Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability
Aim: The article presents the results of developing the composition and technology of obtaining the liposomal form of docetaxel. The effect of the phospholipid composition of the membrane, ionic strength, pH, temperature, cryoprotectant type, and other factors on the stability of liposomes and the d...
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| Date: | 2017 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2017
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| Cite this: | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability / Y.M. Krasnopolsky, А.S. Dudnichenko // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 121-123. — Бібліогр.: 22 назв. — англ. |
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| author | Krasnopolsky, Y.M. Dudnichenko, A.S. |
| author_facet | Krasnopolsky, Y.M. Dudnichenko, A.S. |
| citation_txt | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability / Y.M. Krasnopolsky, А.S. Dudnichenko // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 121-123. — Бібліогр.: 22 назв. — англ. |
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| description | Aim: The article presents the results of developing the composition and technology of obtaining the liposomal form of docetaxel. The effect of the phospholipid composition of the membrane, ionic strength, pH, temperature, cryoprotectant type, and other factors on the stability of liposomes and the docetaxel incorporation has been considered. Results: Reduction of toxicity of the liposomal form of docetaxel (LD₅₀ — 137 ± 7.7 mg/kg) was found in comparison with its free form (LD₅₀ — 101 ± 6.3 mg/kg). Preservation of nanosize particle after lyophilization has been shown. Conclusions: As a result of the studies, the optimal composition and technological scheme for obtaining liposomes containing docetaxel have been developed allowing large-scale production of docetaxel in liposomal form.
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Experimental Oncology ��� �������� ���� ���ne���� �������� ���� ���ne� ���ne� ���
EXPERIMENTAL STUDY OF LIPOSOMAL DOCETAXEL ANALYSIS
OF DOCETAXEL INCORPORATION AND STABILITY
Y.M. Krasnopolsky1, А.S. Dudnichenko2, *
1Department of Biotechnology, Biophysics and Analytical Chemistry of the National Technical University,
“Kharkiv Polytechnick Institute”, Kharkiv 61002, Ukraine
2Department of Oncology and Pediatric Oncology of Kharkiv Medical Academy of Postgraduate Education,
Kharkiv 61176, Ukraine
Aim: The article presents the results of developing the composition and technology of obtaining the liposomal form of docetaxel.
The effect of the phospholipid composition of the membrane, ionic strength, pH, temperature, cryoprotectant type, and other factors
on the stability of liposomes and the docetaxel incorporation has been considered. Results: Reduction of toxicity of the liposomal form
of docetaxel (LD50 — 137 ± 7.7 mg/kg) was found in comparison with its free form (LD50 — 101 ± 6.3 mg/kg). Preservation of nanosize
particle after lyophilization has been shown. Conclusions: As a result of the studies, the optimal composition and technological scheme
for obtaining liposomes containing docetaxel have been developed allowing large-scale production of docetaxel in liposomal form.
Key Words: liposomes, docetaxel, liposomal drugs, toxicity.
The taxanes� in partic�lar docetaxel �Doc�� are
widely �sed as chemotherapy agents for treatment
of breast� ovarian� prostate� stomach� non-small cell
l�ng cancers� sq�amo�s cell carcinoma of the head
and neck. Doc �C4�H5�NO�4� is a semisynthetic dr�g
prod�ced by chemical modification of the s�bstance
extracted from the needles of the E�ropean yew. A wide
spectr�m of antit�mor activity is determined by the
�niq�e mechanism of Doc action. The dr�g facilitates
acc�m�lation of t�b�lin in intracell�lar str�ct�res — mi-
crot�b�les and prevents their breakdown� which leads
to abnormality of mitosis and interphase processes
in t�mor cells [�]. Moreover� Doc exhibits activity against
some cells� prod�cing an excess of P-glycoprotein [�]�
which is encoded by the gene of m�ltidr�g resistance.
Doc is effective for treatment of metastatic cancer
as the second line of chemotherapy for most solid t�-
mors [�]. At present� Doc is intensively st�died in com-
bined chemotherapy with other antit�mor dr�gs incl�d-
ing monoclonal antibodies [4� 5]. At the same time�
Doc is known to ca�se cardiac toxicity� dermatological
toxicity� chronic fatig�e syndrome� m�cositis� allergic
reactions� peripheral ne�ropathy. Also patients treated
with Doc often experience febrile ne�tropenia� which
req�ires �rgent hospitalization [6].
One of the most important trends in modern
pharmace�tical technologies consists in designing
targeted therape�tic systems. Nanosomal carriers
of dr�gs aimed at increasing the target effects as well
as bioavailability of cytotoxic dr�gs are s�ccessf�lly
�sed [���4]. In recent years� there have been reports
of Doc incorporation into nanoparticles of vario�s
polymer carriers� pegylated particles and liposomes
�Lip� of nat�ral and synthesized lipids [��� �����].
Bearing in mind that the bioavailability and stability
of pharmace�tical preparations depends to a great extent
on the sol�bility of the active agent� the aim of o�r st�dy
is to create a sol�ble form of Doc incorporated in Lip. The
report s�mmarizes o�r data on the properties of Lip-Doc
obtained at a different ratio of lipid components forming
nanoparticles. We have analyzed stability of s�ch prepa-
rations� Doc incorporation and their toxicity.
MATERIALS AND METHODS
Lipid substances. We �sed nat�ral phospholi pids
�Ph�: phosphatidylcholines �PC� from egg yolks �Bi-
olek� Kharkiv� Ukraine� or LIPOID E PC S �Lipoid GmbH�
Germany� of �6% p�rity �imp�rities: phosphatidyl eth-
anolamine not more than �NMT� �.�%� Lyso PC NMT
�.�%� sphingomyelin NMT �.�%�; dyphosphatidylg-
lycerol �DPHG� from bovine cardiac m�scle �Biolec�
of ��% p�rity �imp�rities: phosphatidyl ethanolamine
NMT �.5%� PC NMT 6.�%� sphingomyelin and phos-
phatidylserine NMT �%�. The oxidation degree of fatty
acids was determined from the oxidation index val�e
meas�red as a ratio of optical densities at ��5 nm and
��� nm in ethanol. Oxidation index of lipids �sed was:
PC — NMT �.�; DPHG — NMT �.�.
Preparation of Lip. Lip were prepared according
to the technology that we developed earlier [��]. To dis-
trib�te evenly the components of the lipid film� Doc was
dissolved in an organic solvent containing Ph in a certain
ratio and concentration. The solvent was completely
removed on a rotary vac��m evaporator at a tempera-
t�re of �8�4� °C and then the solvent resid�es were
evaporated in a stream of nitrogen. The res�lting thin lipid
film was hydrogenated in an aq�eo�s lactose sol�tion
in a heated bath at a temperat�re of 4��4� °C to obtain
a homogeneo�s s�spension. The res�lting s�spen-
sion was either �ltrasonicated for ����5 min depend-
ing on the temperat�re of the transition phase of the
lipids� or extr�ded thro�gh a two-layer polycarbonate
�.� μm filter to obtain Lip of �niform size. Homogeniza-
tion was also carried o�t by extr�sion on a homogenizer
Submitted: October 02, 2016.
*Correspondence: E-mail: dudas_kharkov@ukr.net
Abbreviations used: Doc — docetaxel; DPHG — dyphosphatidyl-
glycerol; HPLC — high performance liquid chromatography; Lip —
liposomes; PC — phosphatidylcholines; Ph — phospholipids.
Exp Oncol ����
��� �� �������
��� Experimental Oncology ��� �������� ���� ���ne�
Microfl�ids-��� at a preset press�re [��]. The em�lsion
was sterilized by filtration ��.8��.�� μm�� po�red into
vials and freeze-dried followed by filling with an inert
gas. As cryoprotectants� we �sed lactose �or trehalose�
at vario�s ratios Ph:cryoprotectant ��:�� �:�� �:�� �:4�.
The process of Lip s�blimation consists of two stages.
First� we remove free water �p to 8��85%� at a constant
rate of drying �this stage takes 4��5�% of overall time�.
At the second stage� we remove �p to �5��8% of bo�nd
water �those integrated in Lip str�ct�re�. The res�lt-
ing sterile lyophilized Lip-Doc samples were dissolved
in a sterile aq�eo�s solvent. The composition obtained
appeared like a homogeno�s white em�lsion.
Analytical methods. Lip size was meas�red
by photon correlation spectroscopy on nanosizer
Shimadz� SALD-���� �sing a semicond�ctor la-
ser at a wavelength of ��5 nm and a temperat�re
of �� °C. The content of Doc and imp�rities in the samples
of composition was assayed by high performance
liq�id chromatography �HPLC�. The Agilent ���� chro-
matograph was �sed with a chromatographic col�mn
�5� × 4.6 mm filled with Zorbax SB-CIS sorbent with
a particle size of �.5 μm �«Hewlett Packard»�; a mobile
phase was methanol:acetonitrile:water ��6:��:���;
the flow rate was � ml/min; detection at a wavelength
of ��� μm; the detection time �8� min; the col�mn tem-
perat�re was �8 °C. Thin layer chromatography was car-
ried o�t on Sil�fol plates in chloroform:methanol:water
�65:�5:4�. To identify Ph� we �sed standard Ph samples
from «Sigma». The oxidation index was determined
by UV-spectroscopy at two wavelengths: ��� nm and
��5 nm.
Toxicity in vivo. We �sed Balb/c mice weighing
�8��� g. The dr�gs were administered intraveno�sly
twice daily. The signs of toxicity and death of animals
were recorded within the first ho�r after the administra-
tion of the st�dy dr�gs� then at �� 8 and �� ho�rs� and
then for the next �� days with the administration of the
st�dy dr�g. All mice living on the ��th day of the experi-
ment were e�thanized by dislocation of the cervix �nder
anesthesia. To determine the LD5�� Kerber method was
�sed [��]. To achieve greater acc�racy� six doses of the
compositions �nder st�dy �6���6� mg/kg� were admin-
istered spaced by the same interval of �� mg/kg. Six
series of experiments were cond�cted� with three gro�ps
of animals �� mice each. LD��� val�e for each composi-
tion was determined with Taxotere �“Sanofi Aventis”�
being a reference dr�g. LD5� was then calc�lated �sing
the form�la:
LD50 = LD100 — Σ (Z • D)/m,
where Z is the average n�mber of dead animals
in two s�ccessive doses; D is the difference between
two s�ccessive doses �dose interval�; m is the n�mber
of animals in one gro�p. The statistical analysis was car-
ried o�t �sing MS Excel.
RESULTS AND DISCUSSION
Stability of Lip and s�bstance integration into Lip
composition is infl�enced by ionic strength� pH val�e�
temperat�re of technological process� time of every cycle�
press�re� �ltraso�nd intensity� etc. It is important to �se
specified concentration of b�ffer mixt�res� i.e. minimal
salt concentration for b�ffer� allowing to maintain speci-
fied pH val�e. In o�r experiments� pH was shifted to the
acidic range �by adding b�ffer mixt�re� for Doc stabiliza-
tion. Phase behavior of pH bilayer is determined by van
der Waals interactions between neighboring molec�les
of lipids in bilayer� which in t�rn depends on lipids packag-
ing in bilayer and chain length of fatty acid. Ph with longer
“tails” have bigger area of interaction� which leads to the in-
crease of interaction force and th�s to lipid immobilization.
The choice of cryoprotectant� its concentration and
form as well as the time-point of its �se in processing
proced�re are essential factors for preparing Lip-incor-
porated compositions. Early s�pplementation with carbo-
hydrate cryoprotectant �for instance� lactose or trehalose�
may be disadvantageo�s considering Lip size and de-
creased incorporation of active s�bstance. Also we have
de monstrated that the more was amo�nt of s�gar �sed
for nanoparticles protection d�ring lyophilization� the less
was the increase in Lip size after rehydration.
The data on the efficacy of Doc incorporation into Lip
at different ratios of components — membrane-b�ilding
lipids� Doc and cryoprotectant �prior to and after lyophi-
lization� is presented in Table �. At a �:�5 Doc to Ph ratio�
Doc incorporation into Lip amo�nts to 8��8�%. The
increased amo�nt of lipids ��:�8��:��� res�lts in almost
complete Doc incorporation into Lip. Meanwhile� Lip size
in em�lsion samples practically does not depend on Doc
to Ph ratio. More than 85% of nanoparticles were within
the range of �����6� nm. We also noticed q�ite high rate
of Doc incl�sion in lipid bilayer. It is also necessary to take
into acco�nt the possibility direct interaction between
Ph and Doc� which may res�lt in formation of the complex.
Table 1. Characteristics of Lip-Doc samples before and after lyophilization
Doc,
mg
Ph, mg
PC:DPHG
Lac-
tose,
mg
Doc:
Ph
ratio
Doc in-
cor-
pora-
tion into
Lip, %
Lip size,
nm, be-
fore lyo-
philization
Doc
incorpora-
tion into Lip,
%, after lyo-
philization
Lip size,
nm, after
lyophiliza-
tion
20 300
PC:DPHG
270:30
300 1:15 80–87 95–160 80–85 120–180;
300–500
20 350
PC:DPHG
320:30
1050 1:18 > 97 100–160 95–97 120–160
20 400
PC:DPHG
370:30
1600 1:20 > 98 100–150 95–98 100–160
Addition of negatively charged Ph� namely DPHG
into Lip composition may be advantageo�s for Lip
stabilization in processing proced�re as well as �pon
rehydration of the lyophilized prod�ct with an aq�eo�s
solvent. As seen from Table �� Lip size in lyophilized
samples depends on the Doc to Ph ratio and on lipid
s�bstance concentration. At �:�5 Doc to Ph ratio� two
gro�ps of nanoparticles are formed �����8� nm �abo�t
8�%� and ����5�� nm �abo�t ��%�. It is fair to ass�me
that low lipid content of Lip res�lts in the release of a cer-
tain fraction of Doc from nanoparticles at lyophilization
with accompanying formation of Lip with considerably
larger size. Moreover� increase of Ph and cryoprotectant�
Experimental Oncology ��� �������� ���� ���ne���� �������� ���� ���ne� ���ne� ���
in partic�lar� PC and lactose in Lip sample composition�
standardizes and stabilizes lipid particles after their re-
hydration. We have demonstrated that after lyophilization
Lip size of dried samples remained �nchanged.
Using HPLC� we st�died Doc stability after Lip lyo-
philization. We confirmed the identity of q�antitative and
q�alitative composition after drying and conseq�ent rehy-
dration of Lip samples. Imp�rity content and its retention
time do not change� which may reflect Doc stability in the
process of Lip preparation and their s�bseq�ent freeze-
drying; the content of imp�rities in lyophilized sampled did
not exceed �.5%. The res�lts of stability st�dy of Lip Doc
��-year storage below � °C� are given in Table �.
Table 2. Stability of Doc in liposomal form during storage
Characteristics
of the drug*
Particle
size, nm
Doc incor-
poration
into Lip, %
Time of emul-
sion reconsti-
tution, min
рН
Impuri-
ties, %
(HPLC)
The drug after
preparation
100–160 > 95.0 NMT 3 5.45 2.3
The drug after
2 years of storage
110–180 > 90.0 NMT 3 5.38 2.8
Note: * DPHG-Lip at a ratio of Doc:Ph — 1:20.
Therefore� the stability of the liposomal form of Doc
was confirmed with Doc incorporation at the level of not
less than ��% and Lip size of �����8� nm.
The toxicity of Lip samples containing Doc was
compared with that of conventional dosage form of Doc
�pon intraveno�s injection of the compositions �nder
st�dy. We eval�ated LD5� of Lip form of Doc: containing
DPHG �DPHG-Lip� at a �:�� ratio of Doc:Ph �see Table
�� and a Lip form containing only PC �PC-Lip�. Red�c-
tion of toxicity of the liposomal form of Doc �LD5� ��� ±
�.� mg/kg for DPGH-containing Lip� was fo�nd in com-
parison with its free form �LD5� ��� ± 6.� mg/kg� �p < �.��.
We observed identical res�lts �sing liq�id and lyophilized
forms� which proved stability of pharmacological proper-
ties of st�died compositions after lyophilization. Besides�
it was de mon strated that PC increase in composition
res�lted in the increase of n�mber of s�rvived mice while
�sing Lip containing negatively charged lipid DPHG.
To s�m �p� a composition and a technological platform
for creating a liposomal form of Doc have been proposed
and a lyophilized preparation containing Doc� nat�ral
phosphatidylcholine and diphosphatidyl glycerol has been
obtained. As a cryoprotectant� disaccharide lactose was
�sed. The particle size in nanosizes with the incorporation
of Doc into the Lip being at least ��%. The dependence
of LD5� on the composition of the dr�g was st�died. The
stability of the dr�g was demonstrated within � years.
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Copyright © Experimental Oncology, 2017
|
| id | nasplib_isofts_kiev_ua-123456789-137633 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-01T00:27:06Z |
| publishDate | 2017 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Krasnopolsky, Y.M. Dudnichenko, A.S. 2018-06-17T14:23:12Z 2018-06-17T14:23:12Z 2017 Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability / Y.M. Krasnopolsky, А.S. Dudnichenko // Experimental Oncology. — 2017 — Т. 39, № 2. — С. 121-123. — Бібліогр.: 22 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/137633 Aim: The article presents the results of developing the composition and technology of obtaining the liposomal form of docetaxel. The effect of the phospholipid composition of the membrane, ionic strength, pH, temperature, cryoprotectant type, and other factors on the stability of liposomes and the docetaxel incorporation has been considered. Results: Reduction of toxicity of the liposomal form of docetaxel (LD₅₀ — 137 ± 7.7 mg/kg) was found in comparison with its free form (LD₅₀ — 101 ± 6.3 mg/kg). Preservation of nanosize particle after lyophilization has been shown. Conclusions: As a result of the studies, the optimal composition and technological scheme for obtaining liposomes containing docetaxel have been developed allowing large-scale production of docetaxel in liposomal form. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability Article published earlier |
| spellingShingle | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability Krasnopolsky, Y.M. Dudnichenko, A.S. Original contributions |
| title | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability |
| title_full | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability |
| title_fullStr | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability |
| title_full_unstemmed | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability |
| title_short | Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability |
| title_sort | experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/137633 |
| work_keys_str_mv | AT krasnopolskyym experimentalstudyofliposomaldocetaxelanalysisofdocetaxelincorporationandstability AT dudnichenkoas experimentalstudyofliposomaldocetaxelanalysisofdocetaxelincorporationandstability |