Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model
Aim: The new formulation of doxorubicin on the base of phospholipid nanoparticles (particle size <30 nm) is elaborated in the Institute of Biomedical Chemistry (Russian Academy of Medical Sciences) on the base of plant phospholipids. The aim of study is to investigate an antitumor effect of this...
Saved in:
| Published in: | Experimental Oncology |
|---|---|
| Date: | 2012 |
| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Published: |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2012
|
| Subjects: | |
| Online Access: | https://nasplib.isofts.kiev.ua/handle/123456789/139869 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Journal Title: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Cite this: | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model / M.G. Zykova, N.V. Medvedeva, T.I. Torkhovskaya, E.G. Tikhonova, V.N. Prozorovskii, T.S. Zakharova, O.M. Ipatova // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 323-326. — Бібліогр.: 26 назв. — англ. |
Institution
Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859670528371982336 |
|---|---|
| author | Zykova, M.G. Medvedeva, N.V. Torkhovskava, T.I. Tikhonova, E.G. Prozorovskii, V.N. Zakharova, T.S. Ipatova, O.M. |
| author_facet | Zykova, M.G. Medvedeva, N.V. Torkhovskava, T.I. Tikhonova, E.G. Prozorovskii, V.N. Zakharova, T.S. Ipatova, O.M. |
| citation_txt | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model / M.G. Zykova, N.V. Medvedeva, T.I. Torkhovskaya, E.G. Tikhonova, V.N. Prozorovskii, T.S. Zakharova, O.M. Ipatova // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 323-326. — Бібліогр.: 26 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Aim: The new formulation of doxorubicin on the base of phospholipid nanoparticles (particle size <30 nm) is elaborated in the Institute of Biomedical Chemistry (Russian Academy of Medical Sciences) on the base of plant phospholipids. The aim of study is to investigate an antitumor effect of this nanoformulation in mice with two cancer models with various sensitivity to chemotherapy — lymphoid malignancy P-388 and Lewis lung carcinoma (LLC). Methods: Nanophospholipid (NPh) formulation of doxorubicin was prepared by homogenization of soybean phosphatidylcholine and doxorubicin hydrochloride. The effect of this formulation was studied in experiments with single or threefold drug administration. Percents of tumor growth inhibition in mice under influence of free or NPh doxorubicin forms were compared. Results: Single administration of both free and NPh doxorubicin in mice with P-388 resulted in the same quick severe inhibition of tumor growth (60–90% depending from dose), with further gradual decrease of inhibition degree. However for more resistant tumor, LLC, the obvious advantage of NPh doxorubicin form was shown. The little effect of free doxorubicin began to reveal only after 11 days, but NPh formulation induced significant inhibition of tumor growth (40%) from the first experimental point (6 days after administration). The advantages of NPh doxorubicin was manifested particularly in low drug doses, 2 and 4 mg/kg. In other experiment design in mice with LLC, with threefold weekly drug administration, NPh doxorubicin appeared to be 2.5 times more active than free drug. The reason of the same actions of free and NPh doxorubicin form in P-388 is suggested the high drug sensitivity of this model, that gives quick high drug response for any doxorubicin form. Conclusion: Doxorubicin in phospholipids nanoformulation revealed higher antitumor efficiency as compared with free doxorubicin in mice with LLC carcinoma. The mechanism of such changes is supposed to be caused by increase of doxorubicin availability for cancer cells.
|
| first_indexed | 2025-11-30T13:39:34Z |
| format | Article |
| fulltext |
Experimental Oncology ��� �������� ���� ��ecem�er���� �������� ���� ��ecem�er� ��ecem�er� ���
INFLUENCE OF DOXORUBICIN INCLUSION INTO PHOSPHOLIPID
NANOFORMULATION ON ITS ANTITUMOR ACTIVITY IN MICE:
INCREASED EFFICIENCY FOR RESISTANT TUMOR MODEL
M.G. Zykova, N.V. Medvedeva, T.I. Torkhovskaya*, E.G. Tikhonova, V.N. Prozorovskii, T.S. Zakharova,
O.M. Ipatova
Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow 119121, Russia
Aim: The new formulation of doxorubicin on the base of phospholipid nanoparticles (particle size <30 nm) is elaborated in the
Institute of Biomedical Chemistry (Russian Academy of Medical Sciences) on the base of plant phospholipids. The aim of study
is to investigate an antitumor effect of this nanoformulation in mice with two cancer models with various sensitivity to chemo-
therapy — lymphoid malignancy P-388 and Lewis lung carcinoma (LLC). Methods: Nanophospholipid (NPh) formulation of doxo-
rubicin was prepared by homogenization of soybean phosphatidylcholine and doxorubicin hydrochloride. The effect of this formula-
tion was studied in experiments with single or threefold drug administration. Percents of tumor growth inhibition in mice under
influence of free or NPh doxorubicin forms were compared. Results: Single administration of both free and NPh doxorubicin in mice
with P-388 resulted in the same quick severe inhibition of tumor growth (60–90% depending from dose), with further gradual
decrease of inhibition degree. However for more resistant tumor, LLC, the obvious advantage of NPh doxorubicin form was shown.
The little effect of free doxorubicin began to reveal only after 11 days, but NPh formulation induced significant inhibition of tumor
growth (40%) from the first experimental point (6 days after administration). The advantages of NPh doxorubicin was manifested
particularly in low drug doses, 2 and 4 mg/kg. In other experiment design in mice with LLC, with threefold weekly drug administra-
tion, NPh doxorubicin appeared to be 2.5 times more active than free drug. The reason of the same actions of free and NPh doxo-
rubicin form in P-388 is suggested the high drug sensitivity of this model, that gives quick high drug response for any doxorubicin
form. Conclusion: Doxorubicin in phospholipids nanoformulation revealed higher antitumor efficiency as compared with free
doxorubicin in mice with LLC carcinoma. The mechanism of such changes is supposed to be caused by increase of doxorubicin
availability for cancer cells.
Key Words: doxorubicin, phospholipids nanoparticles, P-388, LLC, antitumor action.
Inclusion of drugs into different transport systems
�ased on polymers or lipids� is the modern way to in-
crease their �ioavaila�ility and efficiency [�� �]. For
oncology field such systems are considered to �e par-
ticularly urgent� �ecause they promote the overcoming
of side effects that are relevant to antitumor drugs [�].
Many researches are devoted to developing of new
forms of doxoru�icin — an effective cytostatic� �ut
with severe side effects� particularly cardiotoxicity
[�� 5]. There are some liposomal forms of doxoru�icin
in pharmaceutical market� although they have also
some disadvantages. So� the sta�ilized form of liposo-
mal doxoru�icin �“�oxil”� may reveal some additional
side effects as result of presence of polyethylene gly-
col [�]� and other liposomal form� Myocet �TLC �-99��
is removed rapidly from circulation �y RES �ecause
of relatively large liposome sizes ��5���8� nm� [5].
The new forms of doxoru�icin in polymer-drug conju-
gates on �ase of the �hydroxypropyl�methacrylamide
copolymers �PK�� PK�� are now in clinical trials and
showed the decrease of side effects [�]. In the same
time� the development of new technologies� that gave
the new carrier type — phospholipid nanoparticles [7�
8]� allows to return to phospholipids as to the most
natural su�stances [9] with possi�ility of their usage
as potential carriers for doxoru�icin� �ut yet on new
modern� nanomedicine� level. The use of phospholipid
nanoparticles may give possi�ilities to utilize the ad-
vantages of liposomes as �iocompati�le carriers [9]�
�ut without their weaknesses [�� �� 8].
We have previously shown the increase of antitu-
mor activity of doxoru�icin �y means of its inclusion
into 5���� nm phospholipid nanoparticles� sta�ilized
�y glycyrrhizic acid �the drug Phosphogliv� [��]. Then�
the inclusion of doxoru�icin into other nanophospho-
lipid �NPh� transport system� without other additive
components and with particle size ����� nm� was de-
scri�ed [��]. The em�edding of a num�er of drugs into
such nanoparticles resulted in improvement of their
pharmacokinetics or/and changes of interaction with
�lood components [8]. For doxoru�icin such inclu-
sion decreased drug association with erythrocytes
in incu�ation in vitro with �lood� that increased the part
of availa�le drug in plasma [��]. �rug redistri�ution
from plasma proteins �al�umin� fraction to high density
lipoproteins �H�L� was also shown [��]. It may �e sug-
gested to stimulate doxoru�icin delivery to cancer
cells — through interaction with receptors — SRB� or�
after drug redistri�ution� B�E-receptors� that is known
to �e highly expressed in a num�er of tumors [��� ��]
The aim of this study was to investigate the
antitumor activity of doxoru�icin em�edded in ���
�� nm phospholipid nanoparticles on tumor models.
In order to evaluate possi�le influence of tumor resis-
tance varia�ility on its response to NPh doxoru�icin
formulation� two tumor mice models with known
Received: April 4, 2012.
*Correspondence: E-mail: torti@mail.ru
Abbreviations used: LLC — Lewis lung carcinoma; NPh formulation
(or NPh doxorubicin) — nanophospholipid formulation of doxorubicin.
Exp Oncol ����
��� �� �������
ORIGINAL CONTRIBUTIONS
��� Experimental Oncology ��� �������� ���� ��ecem�er�
different response to chemotherapy were used —
Lewis lung carcinoma �LLC� and lymphoid malignancy
P-�88. The later is known as one of the most sensitive
tumors — fewer than �% of all agents active against
P�88 showed significant effects in other more resis-
tant models [�5� ��]. LLC revealed higher resistance
for a num�er of drugs [�7� �8]. �ifferent responses
of these two models for the same drugs suggested the
necessity to study their responses for new doxoru�icin
nanoformulation — for the more distinct elucidation
of the field of its efficiency.
MATERIALS AND METHODS
NPh formulation of doxoru�icin was prepared ac-
cording to the original technology with homogeniza-
tion� as detailed in the invention [��]. Soy�ean phos-
phatidylcholine Lipoid S��� �Lipoid Gm�H� Germany�
and doxoru�icin hydrochloride ��ian Jiang� Chong
Qing� China� were used. The particle size was not more
than �� nm. The degree of �inding of doxoru�icin with
phospholipid particles was 98% [��]. The medicinal
preparation �oxoru�icin-LANS �“LANS-Pharm”� Rus-
sia� was used as free drug.
Antitumor effects of NPh doxoru�icin were stu-
died on Bal�/c mice weigting ����5 g inoculated
with two tumor strains — LLC and lymphoid leukemia
P-�88 �solid form�� o�tained from N.N. Blokhin Russian
Oncology Center and maintained in the same animals
in P.A. Gertsen Moscow Scientific Oncology Institute.
Tumors were transplanted to mice su�cutaneously: for
P-�88 — ��� tumor cells in �.� ml of �.9% NaCl� for
LLC — �5 mg of tumor tissue in �.� ml of �.9% NaCl.
�oxoru�icin preparations in NPh or free forms
were administered �y single intravenous injections
in the doses of �; �; 8 or �� mg/kg to mice with
P-�88 in �� h after tumor cell inoculation and to mice
with LLC — in �8 h after tumor transplantation. Anti-
tumor efficacy was monitored �y inhi�ition of tumor
growth �% from control� within ����8 days. Experi-
ments with long-term treatment regimen were also
carried out in mice with LLC. Both doxoru�icin prepara-
tions �free or NPh� in dose 5 mg/kg were administered
intraperitoneally weekly — three times� starting � week
after tumor transplantation. Tumor dimensions were
measured on ��nd day after transplantation. The per-
cent of inhi�ition of tumor growth in comparison with
control �untreated� animal group was calculated. Each
group of animals included ����� animals.
The statistical analysis of the o�tained data has
�een carried out using standard Student’s t-criterion.
All experiments were carried out in accordance with
demands of Russia National Bioethic Committee�
on the �ase of “Ethical and law pro�lems of clinical
trials and scientific experiments with human and
animals” �M.� �99��� that corresponds to international
standards of animal welfare.
RESULTS AND DISCUSSION
The effect of doxoru�icin treatment appeared
to �e su�stantially different for two tumor models from
the very �eginning of experiment �Fig. �� a� b�.
0
20
40
60
80
100
4 6 8 10 12 14 16
Days
1
%
2
P- 388
0
10
20
30
40
50
4 8 12 16 20
Days
%
LLC
a
b
Fig. 1. Inhi�ition of tumor growth in mice as compared with
control animals after single administration of free or NPh doxo-
ru�icin forms: a� lymphoid malignancy P-�88 �� — �� mg/kg�
� — � mg/kg �� b� LLC �� mg/kg �. Solid curves — NPh doxoru-
�icin� dashed curves — free doxoru�icin
For P-�88 �Fig. �� a� �oth drug forms induced signifi-
cant inhi�ition of tumor growth in the first experimental
point �5 days after administration� — ����5% at dose
� mg/kg� and 88�9�% at �� mg/kg. The effects of in-
termediate doses� � and 8 mg/kg� were similar �data not
shown�. The use of NPh form did not increase doxoru-
�icin efficiency in this tumor model. It may �e caused
possi�ly �y the fact that the limit of maximal doxoru�icin
effect for this sensitive tumor has �een already reached
quickly in the case of free drug. This assumption is con-
firmed �y the decrease of inhi�ition percent in the next
days — till �����% to ��th days �Fig. �� a�� as result
of possi�ility of quick maximal response of this tumor
model to administered drug [�5� ��].
In contrary� for mice with LLC �Fig. �� b� su�stantial
differences in efficiency of two doxoru�icin forms were
o�served� and effect of NPh doxoru�icin appeared
to �e significantly higher. Free doxoru�icin �� mg/kg�
had any effect within 8�9 days of experiment� and
it was only from ��th day� when a little inhi�ition of tumor
growth �egan ���%�. But NPh doxoru�icin induced sig-
nificant inhi�ition of tumor growth ���%� from the first
experimental time point �� days after administration�.
Unlike to P-�88 tumor �Fig. �� a�� LLC growth inhi�ition
�Fig. �� b� in next experimental days did not decrease�
�ut oppositely — gradually elevated. It testifies that the
�eginning of doxoru�icin effect in LLC reflects gradual
drug accumulation in tumor tissue� and NPh drug form
accelerates this process.
One of the mechanisms of increase of antitumor
activity of NPh doxoru�icin as compared with free
Experimental Oncology ��� �������� ���� ��ecem�er���� �������� ���� ��ecem�er� ��ecem�er� ��5
drug is suggested the a�ility to modulate doxoru�i-
cin delivery in tumor. The quantity of drug in cancer
cells� that is necessary for �eginning of its action�
is reached earlier and at lower doses for doxoru�icin
in phospholipid nanoparticles� than for free drug. But
for the sensitive tumor P-�88 even little drug quantity
is sufficient for the great growth inhi�ition. It is not
excluded� that possi�le differences in response for
NPh doxoru�icin could �e also revealed for this tumor�
�ut at lower drug doses. The mechanism of different
sensitivity of tumor models are suggested to �e as-
sociated with some morphological and/or �iochemi-
cal characteristics [�9���]. For example� there are
data a�out possi�le association of tumor sensitivity
with such factors as activity of cathepsins B� L and ��
causing degradation of cellular matrix [�9]� or vascular
endothelial growth factor [��]� or P-glycoprotein [��]�
or enzyme dihydrodiol dehydrogenase ���H� [�8].
For treatment of LLC the advantage of NPh doxo-
ru�icin form as compared with free doxoru�icin has
�een revealed particularly at low drug doses �� and
� mg/kg�� when the action of free doxoru�icin didn’t yet
manifest itself �Fig. ��. It should �e noted� that such
doses are more close to those used in the clinic
������ mg/m� every � weeks� i. e.� �.���.� mg/kg [���
��]�. Fig. � demonstrates also� that the same extent
of tumor growth inhi�ition �~���5�% after 8 days�
is achieved for NPh doxoru�icin at �.5�� times lower
doses ���� mg/kg�� than for free drug ���8 mg/kg�.
It is important �ecause of known doxoru�icin side
effects [�� 5].
0
20
40
60
80
0 2 4 6 8 10 12
mg/kg
%
Fig. 2. �ependence of tumor growth inhi�ition in mice with LLC
tumor from doxoru�icin doses in free and in NPh forms �8 days
after single administration�. Solid curves — NPh doxoru�icin�
dashed curves — free doxoru�icin
The results for LLC model demonstrated also the
gradual smoothing of distinctions �etween free and
NPh drug forms with increase either of doses �Fig. ��
or of experiment duration �Fig. �� b�. It confirms the
assumption� that the reason of stimulating influence
of phospholipid nanoparticles is their a�ility to modu-
late doxoru�icin accumulation in tumor �y increase
of drug �ioavaila�ility [�� �� ��]. The quantity of drug
in cancer cells� that is necessary for �eginning of its
action is reached earlier and at lower doses for doxoru-
�icin in phospholipid nanoparticles� than for free drug.
Pronounced advantage of NPh form of doxoru�icin
was o�served more nota�ly in other experimental set-
ting — after three times weekly administration of drugs
in the dose of 5 mg/kg to mice with LLC �Ta�le ��. After
treatment with free doxoru�icin the average tumor
volume was 5�9� mm� �compared to �7�� mm� in the
control group�� i. e. growth inhi�ition was only ��%.
But administration of NPh doxoru�icin resulted in more
than �-fold greater effect� causing growth inhi�ition
�y 5�% �tumor volume �9�� mm��.
There are several possi�le mechanisms promoting
doxoru�icin delivery to cancer cells after inclusion
into phospholipids nanoparticles. It may �e related
to its decreased �inding with �lood cells and proteins
and correspondent redistri�ution to lipoproteins� that
we have shown earlier for this doxoru�icin form [��].
As others possi�le contri�uting factors one can as-
sume the penetration of phospholipid nanoparticles
through defects of tumor vessels �EPR effect� [��]�
or the overcoming of multidrug resistance �M�R� �ar-
rier� as it was shown recently for phospholipid-coated
solid lipid nanoparticles �SLN� [�5]. The possi�i lity
of endocytosis of nanoparticles �ecause of their
nanosize [��] may also �e supposed. The positive
influence of phospholipid particles nanosize is con-
firmed �y more pronounced effect of NPh doxoru�icin
in this study ��-fold� Ta�le �� as compared with our
previous results for doxoru�icin in other phospholipid
nanoparticles� with the size of 5���� nm� in the same
experimental conditions �tumor model� dose and treat-
ment scheme� — only ��% [��].
Table. Inhibition of tumor growth in mice with LLC tumor after 3-times week-
ly administration of free doxorubicin or its NPh form
Animals groups Tumor vo-
lume, mm3
Tumor growth
inhibition per-
cent* (%)
1. Control (n = 10) 6713 ± 453 —
2. Administration of free doxorubicin (n = 11) 5390 ± 389 20.0 ± 5.6
3. Administration of NPh doxorubicin (n= 13) 2934 ± 182
P3–2 <0.001
56.1 ± 3.8
P3–2 <0.001
Notes: Doxorubicin preparations were administered intraperitoneally in the
dose of 5 mg/kg weekly — three times, starting 7 days after tumor trans-
plantation. Tumor dimensions were measured on 22nd day after transplan-
tation. * differences are significant as compared with control group values
Thus� treatment with doxoru�icin in nanoformula-
tion of natural phospholipids� o�tained as the ultra-fine
emulsion with a particle size less than �� nm [��]� has
demonstrated in mice with LLC su�stantially higher
antitumor efficiency as compared with free doxoru�i-
cin� despite of a�sence of such effect in more sensitive
tumor model� lymphoid malignancy P-�88. Preferential
effect of NPh doxoru�icin as compared with free drug
in LLC tumor was especially nota�le at low drug doses
and particularly at the regimen of repeated weekly
administrations. The results confirm the necessity
to take into consideration the sensitivity or resistance
of various used tumor models in the ela�oration of new
forms of drug delivery [�5]� and also testify to possi�le
potential prospectivity of NPh form of doxoru�icin for
tumors with poor response to therapy. The treatment
of such tumors may require high doses of cytostatics�
which may �e often impossi�le �ecause of their se-
vere side effects� and in this case replacement of free
doxoru�icin for its NPh form could �e advisa�le.
��� Experimental Oncology ��� �������� ���� ��ecem�er�
ACKNOWLEDGMENTS
We thank P.A. Gertsen Moscow Scientific Oncology
Institute for maintenance of tumor models.
REFERENCES
1. Singh S. Nanomedicine-nanoscale drugs and delivery
systems. J Nanosci Nanotechnol 2010; 10: 7906–18.
2. Arias JL, Clares B, Morales ME, et al. Lipid-based drug
delivery systems for cancer treatment. Curr Drug Targets 2011;
12: 1151–65.
3. Rafati H, Mirzajani F. Experimental design and desir-
ability function approach for development of novel anticancer
nanocarrier delivery systems. Pharmazie 2011; 66: 31–6.
4. You S, Zuo L, Li W. Optimizing the time of Doxil in-
jection to increase the drug retention in transplanted murine
mammary tumors. Int J Nanomedicine 2010; 5: 221–9.
5. Leonard RC, Williams S, Tulpule A, et al. Improving
the therapeutic index of anthracycline chemotherapy: focus
on liposomal doxorubicin (Myocet). Breast 2009; 18: 218–24.
6. Seymour LW, Ferry DR, Anderson D, et al. Hepatic
drug targeting: phase I evaluation of polymer-bound doxoru-
bicin. J Clin Oncol 2002; 20: 1668–76.
7. Zhou XJ, Hu XM, Yi YM, Wan J. Preparation and body
distribution of freeze-dried powder of ursolic acid phospho-
lipid nanoparticles. Drug Dev Ind Pharm 2009; 35: 305–10.
8. Ipatova OM, Prozorovskiy VN, Medvedeva NV, et al.
Phospholipid nanoparticles as carriers for drug delivery. Europ
Congress for Drug Discovery (MipTec) 2010, Basel, abs. 80.
9. Fanciullino R, Ciccolini J. Liposome-encapsulated
anticancer drugs: still waiting for the magic bullet? Curr Med
Chem 2009; 16: 4361–71.
10. Ipatova ОМ, Zykova МG, Torkhovskaya ТI, et al.
Possibility for use of phospholipid nanosystem with glyzir-
rhizic acis (“Phosphogliv”) for optimization of drugs: doxo-
rubicin and budesonide as examples. Biomed Khim 2009;
55: 185–94 (in Russian).
11. Archakov АI, Ipatova ОМ, Medvedeva NV, et al.
Pharmaceutic composition on the base of doxorubicin and
phospholipid nanoparticles for treatment of oncological dis-
eases. RF Patent 2010, № 211935.
12. Zykova МG, Ipatova ОМ, Prozorovskyi VN, et al.
Changes of doxorubicin distribution in blood and plasma after
its inclusion into nanophospholipid formulation. Biochemistry
(Moscow), Suppl. Series B: Biomed Chemistry 2012; 6: 39–41.
13. Ng KK, Lovell JF, Zheng G. Lipoprotein-inspired
nanoparticles for cancer theranostics. Acc Chem Res 2011;
44: 1105–13.
14. Wasan KM, Brocks DR, Lee SD, et al. Impact of li-
poproteins on the biological activity and disposition of hydro-
phobic drugs: implications for drug discovery. Nat Rev Drug
Discov 2008; 7: 84–99.
15. Khleif SN, Curt GA. Animal models in developmental
therapeutics. In: Bast RC, Gansler TS, Holland JF, Frei E
(eds). Cancer Medicine, 5th edn. Hamilton, Ont.; Lewiston,
New York: Decker, 2000: 573–84.
16. Staquet MJ, Byar DP, Green SB, Rozencweig M.
Clinical predicitivity of transplantable tumor systems in the
selection of new drugs for solid tumors: rationale for a three-
stage strategy. Cancer Treat Rep 1983; 67: 753–65.
17. Potebnya GP, Voeykova IM, Lisovenko GS. Antitumor
and antimetastatic activities of vaccine prepared from cisplatin-
resistant Lewis lung carcinoma. Exp Oncol 2009; 31: 226–30.
18. Chen J, Emara N, Solomides C, et al. Resistance
to platinum-based chemotherapy in lung cancer cell lines.
Cancer Chemother Pharmacol 2010; 66: 1103–11.
19. Yasukochi A, Kawakubo T, Nakamura S, Yama-
moto K. Biol Chem 2010; 91: 947–58.
20. Solyanik GE, Pyaskovskaya ON, Garmanchuk LV. In-
crease of level of VEGF production by resistance to cisplatin
Lewis lCathepsin E enhances anticancer activity of doxo-
rubicin on human prostate cancer cells showing resistance
to TRAIL-mediated apoptosis.ung carcinoma. Exp Oncol
2003; 25: 260–5.
21. Sukhanov VA, D’iakov VL, Lalaev VV, et al. The
expression of P-glycoprotein in leukemia P388 cells with
induced doxorubicin resistance. Bull Eksp Biol Med 1991;
111: 290–91 (in Russian).
22. Negoro S, Masuda N, Furuse K, et al. Dose-intensive
chemotherapy in extensive-stage small-cell lung cancer. Can-
cer Chemother Pharmacol 1997; 40: S70-3.
23. Valdivieso M, Burgess MA, Ewer MS, et al. Increased
therapeutic index of weekly doxorubicin in the therapy of non-
small cell lung cancer: a prospective, randomized study. J Clin
Oncol 1984; 2: 207–14.
24. Maeda H. Tumor-selective delivery of macromolecular
drugs via the EPR effect: background and future prospects.
Bioconjug Chem 2010; 21: 797–802.
25. Kang KW, Chun MK, Kim O, et al. Doxorubicin-load-
ed solid lipid nanoparticles to overcome multidrug resistance
in cancer therapy. Nanomedicine 2010; 6: 210–3.
26. Wang SH, Lee CW, Chiou A, Wei PK. Size-dependent
endocytosis of gold nanoparticles studied by three-dimensional
mapping of plasmonic scattering images. J Nanobiotechnol-
ogy 2010; 8: 33.
Copyright © Experimental Oncology, 2012
|
| id | nasplib_isofts_kiev_ua-123456789-139869 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-11-30T13:39:34Z |
| publishDate | 2012 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Zykova, M.G. Medvedeva, N.V. Torkhovskava, T.I. Tikhonova, E.G. Prozorovskii, V.N. Zakharova, T.S. Ipatova, O.M. 2018-06-21T12:47:44Z 2018-06-21T12:47:44Z 2012 Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model / M.G. Zykova, N.V. Medvedeva, T.I. Torkhovskaya, E.G. Tikhonova, V.N. Prozorovskii, T.S. Zakharova, O.M. Ipatova // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 323-326. — Бібліогр.: 26 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/139869 Aim: The new formulation of doxorubicin on the base of phospholipid nanoparticles (particle size <30 nm) is elaborated in the Institute of Biomedical Chemistry (Russian Academy of Medical Sciences) on the base of plant phospholipids. The aim of study is to investigate an antitumor effect of this nanoformulation in mice with two cancer models with various sensitivity to chemotherapy — lymphoid malignancy P-388 and Lewis lung carcinoma (LLC). Methods: Nanophospholipid (NPh) formulation of doxorubicin was prepared by homogenization of soybean phosphatidylcholine and doxorubicin hydrochloride. The effect of this formulation was studied in experiments with single or threefold drug administration. Percents of tumor growth inhibition in mice under influence of free or NPh doxorubicin forms were compared. Results: Single administration of both free and NPh doxorubicin in mice with P-388 resulted in the same quick severe inhibition of tumor growth (60–90% depending from dose), with further gradual decrease of inhibition degree. However for more resistant tumor, LLC, the obvious advantage of NPh doxorubicin form was shown. The little effect of free doxorubicin began to reveal only after 11 days, but NPh formulation induced significant inhibition of tumor growth (40%) from the first experimental point (6 days after administration). The advantages of NPh doxorubicin was manifested particularly in low drug doses, 2 and 4 mg/kg. In other experiment design in mice with LLC, with threefold weekly drug administration, NPh doxorubicin appeared to be 2.5 times more active than free drug. The reason of the same actions of free and NPh doxorubicin form in P-388 is suggested the high drug sensitivity of this model, that gives quick high drug response for any doxorubicin form. Conclusion: Doxorubicin in phospholipids nanoformulation revealed higher antitumor efficiency as compared with free doxorubicin in mice with LLC carcinoma. The mechanism of such changes is supposed to be caused by increase of doxorubicin availability for cancer cells. We thank P.A. Gertsen Moscow Scientific Oncology Institute for maintenance of tumor models. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model Article published earlier |
| spellingShingle | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model Zykova, M.G. Medvedeva, N.V. Torkhovskava, T.I. Tikhonova, E.G. Prozorovskii, V.N. Zakharova, T.S. Ipatova, O.M. Original contributions |
| title | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model |
| title_full | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model |
| title_fullStr | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model |
| title_full_unstemmed | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model |
| title_short | Influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model |
| title_sort | influence of doxorubicin inclusion into phospholipid nanoformulation on its antitumor activity in mice: increased efficiency for resistant tumor model |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/139869 |
| work_keys_str_mv | AT zykovamg influenceofdoxorubicininclusionintophospholipidnanoformulationonitsantitumoractivityinmiceincreasedefficiencyforresistanttumormodel AT medvedevanv influenceofdoxorubicininclusionintophospholipidnanoformulationonitsantitumoractivityinmiceincreasedefficiencyforresistanttumormodel AT torkhovskavati influenceofdoxorubicininclusionintophospholipidnanoformulationonitsantitumoractivityinmiceincreasedefficiencyforresistanttumormodel AT tikhonovaeg influenceofdoxorubicininclusionintophospholipidnanoformulationonitsantitumoractivityinmiceincreasedefficiencyforresistanttumormodel AT prozorovskiivn influenceofdoxorubicininclusionintophospholipidnanoformulationonitsantitumoractivityinmiceincreasedefficiencyforresistanttumormodel AT zakharovats influenceofdoxorubicininclusionintophospholipidnanoformulationonitsantitumoractivityinmiceincreasedefficiencyforresistanttumormodel AT ipatovaom influenceofdoxorubicininclusionintophospholipidnanoformulationonitsantitumoractivityinmiceincreasedefficiencyforresistanttumormodel |