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Controlled Release of the Anti-cancer Drug Paclitaxel from
Bioresorbable Poly(ester-ether-ester) Microspheres
G. D. GUERRA1, M. GAGLIARDI2, N. BARBANI2, C. CRISTALLINI1
1Institute for Biomedical and Composite Materials, U.O.S. of
Pisa; 2Department of Chemical Engineering 1Italian National
Research Council (CNR), 2University of Pisa
1,2Largo Lucio Lazzarino, I-56122 Pisa ITALY
[email protected]
http://www.imcb.cnr.it/home.htm
Abstract: - The release of the anti-cancer drug paclitaxel (PTX)
from microspheres of the bioresorbable
poly(ε-caprolactone-oxyethylene-ε-caprolactone) tri-block copolymer
was studied. The microspheres, both loaded and not with PTX, were
prepared by emulsion-evaporation technique, then characterized by
SEM, AFM, total reflection and spotlight FT-IR spectroscopy, and
DSC. The quantities of PTX released were measured by HPLC. The
results showed a slow and very regular release, which fits very
well the Peppas equation, Mt/M∞ = k · tn, where Mt is the amount of
solute released at the time t, M∞ is the amount of drug released at
the plateau condition, k represents the Peppas kinetic constant and
n the diffusion order. Key-Words: - Poly(ester-ether-ester),
Paclitaxel, Microspheres, Bioresorbable Material, Characterization,
Controlled Release 1 Introduction Poly(ester-ether-ester) tri-block
copolymers have been proposed as bioresorbable materials since many
years [1,2]. The development of the non-catalyzed synthesis of
these copolymers [3-5] allowed to avoid the use, as a catalyst, of
2-ethylhexanoic acid, tin(II) salt, commonly known as stannous
octoate, which was found to be cytotoxic [6]. The copolymers having
poly(ε-caprolactone) chains as the polyester blocks (PCL-POE-PCL)
were tested for cell adhesion and proliferation and cytotoxicity
[7], as well as for cytocompatibility and hemocompatibility [8].
All the copolymers were found to be biocompatible with respect to
the tests carried out. The degradation in vitro of the copolymers
both in the absence and in the presence of cells was also tested
[9], and the degradation product, 6-hydroxyhexanoic acid, were
found to not alter the endothelial metabolism [10], and to modulate
the endothelin release by human umbilical vein endothelial cells,
with no significant alteration of the vasoconstrictor-vasodilator
balance [11]. PCL-POE-PCL was melt-spun to make fibers to be used
as bioresorbable suture threads [12]. Composites of hydroxyapatite
and copolymers with the same monomer composition were prepared both
by direct copolymer synthesis [13] and by blending; the latter
material was employed to make periodontal membranes, which were
successfully tested for the bioresorption in vitro and in vivo
[14]. The release of the anti-cancer drug 5-fluorouracil by thin
sheets of PCL-POE-PCL was also investigated [15]; the dependence of
the release kinetics on the interactions between the copolymers and
the drug was evaluated with ab initio calculations at the
Hartree-Fock and second order Møller-Plesser levels [16]. This
paper regards the use of PCL-POE-PCL for the release of a different
anti-cancer
drug, the
5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one-4,10-diacetate-2-benzoate
13-ester with (2R, 3S)-N-benzoyl-3-phenylisoserine (paclitaxel,
PTX).
Fig.1 Structural formula of paclitaxel. PTX (see Fig.1) is a
diterpenoid first isolated from the bark of the western yew Taxus
brevifolia. It aids the polymerization of tubulin dimers to form
microtubules, which are not only very stable, but also
dysfunctional, leading to cell death; this property makes PTX a
very effective anti-tumor agent [17]. The use of PTX in cancer
therapy gives rise to the problem of its administration to the
patients. Direct intravenous administration was found to have
undesirable side effects on healthy cells [17-20], so that
different PTX administration techniques were needed. Films of
chitosan-poly(vinyl alcohol) blends made by casting, both as such
and cross-linked with glutaraldehyde, released a very scarce
percentage of the PTX initially put into them [21]. Release of PTX
from microspheres of
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biodegradable macromolecular materials was tested successfully
[22-28]. The controlled release of PTX from PCL-POE-PCL
microspheres is now reported. 2 Experimental 2.1 Materials The
PCL-POE-PCL copolymer was the previously synthesized C27 sample
[7], having an ester to ether units 66:34 molar ratio, a central
polyether chain with a mean Mn value of 3.5 × 104, and a total mean
Mn value of 20.37 × 104. PTX (Sorin, Italy) was used as supplied.
2.2 Microspheres Fabrication The PCL-POE-PCL microspheres loaded
with PTX were prepared adding to 5 mL of copolymer solutions 60 g/L
in CH2Cl2 either 15 or 60 mg of PTX, in order to obtain
drug/polymer percentages of 5% and 20% w/w, respec-tively. Each
solution was rapidly poured into 100 mL of 25 g/L solution of
poly(vinyl alcohol) (Aldrich) in a three-neck flask; the two-phases
liquid was stirred at 800 rpm for 2 h, then the so obtained
micro-emulsion was stirred at 250 rpm overnight, keeping the flask
opened to allow CH2Cl2 evaporation. The microspheres were separated
by centrifugation at 14000 rpm, washed tenfold with H2O and
lyophilized. “Placebo microspheres” without PTX were also prepared
by the same procedure. 2.3 Characterization 2.3.1 Microscopy
Scanning Electron Microscopy (SEM) was carried out, using a JEOL
T-300 instrument, on samples coated with 24 carat gold in a vacuum
chamber. Atomic Force Microscopy (AFM) was carried out by means of
an Auto Probe CP apparatus (Park Scientific Instruments), operating
in “non-contact” mode (NC-AFM), to minimize damages of the sample
by the tip. The apparatus was equipped with a probe tip by etched
silicon (2 µm thick silicon Ultralever, spring constant 10-20 N
m-1) and with a 5 µm piezoelectric scanner. The images were
acquired at the rate of 1 scanning line per second. 2.3.2 FT-IR
spectroscopy Total reflection and spotlight Fourier-transform
infrared (FT-IR) spectra and maps were carried out by means of a
Perkin Elmer Spectrum One FT-IR Spectrometer, equipped with a
Perkin Elmer Universal ATR Sampling Accessory and a Perkin Elmer
Spectrum Spotlight 300 FT-IR Imaging System, using the “image” mode
of the instrument. All
spectra were recorded in the mid infrared region (4000–700 cm 1)
at 32 scans/pixel and a spectral resolution of 4 cm 1. 2.3.3
Differential scanning calorimetry Differential scanning calorimetry
(DSC) was carried out in triplicate with a Perkin Elmer DSC7
apparatus, on 5 to 7 mg of both PTX loaded and placebo microspheres
in Al pans, from 40.00 to 240.00°C at 20.00°C per min under N2
flux. 2.3.4 Liquid chromatography High performance liquid
chromatography (HPLC) was carried out using the following
apparatus: a Perkin Elmer 410 LC Pump, an Alltech C8 5U Alltima
column having 4.6 mm diameter and 10 cm length, and a Perkin Elmer
LC 90 UV Spectrophotometric Detector. The moving phase was a 58:42
v/v CH3CN-H2O solution; the flux speed was 1 mL/min; the injected
volume was 100 µL; the detector wavelength was kept at 230 nm; the
PTX retention time was 3.04 min. 2.3.5 PTX release 10 mg of
PLX-loaded microparticles, both containing 5% and 20% in weight of
drug, were weighted and immersed in 5 ml of the delivery medium
composed of a phosphate buffered solution (PBS) at pH 7.4
containing 0.05% (w/v) in sodium dodecyl sulphate (SDS, Sigma®). In
order to avoid the tendency of the microparticles to aggregate,
samples were sonicated after the immersion in the delivery medium.
The use of the SDS surfactant was finalized to increase the
solubility of the PLX in water and also to reproduce a condition
more similar to the in vivo one. Samples were maintained in a
lightly stirred bath at a fixed temperature (37°C ± 1°C) through
all the testing period (34 days). Withdraws from the delivery
medium were carried out at established times and the delivery
solution was replaced by fresh solution after each withdraw, in
order to maintain a sink condition. The sink condition occurs when
the amount of solute delivered is lower than 10-20% or even 30% of
the maximum solubility of the solute in the dissolution medium
[29]. For this reason, the solubility limit of PLX in the delivery
solution at 37°C has to be known. This value was gathered from
literature [30] and used to verify if the sink condition was always
verified. Withdraws from the delivery medium were analyzed using
HPLC at room temperature. The quantities of released PTX calculated
by a previously made calibration curve. The solute delivery
kinetics was studied using two different mathematical models,
expressed by the equations of Peppas (1) and Hopfenberg (2),
respectively [31]:
(1)
(2)
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Mt represents the amount of solute released at the generic time
t, M∞ is the amount of drug released when the system reaches the
plateau condition, k and n represent the Peppas kinetic constant
and the diffusion order respectively, k0 is the Hopfenberg kinetic
constant, c0 is the uniform starting drug concentration, a is the
mean radius of the microparti-cles, m is a “shape factor” and was
assumed to be 3 because of the spherical geometry of the delivery
platform [31]. In the present work, the value of M∞ was considered
equal to M0, considering that polymer used to obtain microparticles
is biodegradable and it ensures that the entire amount of drug
contained in the delivery platform is released at infinite times.
Values of M0 were calculated considering the percentage
encapsulation efficiency (%EE) [32]. Mean values of %EE were found
to be 86.9% (± 1.7%) for samples loaded with 5% in PTX and 82.6% (±
1.3%) for samples loaded with 20%. Using %EE the actual amount of
drug loaded within samples was estimated. Eq. 1 and Eq. 2 are only
valid for the first 60% of the total released drug [33]. Release
orders allowed establishing the regime governing the release
process. In particular, for spherical swellable samples, three
different controlled release mechanisms can be identified [34]: n =
0.43 (Fickian diffusion, concentration gradient-controlled regime),
0.43 < n < 0.85 (anomalous non-Fickian transport) and n =
0.85 (case-II transport, swelling-controlled regime). A not very
different behaviour can be supposed for the rather hydrophilic C27
copolymer. 3 Results and Discussion SEM analysis (Fig.2) showed
microspheres of regular shape, having average diameters ranging
between 1.2 µm and 3.5 µm. No aggregation was observed for each
sample.
Fig.2 SEM image of PCL-POE-PCL microspheres, loaded with 5% PTX.
Fig.3 shows the AFM image of a microsphere with a diameter of about
1.7 µm. The particle appears to have a quite smooth and non-porous
surface. The morphological analysis, carried out by both scanning
electron and atomic
force microscopy, indicates that the technique used is very
suitable for the fabrication of microspheres able to be injected,
in the form of a liquid suspension, into the cancerous tissue, with
the aim to release in situ the anti-cancer drug PTX.
Fig.3 AFM image of a PCL-POE-PCL microsphere, loaded with 5%
PTX. Spotlight FT-IR Chemical Imaging Analysis was used first to
confirm that the microspheres were full solid and not hollow ones.
Indeed, the group of particles shown in Fig.4 has the maximum
absorbance in the central part, owing to the greatest density of
matter present there.
Fig.4 Transmission chemical map of a small group of
microspheres, loaded with 5% PTX. Moreover, spotlight FT-IR gives
useful information about the presence of PTX in the copolymer
structure. The spectrum of the drug (Fig.5) shows the wide
absorption band at 3339 cm-1, due to the stretching of the —NH and
—
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OH groups [35]. The same band is absent from the spectrum of the
pure copolymer, shown in Fig.6.
Fig.5 FT-IR spectrum of pure PTX. The absorption band at 3339
cm-1 is visible in the left region of the spectrum.
Fig.6 FT-IR spectrum of the pure PCL-POE-PCL. No absorption band
is visible at 3339 cm-1. The chemical maps and the correlation
maps, evaluated by generating in real time thousands of spectra,
allow an accurate analysis of the surface. The chemical map, taken
on a 1-mm2 area of grouped microspheres is shown in Fig.7. Fig.8
shows the spectrum taken at a medium point of the chemical map,
having the abscissa of -300 µm and the ordinate of 100 µm in the
map. The presence of the absorption band at 3339 cm-1 is the most
evident sign of the presence of the drug within the microspheres.
The correlation between the chemical map in Fig.7 and the medium
spectrum in Fig. 8 is shown in Fig.9. The presence a high
correlation in the most part of the map is the greatest evidence of
the uniform distribution of the drug within the particles. This
fact is very important for the use of the microspheres as a device
for the controlled release in situ of the anti-cancer drug. Indeed,
the uniform distribution
avoids the risk that the release may depend on the region of the
microparticle, more or less rich in PTX, in contact with the
cancerous tissue.
Fig.7 Chemical map of a group of microspheres loaded with 5%
PTX.
Fig.8 Medium spectrum taken at the signed point of the chemical
map. The DSC traces of pure PTX and of the microspheres are shown
in Fig.10. The DSC trace of the pure PTX shows a single melting
endotherm at 223°C, according to the result of Liggins et al. [36].
Conversely, in the PTX loaded microspheres, no melting peak of the
PTX crystals at the same temperature is visible, indicating that in
the particles the drug is present in an amorphous form rather than
in a crystalline one. Moreover, the melting signal of the loaded
microspheres is split in two peaks, and the main one has its
maximum at a lower temperature than the melting peak of the placebo
microspheres visible in the curve (b), a signal that in the curve
(a) appears only as a weak shoulder; the melting temperature and
enthalpy values calculated from the curves are listed in Table 1.
This fact is correlated to the
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presence of less perfect copolymer crystals in the loaded
microspheres.
Fig.9 Correlation of the map of the microspheres with the medium
spectrum.
Fig.10 DSC traces of pure PTX (upper graph) and of the
microspheres (lower graph), loaded (a) and not loaded (b) with 20%
PTX. Table 1. Melting temperature (Tm) and enthalpy (∆H) values of
the microspheres loaded with PTX (20% w/w) and of the placebo
ones.
Microspheres Tm (°C) ∆H (J/g) PTX-loaded 56.3 66.3
Placebo 60.3 84.9
In Fig.11 the values of Mt/M∞ versus time are reported. From
literature, solubility limit of PTX in the PBS solution containing
SDS was found to be 0.08±0.01 mg/ml at 37°C. Then, the perfect sink
condition is satisfied if the concentration of PTX detected in the
delivery medium is smaller than 2.4·10-3 mg/ml, that represent the
upper limit of 30% in respect of the maximum solubility. This
condition was verified for all tested samples in each withdraw.
Releasing profiles obtained showed that the fraction of drug
released from samples loaded with a smaller amount of PTX was
greater than the fraction eluted from microparti-cles loaded with
20% in PTX. It could be reasonably attributed to greater
interactions established between drug molecules in the samples
loaded with a greater amount of active principle in respect to the
samples loaded with a smaller amount of drug, where drug molecules
are more dispersed in the polymeric matrix. In addition, a
contained burst effect was detected in the first days (< 1% for
microspheres loaded with 20% in PTX and < 1.5% for 5%) and a
linear trend after the first week of test. This behaviour is
desirable in the case of the release of drugs that could show toxic
effects, such as Paclitaxel [37].
Fig.11 Profiles of the PTX released from microparticles loaded
with both 5% (■) and 20% () PTX. Table 2. Kinetic parameters
evaluated using Peppas and Hopfenberg models.
Peppas model Hopfenberg model PTX loaded k (d-n) n k0 (µm/d)
5% 0.012 (± 0.003) 0.523
(± 0.004) 7.30·10-5
(± 1.59·10-5)
20% 0.005 (± 0.002) 0.567
(± 0.011) 1.47·10-4
(± 4.05·10-5) Kinetic parameters of releasing profiles were
evaluated using equations (1) and (2) and obtained results are
summarised in Table 2. For the Peppas model, kinetic constant
decreased with the increase in PTX and it could be attributed to
the slower kinetic release of the drug in the presence of a greater
amount of active principle, according as previously stated.
Concerning drug release orders, values
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are comprised in the range from 0.43 to 0.85, indicating an
anomalous non-Fickian transport mechanism for swellable spheres.
This transport mechanism is typical of polymeric systems not
showing a solute transport controlled by the concentration gradient
nor the macromolecular relaxation rate but the superposition of
both diffusion and relaxation phenomena influence the delivery
kinetics. Concerning the Hopfenberg model, kinetic constants k0
increased with the increase of the starting drug loading.
Fig.12. Comparison between experimental and theoretical data
obtained through the Peppas (upper) and the Hopfenberg (lower)
models for the PTX released from microparticles loaded with both 5%
() and 20% () PTX. In Fig.12 the comparison between the
experimental releasing profiles and theoretical trends evaluated
using kinetic parameters obtained through the theoretical models
are reported. Correlations between data and Peppas equation are
0.989 for samples loaded with 5% and 0.992 for samples loaded with
20 % PTX. From correlation values theoretical models evaluated can
be considered accurate and the Peppas equation can be used to
describe the release behaviour of these systems. On the contrary,
Hopfenberg model is less accurate for the description of releasing
profiles. It could be justified considering that Hopfenberg model
was developed for surface-eroding polymer matrices while copolymer
CL27 could be supposed to undergo a bulk hydration, considering
that its macromolecules contain a fraction (~0.34) of POE that is
highly hydrophilic, and then tend to absorb water within the whole
structure of the microparti cle. However, a further investigation
of the degradation
mechanism is necessary to validate this hypothesis. The
particulate structure of the tested samples seems to overcome one
of the major limits related to the release of drugs from
biodegradable matrices, represented by a delivery kinetics showing
a discontinuous trend. This characteristic was highlighted, for
poly(L-lactide)-block- poly(oxyethylene)-block-poly(L-lactide)
copolymers, in a paper reporting the analysis of tetracycline
release from sintered tablets [38]. In the case of the PTX release
from PCL-POE-PCL microparticles, two distinct release mechanisms
were not shown, likely since the degradation of the C27 is still
very scarce after 35 days of dipping [9], and then only the PTX
extraction by absorbed water occurs; this behaviour offers the
advantage of more controlled delivery kinetics. 4 Conclusion In the
present work a preliminary morphological, chemical and functional
characterization of a micro-particulate delivery platform, obtained
using PCL-POE-PCL copolymer, was reported. Morphological analysis,
carried out by SEM, showed that the obtained particles are
spherical, not aggregated and with a sharp radius distribution. AFM
analysis confirmed these results, giving additional information
about the surface characteristics of the particles, which resulted
smooth and non-porous. Physicochemical analysis, carried out by
FT-IR Chemical Imaging and DSC, confirmed the presence of the PTX
drug within the microparticles, as well as that the drug interferes
with the crystalline structure of the copolymer. Drug delivery
tests showed that the starting drug payload, contained within the
sample, affects the release kinetics; in particular, a faster
release was detected in the samples loaded with the smaller amount
of PTX. However, both systems showed the tendency to release the
drug slowly, and it may portend that the delivery of the overall
amount of PTX occurs with a vey sustained kinetics. It is a
desirable characteristic of anti-mitotic delivery systems, because
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