used various EUDRAGIT® and their mixtures for the release of furosemide, a chloride channel blocker generally used as a high-ceiling or loop diuretic. Of the various forms of EUDRAGIT® used, the relative percentage of E100 (poly(butyl methacrylate-co-(2-demethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1) in the electrospun EUDRAGIT® polymer mixture modulated the percentage release of furosemide both at pH 6.8 and 1.2. EUDRAGIT® E100 is acidic pH-dependent. At low pH of 1.2, the presence of E100 increases furosemide release. Conversely, at higher pH of 6.8, higher amount of E100 reduces furosemide release.

To further control the rate of drug release in pH responsive polymer matrix material, Chang et al (2020) constructed dual-core fibers using different Eudragit materials in each of the two cores and the sheath. Paracetamol was used as the active ingredient in the core matrix. For this setup, there were two core chambers surrounded by a sheath wall. The resultant fiber contained two separate cores encapsulated within a single sheath material.

Designs of the complex spinneret for implementing trifluid electrospinning: (a) a digital image showing a full view of the spinneret; (b) front view; (c) side view; and (d) a diagram about the organization of a structural outlet from three inlets [Chang et al 2020].

Eudragits of different molecular weight and response to pH were used as the sheath and core materials. For dual cores and the sheath material, an active ingredient, paracetamol, was added to Eudragits. The resultant electrospun fibers have an average diameter of 660 nm. From their SEM and TEM images, it is possible to see two distinct cores within a single sheath material.

Morphologies and inner structural characteristics of the resultant sheath-separate-core nanofibers: (a) SEM images of the cross-sections, and (b) TEM image of the inner complex nanostructures [Chang et al 2020].

Drug release tests were carried out at three dissolution media with pH values of 2.0, 6.0 and 7.4. The paracetamol was found to release in three different stages depending on the pH and duration. Such release may coincide with the location of the drug release agent. Base on the release profile with respect to pH and time, the release at the three targeted places, stomach, small intestines and colon were 24.4%, 46.7%, and 28.6%, respectively

Photo-responsive

Electrospun polymer may be incorporated with light sensitive additives to initiate changes in response to light. Ramanan et al (2011) constructed a nanofibrous composite of poly(N-isopropylacrylamide-co-polyethylene glycol acrylate) (PNPA) and PEGylated gold nanorods (AuNRs) which significantly increases the release of incorporated proteins when triggered under near infrared red light. AuNRs was able to strongly absorb near infrared red light to generate heat and this triggered a thermal transition in the polymer matrix. With the heat, the PNPA fibers shrink and the resultant expulsion of water causes an increased release of protein that is tenfold that of the composite fibers without stimulus.

Combinations

Smart fiber may be designed to respond to multiple stimuli. Wei et al (2021) used poly(N-isopropyl acrylamide- N-Methylol acrylamide-acrylic acid) (PNIPAm-NMA-Ac) as the material for drug loading and electrospinning into fibrous membranes. The drug release rate from electrospun PNIPAm-NMA-Ac fibrous membrane is dependent on both thermal and pH of the environment. This is because this copolymer is made of poly(N-isopropyl acrylamide) (PNIPAm) which is thermo-responsive, switching between hydrophilic and hydrophobic forms at 32 °C. The other part of the copolymer is poly(acrylic acid) (PAc) which is pH-sensitive and extends and shrinks at pH above and below 4.75 respectively. Two antimicrobial drugs, gatifloxacin hydrochloride (GH) and silver nanoparticles (Ag) were incorporated in the electrospun fibrous membrane. GH is by blending and Ag is by post-spinning reduction of Ag salt which was loaded into the solution prior to electrospinning. At a temperature of 20°C which is below the lower critical solution temperature (LCST) of PNIPAm-NMA-Ac, swelling of the fibers reduced the release of GH and Ag. Maximum release of GH and Ag is at temperature above 37°C or pH 4.0.

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