Drug delivery for Cancer Treatment

Drug delivery using electrospun fibers offer several benefits over application from pristine drug. An obvious advantage is electrospun fibers allow localized and sustained delivery to the tumor site. In an in vivo study, dichloroacetate released from electrospun polylactide mats covering solid tumor showed 89% necrosis of the tumor compared to only 51% for oral administration of dichloroacetate [Liu et al 2012]. For some drugs, prolong exposure to the surrounding liquid may cause it to lose its effectiveness. Having the drug loaded in a matrix reduces the exposure and maintains its effectiveness until it is released.

Blending is the most common and simplest method of incorporating drugs into electrospun fibers. The drugs are normally directly mixed into the solution or dissolved in a suitable solvent before mixing with the solution for electrospinning. Small amount of drugs may enhance the electrospinning process as they may contribute to the conductivity of the solution resulting in reduced fiber diameter [Li et al 2013]. However, there is limit on the amount of drugs that can be loaded into the solution without precipitation and adversely affect the quality of the electrospun fibers such as surface unevenness [Li et al 2013] and beads formation [Chen et al 2010]. Drug loading limit for 5-fluorouracil and titanocene dichloride in PLLA is about 10% [Li et al 2013, Chen et al 2010]. Most drug blended fibers demonstrated an initial burst release where most of the drugs are released within the first 24 hours [Li et al 2013]. 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) blended in poly(ethylene glycol)-poly(L-lactic acid) (PEG-PLLA) diblock electrospun fibers releases almost 70% of its load within the first 10 hours [Xu et al 2006]. The same goes for Brefeldin A (BFA) when loaded in the same matrix material [Liu et a 2013]. Not surprisingly, greater percentage of the drugs is released when more drugs are loaded into the fiber matrix. However, there are also drugs in fiber that showed sustained release for more than week. Titanocene dichloride loaded in PLLA through blending showed very slow release rate in PBS. Proteinase K has been blended into the mixture to increase the release rate with most of the release occurring at the first 30 hours [Li et al 2013]. Plant polyphenol loaded in polycaprolactone did not exhibit a distinct burst release but demonstrates a very slow release. This may be due to interaction between ester carbonyl groups of PCL and phenolic hydroxyl groups of plant polyphenol which is strong enough to prevent burst release but sufficiently weak to release the drug upon contact with water [Kim et al 2012].

Although drug loading into electrospun fibers by blending typically demonstrates a burst release profile, this can be controlled by taking advantage of the hydrophobic characteristic of electrospun fibers. Yohe et al (2012a) proposed that as wetting takes place gradually through the porous membrane thickness, drugs loaded into the fibers will be released upon contacting water. Electrospun polycaprolactone (PCL) when doped with 10% poly(glycerol monostearate-co-ε-caprolactone) (PGC-C18) and loaded with with 1 wt.% SN-38 (camptothecin active metabolite) is sufficient to be cytotoxic to human colorectal tumor cell (HT-29) for at least 90 days Yohe et al (2012b). Ramachandran et al (2017) used a mixture of copolymer poly(lactic-glycolic acid) (PLGA) with different lactic to glycolic ratio, polylactic acid (PLA) and PCL to tailor the drug release rate of anti-glioma drug Temozolomide (TMZ) from their composite electrospun fibers. In vivo study using orthotopic brain tumor model of Wistar rats showed the importance of sustained TMZ release in controlling tumor growth and prohibiting tumor recurrence. In electrospun scaffold with complete TMZ release in 7 days, more than 50% of the animal showed tumor recurrence with median survival of only 74 days. However with sustained release over one month, there is long term survival of over 4 months for more than 85% of the animals.

Coaxial Nozzle for electrospinning core-shell fibers from ramé-hart instrument [Sponsored Info]

With suitable modification of the electrospun fibers, the rate of drug release may be controlled by using an external stimulus. 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. Carbon nanotubes (CNTs) have been shown to be an excellent photothermal agent where it converts near-infrared light (NIR) into heat. 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.

Core-shell electrospun fibers have been tested for controlled and tailored drug release. Such structures may be produced using coaxial spinneret. Emulsion electrospinning where water soluble parts are emulsified with "oil" or non-polar solvents for electrospinning has also been shown to be capable of producing core-shell fibers. Using coaxial spinneret, Yan et al (2014) varied the feed ratio between the inner polyvinyl alcohol solution and the outer chitosan solution and showed the reduction in the release of doxorubicin (DOX) from the core when the feed ratio of chitosan solution increases. Chitosan was selectively crosslinked by glutaraldehyde vapor to reduce DOX release rate. Although human ovary cancer cells (SKOV3) seeded on the drug loaded scaffold showed good attachment, proliferation and spreading initially, they start to deteriorate after 8 days which is due to the time dependent drug release from the fibers. Luo et al (2012) used emulsion electrospinning to fabricate core-shell fibers loaded with hydroxycamptothecin (HCPT) at the core. 2-hydroxypropyl-β-cyclodextrin (HPCD) was added for the formation of HPCT/HPCD inclusion complexes and to increase the drug release rate as HCPT is hydrophobic which shows a low initial release of 15%. With HPCD, the initial burst release was increased to 30% followed by constant release of up to 90% over the next twenty days. The polymer matrix, poly(dl-lactic acid)-poly(ethylene glycol) (PELA) was able to restrict exposure of HCPT to the liquid environment and help to retain its activity. In vivo studies demonstrates significantly better inhibitory effect on tumor growth using the drug loaded electrospun fibers compared to free HCPT [Luo et al 2012].

Methods to deliver multiple drugs using electrospun fibers have also been developed to take advantage different effects of each drug. Yang et al (2014) used a combination of blending micelle encapsulated circumin and hydrophilic doxorubicin hydrochloride (Dox) into polyvinyl alcohol (PVA) solution for electrospinning. The resultant fibers showed inhibitory effects on HeLa cells (Cervical cancer cells) which otherwise proliferate well on pure PVA fibers. Chen et al (2014) blended DOX loaded core-shell structured nanoparticles and indomethacin(MC) into a solution of poly(ε-caprolactone) and gelatin before electrospinning to form drug loaded fibrous mat. This mat is implanted on the tumor of rat tumour model. The study showed significant reduction in the tumor size with the multi-drug loaded nanofibrous mat after 18 days but the tumor size increases for rat that is injected with pure DOX and DOX loaded core-shell structured nanoparticles without the nanofiber carrier mat. This shows that the electrospun mat is very effective in localized and targeted delivery of the anti-cancer drugs.

Drug	Delivery Technique	Cancer Target	Reference
Doxorubicin	Core-shell fibers	Ovary cancer cells	Yan et al 2014
Camptothecin active metabolite	Hydrophobic membrane with uniformly dispersed in fiber matrix	Human colorectal tumor cell	Yohe et al 2012b
5-fluorouracil	Blending	Human colorectal cancer	Li et al 2013
Titanocene dichloride	Blending	Human lung tumor cells (spc-a-1 cell line)	Chen et al 2010
Hydroxycamptothecin	Core-shell fibers emulsion electrospnning	Hepatoma H22 cells	Luo et al 2012
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)	Blending	Rat Glioma C6	Xu et al 2006
Brefeldin A	Blending	human liver carcinoma HepG2 cells	Liu et al 2013
Dichloroacetate	Blending	cervical carcinoma	Liu et al 2012
(-)-Epigallocatechin-3-O-gallate (EGCG)	Blending	gastric cancer cell line (MKN28)	Kim et al 2012
Caffeic acid	Blending	gastric cancer cell line (MKN28)	Kim et al 2012

Silencing of Cdk2 and cell death by the Cdk2i scaffold. LIVE/DEAD assay of MCF-7 cells grown on each of the three scaffolds, Control (A, B, C), and those containing plasmid DNA encoding for Cdk2 (Cdk2i, D, E, F) or EGFP (EGFPi, G, H, I) shRNA. A, D, H show living cells (green); B, E, H show dead cells (red); C, F, I represent the overlay of the two corresponding red/green images. Scale bar = 50 µm. [Achille et al 2012. PLoS ONE 7(12): e52356. doi:10.1371/journal.pone.0052356. This work is licensed under a Creative Commons Attribution 2.5 Generic.]

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Content [Biomedical (Cancer)]