Nanofibers for drug delivery – incorporation and release of model molecules, influence of molecular weight and polymer structure

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Nanofibers were prepared from polycaprolactone, polylactide and polyvinyl alcohol using Nanospider TM technology. Polyethylene glycols with molecular weights of 2 000, 6 000, 10 000 and 20 000 g/mol, which can be used to moderate the release profile of incorporated pharmacologically active compounds, served as model molecules. They were terminated by aromatic isocyanate and incorporated into the nanofibers. The release of these molecules into an aqueous environment was investigated. The influences of the molecular length and chemical composition of the nanofibers on the release rate and the amount of released polyethylene glycols were evaluated. Longer molecules released faster, as evidenced by a significantly higher amount of released molecules after 72 hours. However, the influence of the chemical composition of nanofibers was even more distinct – the highest amount of polyethylene glycol molecules released from polyvinyl alcohol nanofibers, the lowest amount from polylactide nanofibers.

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# Nanofibers for drug delivery – incorporation and release of model molecules, influence of molecular weight and polymer structure

Jakub Hrib 1, Jakub Sirc *1, Radka Hobzova 1, Zuzana Hampejsova 2, Zuzana Bosakova 2,
Marcela Munzarova 3 and Jiri Michalek 1

Full Research Paper [Open Access](http://www.beilstein-journals.org/bjnano/about/openAccess.htm)

Address:
1The Institute of Macromolecular Chemistry, Academy of Sciences of

the Czech Republic, Heyrovsky Sq. 2, 162 06 Prague 6, Czech
Republic, 2 Department of Analytical Chemistry, Faculty of Science,

Charles University in Prague, Albertov 2030, 128 43 Prague 2, Czech
Republic and 3 Nanovia Ltd., Podkrusnohorska 271, 436 03

Litvinov-Chuderin, Czech Republic

Email:
Jakub Sirc * [- sirc@imc.cas.cz](mailto:sirc@imc.cas.cz)

- Corresponding author

Keywords:

nanofibers; nanofibrous carriers; needle-free electrospinning; release

kinetics

_Beilstein J. Nanotechnol._ 2015, _6,_ 1939–1945.

[doi:10.3762/bjnano.6.198](http://dx.doi.org/10.3762%2Fbjnano.6.198)

Received: 07 May 2015

Accepted: 14 September 2015

Published: 25 September 2015

Associate Editor: K. Koch

License and terms: see end of document.

## Abstract

Nanofibers were prepared from polycaprolactone, polylactide and polyvinyl alcohol using Nanospider TM technology. Polyethylene

glycols with molecular weights of 2 000, 6 000, 10 000 and 20 000 g/mol, which can be used to moderate the release profile of

incorporated pharmacologically active compounds, served as model molecules. They were terminated by aromatic isocyanate and

incorporated into the nanofibers. The release of these molecules into an aqueous environment was investigated. The influences of

the molecular length and chemical composition of the nanofibers on the release rate and the amount of released polyethylene

glycols were evaluated. Longer molecules released faster, as evidenced by a significantly higher amount of released molecules after

72 hours. However, the influence of the chemical composition of nanofibers was even more distinct – the highest amount of poly
ethylene glycol molecules released from polyvinyl alcohol nanofibers, the lowest amount from polylactide nanofibers.

## Introduction

To date, numerous drug delivery systems have been developed,

such as hydrogels that carry drugs or highly sophisticated elec
tronic microchips [1,2]. The required release rates of the thera
peutic agents depend on the medicinal application; for example,

the optimal release time of hormones is in the range of months,

while peroral administration requires that the drug is released as

fast as possible [3]. Nano-shaped materials are advantageous for

the rapid release of the drugs due to their high surface area/

volume ratio.

Due to the internal architecture, nanofibers are well suited for

various medicinal applications, such as carriers for cell cultiva

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tion [4,5], tissue engineering scaffolds [6] or wound dressings

[7]. The incorporation of biologically or pharmacologically

active compounds into the nanofibers may be very useful for

these applications [8].

Although several methods of nanofiber preparation have been

invented [9], electrospinning technique can be considered as a

simple and versatile method for the production of continuous

polymeric nanofibrous mats formed of nano- to micro-sized

fibers [10-14]. Moreover, this fabrication enables to set-up

process parameters for facile control of nanofibrous mat prop
erties such as surface area, fiber diameter, porosity, and

thickness [15].

In the recent years, much effort has been devoted to modifying

the electrospinning process, so coaxial, multi-jet, or side-by
side techniques were developed [16,17]. However, these

techniques are of a little interest in terms of potential mass

production.

In contrast, Nanospider TM technology as an alternative ap
proach based on a needle-free method represents the perspec
tives for industry due to the high production capacity, stability

and easy maintenance [18,19]. This technology is relatively

universal and nanofibrous materials from a variety of polymers

can be obtained. Moreover, adjusting the process parameters

such as the concentration of polymer in solution, electric field

strength, tip-to-collector distance or temperature the materials

enables to control the final structure of the prepared materials

[6,20].

Generally, nanofibers that carry drugs follow several basic

designs – nanofibers with homogenous structures in which the

drug is dispersed throughout the polymer matrix, core–shell

nanofibers for which the matrix carrying the drug is covered by

pure polymer [21,22] and nanofibers with the pharmacologi
cally active compounds immobilized on their surface [16,23].

Nowadays, also more sophisticated structures of nanofibrous

mats are described, such as multilayer constructs [16]. The two

basic fiber designs are the primary factors that affect the diffu
sion mechanism and drug release. For homogenous nanofibers,

the rate of release decreases with time, because the drug must

travel progressively longer distances to diffuse to the fiber

periphery, which requires more time. Contrary, the core–shell

Figure 1: Derivatization reaction scheme of PEG with phenyl isocyanate.

_Beilstein J. Nanotechnol._ 2015, _6,_ 1939–1945.

design provides the delivery system with the diffusion rate of

the therapeutic agent stable throughout the life. The structure of

the nanofibrous drug delivery system plays a key role in the

drug release process. The fiber diameter, specific surface area,

size and total volume of pores significantly influence the

convection and diffusion of the liquid in which the nanofibers

are immersed. Therefore, the drug release is also influenced.

The great advantage of nanofibrous materials is that their struc
ture, i.e., their fiber diameter, density and thickness of the

nanofibrous layer, can be tailored to various requirements by

varying the process parameters [24].

In this work, we designed a nanofibrous carrier in which the

model molecule is dispersed throughout the polymer matrix.

For the purposes to evaluate the influence of molecular size on

the release rate and the total released amount in general, poly
ethylene glycols with molecular weights of 2,000, 6,000, 10,000

and 20,000 g/mol were selected as model molecules. Polyeth
ylene glycol (PEG) is a hydrophilic polyether commercially

available in various molecular weights with narrow distribution.

It is widely used in various medical applications, for example as

surfactant, solvent or tablet excipient. Apart from these applica
tions the PEG has significant effect on the drug release. It has

been shown that addition of PEG molecules is an efficient way

to modify the release of hydrophobic paclitaxel from poly(lactic

acid- _co_ -glycolic acid) matrix [25] or proteins from lipidic

implants [26]. In present work the PEGs were added to the solu
tions of polymers and were incorporated in nanofibers made

from polycaprolactone (PCL), polylactide (PLA) and polyvinyl

alcohol (PVA) during electrospinning. The release behavior of

these molecules into the water environment was investigated

and the results are discussed in terms of molecular weight of

PEGs and chemical composition of nanofibers.

## Results and Discussion

Prior to use, linear PEGs were terminated with phenyl

isocyanate to incorporate spectrophotometrically detectable

groups (Figure 1). The reaction products were confirmed by

NMR, elemental analysis, IR spectroscopy and melting point

measurements.

The needle-free electrospinning process was optimized for each

type of nanofiber with respect to the different physicochemical

properties of polymers. SEM images revealed that the textures

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of all resultant samples were homogenous and free of hetero
geneities or artifacts (Figure 2a–c). It can be expected that the

addition of PEGs will change the physicochemical properties of

_Beilstein J. Nanotechnol._ 2015, _6,_ 1939–1945.

the polymer solution in electrospinning, however, it was not

noticeable in concentration of PEG 3%. The addition of PEG

molecules to the electrospun mixture did not noticeably influ

Figure 2: SEM images of PLA (a, d), PCL (b, e) and PVA (c, f) nanofibers prepared without (a–c) and with (d–f) addition of PEG 20 molecules.

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ence the nanofiber structure. According to the results of

morphological characterization, the nanofibrous structures

remained similar to those of nanofibers without model mole
cules, even for nanofibers that contained PEG 20 (Figure 2d–f).

Clusters or other artifacts were not detected.

The properties and behavior of each polymer during electro
spinning were unique. The process parameters, such as the

polymer mixture composition, voltage, electrode distance,

temperature or humidity, were individually and precisely

adjusted in order to produce structures that were as similar as

possible. However, the morphological characterization revealed

several differences in the parameters of resultant samples

(Table 1). The thinnest fibers with a mean fiber diameter

157 nm were prepared from PVA, and the thickness of PCL

nanofibers (179 nm) was almost similar to this value. PLA

fibers were the thickest, with a diameter of 282 nm. The surface

areas corresponded to the fiber diameters; the surface area was
largest for the thinnest PVA fibers (7.7 m 2 /g) and smallest for
PLA (4.7 m 2 /g). These differences are due to the needle-free

electrospinning method. Needle-free electrospinning does not

allow the fine-tuning of parameters, but the disadvantage of this

method is balanced by the fact that it may allow the large-scale

production. The possible effect of these characteristics is

discussed further below.

Table 1: Morphological characterization of nanofibrous carriers.

fiber diameter (nm) porosity (%) surface area (m 2 /g)

PCL 179 77.4 6.0

PVA 157 78.2 7.7

PLA 282 86.6 4.7

The porosities determined by mercury porosimetry ranged from

77.4% for PCL nanofibers to 86.6% for PLA nanofibers. These

differences may have slightly influenced the release of incorpo
rated molecules. However, the mercury porosimetry measure
ments were conducted in a vacuum. In an aqueous environment,

in which the nanofibers are supposed to be used, the porosity

may differ due to the variable water content between

nanofibers, which is the result of their variable swelling.

The release experiments revealed two trends – the release rate

depends on the molecular weight of model PEGs as well as on

the type of nanofibrous carrier. Although we expected that long

molecules will be anchored in nanofibrous structures and so

more strongly retained, we observed the opposite effect. Larger

molecules were apparently released faster than smaller ones

(see Figure 3). Figure 4 depicts the amount of PEG molecules

released within 72 hours. Except for the amount of PEG 10

_Beilstein J. Nanotechnol._ 2015, _6,_ 1939–1945.

released from PCL nanofibers, which we attribute to random

error, the percentage of PEG that was released positively corre
lated with molecular size. The most distinct increase in the

release rate was observed for PEG 20, whose release was

approximately 30% higher than that of PEG 10. This effect was

attributed to the insufficient interweaving of PEG and chains of

the polymer matrix during the electrospinning process.

Expecting the well interweaving of PEG molecules, their

release is primarily influenced by the dissolution rate and

consequent transport through the material, i.e., the molecules

with lower molecular weight and so higher mobility should

release faster. However, our samples behaved differently. Our

findings suggest that chains of PEG likely form domains that

are separated from nanofibers and these domains accelerate

their release from the material. This effect is more apparent in

longer chains. Shorter chains are more mobile, which allows

them to partially penetrate the nanofibers. In this case, the dis
tance from the surface controls the dissolution rate. The longer

chains of PEG 20 contain parts of molecules which remain near

Figure 3: Release of PEG from PVA nanofibers, PEG 2 (filled
squares), PEG 6 (open squares), PEG 10 (filled circles), PEG 20
(open circles).

Figure 4: Amount of PEG molecules of various molecular weights
released from PCL, PVA and PLA nanofibers immersed to distilled
water within 72 h at 20 °C.

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the surface and are more accessible to water. This effect accel
erates the release of longer PEG chains compared to shorter

ones.

The formation of PEG domains can be also supported by the

formation of a crystalline phase. Larger PEGs are more likely to

crystalize. During the formation of a crystalline phase, the

domains of the crystalline polymer are formed separately from

the remaining system, which makes them more accessible to

water and easier to release.

The release of PEG molecules from PCL, PVA and PLA

nanofibers varied, as evidenced by the amount of released

model molecules after 72 h (Figure 4) compared to the amount

of PEG 2 released from various nanofibers (Figure 5). PEGs of

other molecular weights also followed similar trends. This

effect may be partly due to the varied chemical composition of

nanofibers as well as differences in their morphologies. From a

chemical point of view, the fact that PEGs released fastest from

PVA nanofibers can be explained by the interaction of PVA

with water molecules during immersion – the PVA molecular

structure contains hydroxy groups, which interact with water

molecules at the expense of the interaction with PEG molecules,

which are consequently released faster. The lower polarity of

PCL and PLA and therefore weaker interaction with water

molecules may result in such distinct differences between the

release rates from PVA. The higher amount of released PEG

from PVA brings the question whether it is not related to the

dissolution of the fibers in an aqueous environment. Therefore,

the SEM images of PVA nanofibers after release experiments

were made (Figure 6). No significant changes in structure

compared to starting material are apparent suggesting that the

thermal crosslinking of the PVA fibers during the preparation

ensures sufficient stability of the fibrous structure during the

immersion into the water. Therefore, it can be concluded that

the release kinetics are given by effects discussed above.

Figure 5: Release of PEG 2 from nanofibers prepared from PCL (open
circles), PLA (open squares) and PVA (open triangles).

_Beilstein J. Nanotechnol._ 2015, _6,_ 1939–1945.

Figure 6: SEM image of PVA nanofibers containing PEG 20 after
immersion into the water for 72 h.

Despite attempts to ensure the similar nanofibrous structures,

the varied morphology may be also responsible for the varia
tion in the PEG release rate. The release of model molecules

directly correlated with the specific surface areas and inversely

correlated with the fiber diameters. A higher specific surface

area provides a larger area for interaction with the surrounding

liquid and consequent faster release of drug molecules. A larger

fiber diameter increases the distance that molecules located in

the middle of fiber must diffuse through to reach the periphery

of the material, which prolongs release times. The porosity of

nanofibers did not appear to affect the release rate. A larger

porosity may increase the volume of liquid that surrounds the

fibers and consequently accelerate the release, but this effect

was not observed and may have been suppressed by other

factors, i.e., the degree of hydrophilicity of nanofibers.

The obtained results showed the successful preparation of

morphologically comparable nanofibrous materials with incor
porated PEG molecules. It was demonstrated that combination

of chemically different polymers and PEG of various molecular

weights leads to materials with significantly different release

kinetics of PEGs. These basic findings on relationships between

PEG size and polymer structure on release kinetics were done in

respect that even PEG serves as additive compound it has main

effect on the release of potentially incorporated drug [27,28].

Especially, the addition of PEG has a great impact in systems

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with hydrophobic drugs (e.g., cyclosporine, paclitaxel) in which

it can overcome the complication with homogenous dispersion

of drug in the polymer matrix and mainly can facilitate the

release into aqueous media in which the solubility of such drugs

are very low.

## Conclusion

The release kinetics of polyethylene glycol molecules of various

molecular weights from nanofibers prepared from polycaprolac
tone, polylactide and polyvinyl alcohol were assessed. The

release rate and the total released amount positively correlated

with molecular weight of the incorporated molecules. This trend

was observed for all of the prepared nanofibrous carriers. The

strongest effect appeared for PVA fibers containing hydroxy

functional groups, i.e., 90% of PEG 20 model molecules

released within 72 h. These findings can be applied to develop

nanofibrous drug carriers for the local delivery of hydrophobic

pharmacologically active compounds, because the release of

auxiliary hydrophilic molecules can effectively control the drug

release kinetics.

## Experimental

Reagents
PCL ( _M_ w ≈ 80 kDa) and trifluoroacetic acid were obtained from
Sigma, St. Louis, MO, USA. PVA was provided by Nippon

Gohsei, Osaka, Japan. PLA ( _M_ w ≈ 100 kDa) was kindly
provided as a sample from Natureworks, Blair, NE, USA. Phos
phoric acid (85 wt % aqueous solution), _N_, _N_ -dimethylform
amide, tetrahydrofuran and dichloromethane were obtained

from Penta, Prague, Czech Republic. The deionized water was

produced by Milli-Q Millipore, Bedford, MA. Polypropylene

nonwoven spunbond material used as a substrate for all poly
mers was purchased from ATEX, Milan, Italy. Polyethylene

glycols with molecular weights of 2,000, 6,000, 10,000 and

20,000 were supplied by RAPP Polymere GmbH, Tübingen,

Germany.

Synthesis of derivatized polyethylene glycols

Prior to the derivatization reaction, the PEGs were dried as

follows: the PEGs were dissolved in dry butyl acetate to obtain

10 wt % solutions, 4 Å molecular sieves were added and the

solutions were stirred at room temperature (RT) for 3 days. The

water content was determined using the Karl-Fischer method

and was reduced from ca. 6000 ppm (not dried) to ca. 400 ppm

(dried).

The derivatization reaction scheme is shown in Figure 1. Ten

grams of PEG was dissolved in 80 mL of dry dioxane, and a 5%

excess of the derivatization agent phenyl isocyanate was added.

Dibutyltin dilaurate (500 ppm) was used to increase the reac
tion rate between phenyl isocyanate and the hydroxy groups and

_Beilstein J. Nanotechnol._ 2015, _6,_ 1939–1945.

to ensure the double derivatization of PEGs. The reaction solu
tion was stirred for 7 h. The reaction yield was 89.5%.

Preparation of nanofibers
The nanofibers were prepared with the Nanospider TM tech
nology [21,22]. The process parameters used for each polymer

were optimized in order to produce nanofiber samples of similar
structures and a thickness (weight per unit area) of 5 g/m 2 .

Model PEGs of various molecular weights were added to the

polymer mixtures at a concentration of 3 wt %. PCL was

dissolved in a 1:1 (w/w) mixture of tetrahydrofuran and _N_, _N_
dimethylformamide at a concentration of 10 wt %. The electro
spinning parameters were 6 rpm, 15 cm and 5.5 kV/cm. The

maximum temperature was 30 °C, and the maximum relative

humidity was 35%. PLA was dissolved in a 2:1 (w/w) mixture

of dichlormethane and trifluoroacetic acid at a concentration of

12 wt %. This mixture was held at 22 °C to maintain the

viscosity of this polymer (due to very fast solvent evaporation).

The electrospinning parameters were 4 rpm, 15 cm and

5.3 kV/cm. PVA was dissolved in water/phosphoric acid at a

concentration of 11 wt %. The electrospinning parameters were

2 rpm, 13 cm and 45–55 kV/cm. The relative humidity was

25–30%, and the temperature was 22 °C. The PVA layers were

crosslinked thermally in a drying oven at 145 °C for 15 min to

reach their proper stability [27,28].

Characterization of nanofibers

The structures of the prepared nanofibers were observed with a

scanning electron microscope TS 5130 VEGA, TESCAN,

Czech Republic. The samples were dried at 80 °C under

vacuum overnight and platinum sputtered. Similar preparation

procedure was used for the samples after immersion into the

water for 72 h. The mean fiber diameter was determined from

30 measurements on the SEM images at a magnification of

5000×. Mercury porosimetry measurements were made using an

Autopore IV 9500 porosimeter, Micromeritics, USA, and the

specific surface areas were calculated based on nitrogen absorp
tion/desorption isotherms recorded on an ASAP 2020 apparatus

Micromeritics, USA.

In vitro polyethylene glycol release assay

Samples of nanofibers (0.3 g) were placed into glass vials filled

with 5 mL of distilled water. The samples were continuously

shaken at room temperature for 5 days. At specific time points,

0.5 mL of solution was withdrawn, and the same amount of

fresh water was added. The concentration of PEG was deter
mined based on a calibration curve using a high performance

liquid chromatography apparatus Shimadzu Prominence 20,

USA with UV detection at a wavelength of 234 nm. The accu
mulative weight and relative percentage of the released PEGs

were then calculated. This experiment was conducted for each

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of the above-mentioned nanofibers (PCL, PLA and PVA) and

PEGs of various molecular weights.

## Acknowledgement

The financial support of the Ministry of Education, Youth and

Sports of the Czech Republic (grant No. EE2.3.30.0029), the

Grant Agency of the Czech Republic (grant No. 13-00939S),

the Charles University in Prague (project no. 307115 and

project SVV) and BIOCEV, the European Regional Develop
ment Fund (grant number CZ.1.05/1.1.00/02.0109) is gratefully

acknowledged.

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