study of angiogenic gene ointments designed for skin

Developmental Period Medicine, 2013, XVII,311
© IMiD, Wydawnictwo Aluna
PR ACE ORYGI N A L N E / OR I GI N A L A RTI CL ES
Karolina Hajdukiewicz1, Anna Stachurska1, Robert Proczka2, Maciej Małecki1,3
STUDY OF ANGIOGENIC GENE OINTMENTS DESIGNED
FOR SKIN NEOVASCULARIZATION*
BADANIE ANGIOGENNYCH MAŚCI GENOWYCH UŻYTECZNYCH
DO INDUKCJI SKÓRNEJ NEOWASKULARYZACJI
1
Department of Molecular Biology, Medical University of Warsaw, Poland
2
Department of General, Vascular and Oncological Surgery,
Medical University of Warsaw, Warsaw, Poland
3
Institute of Mother and Child, Warsaw, Poland
Abstract
Aim: In this study attention was focused on gene preparations that stimulate angiogenesis in the skin.
Angiogenesis was stimulated by gene preparations encoding angiogenic factors introduced into the
skin by injection, and applied as ointments.
Material and methods: The appropriate angiogenic formulations containing angiogenic nonviral
vectors (pVEGF, pFGF, pSDF, pVIF), or viral vectors (rAAV/VEGF, rAAV/SDF) were prepared for the test.
Cholesterol ointment was used as the vehicle for viral and non-viral vectors. The new vessels in the mouse
skin were counted according to the criteria suggested by Sidky and Auerbach.
Results: Studies indicate that all non-viral (pVEGF, pFGF, pSDF, pVIF) and viral (rAAV/VEGF, rAAV/SDF)
vectors strongly stimulate new vessel formation when administered into mouse skin as injections. The
impact of angiogenic gene ointments for skin angiogenesis was about 3-4 times weaker than that
observed for injection preparations.
Conclusions: Angiogenic injection gene preparations strongly stimulate skin neovascularization.
The clinical usefulness of gene ointments should stimulate further laboratory studies in the field of
experimental skin gene therapy.
Key words: gene ointments, angiogenesis, gene therapy
Streszczenie
Cel: W pracy skupiono uwagę na preparatach genowych stymulujących angiogenezę skórną. Celem
badań była ocena stymulacji angiogenezy skórnej za pomocą proangiogennych preparatów genowych
wprowadzanych do skóry w formie iniekcji oraz zastosowanych w postaci maści.
Materiał i metody: Do badań wykorzystano preparaty genowe niewirusowe oraz wirusowe kodujące
czynniki proangiogenne (VEGF, SDF, FGF). Preparaty DNA lub rAAV wprowadzano w formie iniekcji lub
maści. Za pomocą testu angiogenezy skórnej oceniano stymulację neowaskularyzacji przez zastosowane preparaty.
Wyniki: Badania wskazują, iż wykorzystane iniekcyjne preparaty wektorów niewirusowych (pVEGF,
pFGF, pSDF, pVIF) oraz wirusowych (rAAV/VEGF, rAAV/SDF) silnie stymulują angiogenezę w skórze. Zastosowane maści stymulują angiogenezę w skórze około 3-4x słabiej niż formy iniekcyjne.
Wnioski: Angiogenne iniekcyjne preparaty genowe silnie stymulują proces neowaskularyzacji w skórze.
Kliniczna przydatność angiogennych maści genowych powinna stymulować dalsze badania w zakresie
eksperymentalnej terapii genowej skóry.
Słowa kluczowe: maści genowe, angiogeneza, terapia genowa
DEV. PERIOD MED., 2013, XVII, 1, 3136
*This work was supported by a grant from the Polish Ministry of Science and Higher Education (N N 405 456039).
Karolina Hajdukiewicz i wsp.
32
INTRODUCTION
Searching for gene therapy products that deliver genes
encoding therapeutic proteins in the skin is associated
with extensive progress in methodology that is observed
in the field of gene therapy-related studies, and at the
same time is a consequence of the need to conduct studies
on new medicinal products that can be used directly
in research hospitals specialising e.g. in oncology or
vascular medicine. It is known that the efficiency of
gene therapy directly depends on the type and form of
vectors that determine the efficient delivery of genes into
cells, and are the basis for efficient transgene expression
(1, 2). Lentiviruses and adenoviruses are mainly used in
experimental and clinical studies, mostly due to their high
efficiency of infecting cells and the long-term expression
of the introduced genes (1, 2). It is also known that, in
contrast to non-viral vectors, the viral carriers are less
safe for humans. For example they may cause insertional
mutagenesis and a strong immune response observed in
patients undergoing gene therapy (1, 2). Therefore, the effort
to seek effective and safe non-viral carriers appears to be
understandable. Studies are carried out using liposomes,
nanosomes, poliplexes composed of plasmid DNA and
selected carriers, such as polyethyleneimine, polyethylene
glycols, cellulose derivatives, chitosan (3, 4). Currently,
gene therapy clinical trials are mainly carried out with
injection preparations (5). The treatment of patients
with genes encoding therapeutic protein administered as
injection solutions is an efficient method of transfection
in vivo, but strongly limits their clinical availability. The
use of gene injection formulations for the treatment
of organs directly depends on the clinical skills of the
physician. The use of injectable formulations requires
outpatient visits, and the presence of qualified medical
staff. Moreover, the invasiveness of the injections is
often the cause of discomfort and stress for the patients.
Therefore, searching for non-injection gene therapy
products seems to be reasonable. For external use on
the skin, various forms of ointments, creams, gels, pastes,
powders, solutions, emulsions are used in medical practice
(6). Transdermal administration of drugs may also be
accomplished through transdermal therapeutic systems
(6). The experimental studies associated with ointments
focus on finding a formula that will facilitate gene transfer
across the epidermal barrier. They rely on the use of
absorption activators (e.g. fatty acids, cyclodextrins,
chelating agents), or mechanical methods (e.g. peeling)
(7, 8). Some studies illustrate the use of ointments as
carriers for reporter or therapeutic genes, and siRNA
preparations (9). Interesting results were published by
the team of Asai et al. (10). The authors report an efficient
transfer to the skin of proangiogenic gene – Shh applied
in combination with methylcellulose (10). The study of
Takanashi M. et al. (11) demonstrated, in turn, that the
gene preparations for topical use containing siRNA can
effectively inhibit the development of immunological
diseases, such as rheumatoid arthritis. The authors have
developed GeneCream containing siRNA sequences
silencing the expression of a key gene for the disease –
ostepontin. The work of Nakamura H. et al. (12) noted
that designed gene ointments containing oligonucleotides
against the NF-kB transcription factor can effectively
administer studied sequences to the skin and inhibit the
development of atypical dermatitis. Related results were also
published by Uchida T. et al. (13). The authors administered
anti-RelA siRNA sequences into the skin using peptides.
Recently the possibility of effective administration of
plasmid DNA into the skin with nanoparticles has also
been shown. In the study of Badea I. et al. (14), plasmid
DNA encoding interferon (IFN-γ) was introduced to
the skin of scleroderma animals as nanoparticles. It has
been shown that the increased expression of transgene
IFN-γ reduced collagen synthesis and slowed down the
development of the disease (14). The team of Foldvari M. et
al. (15) reviews the topically applied dermal preparations
indicating the high efficiency of the introduction of
plasmid DNA into the skin by biphasic lipid vesicles
built from nanoscale components, to the delivery of
several therapeutic agents and vaccine antigens.
AIM
In this study attention is focused on gene preparations
that stimulate angiogenesis in the skin. Angiogenesis was
stimulated by gene preparations encoding angiogenic
factors introduced into the skin by injection, and applied
as ointments.
MATERIALS AND METHODS
Gene prepara!ons
The appropriate angiogenic formulations were
prepared for the test in the composition described in
table I. Preparations used in the study were previously
cloned at the Cancer Center in Warsaw by prof. Maciej
Malecki. They were – angiogenic nonviral vectors (pVEGF,
pFGF, pSDF, pVIF c=4.0 mg/ml, 260/280nm λ=1.8) and
viral vectors (rAAV/VEGF, rAAV/SDF, lc=107 vp/ml).
Cholesterol ointment (unquentum cholesteroli, FPVI)
was used as the vehicle for viral and non-viral vectors.
The base ointment was transferred to a porcelain mortar,
then the contents were heated to melt, then cooled slightly.
Subsequently, the appropriate amount of NaCl or viral
or non-viral vector (table I) was added to the surface,
then suspended, and finally the mixture was stirred
with a pestle to achieve a homogeneous consistency.
The formulations were then transferred to a box, signed
and stored for further research. The preparations applied
on the skin were obtained immediately before use (ex
tempore).
In vivo angiogenesis assay
In the work 6-8 week old Balb/c mice (males) were
used. The animals were anesthetized with a 3.6% solution
of chloral hydrate and shaved on both sides. For further
study the animals were divided into three groups (table I):
Group I – control mice, Group II mice tested (injections),
III group – mice tested (ointment). As control injections
an empty vector or 0.9% NaCl solution was used. The
standard cholesterol ointment served as control ointment
formulation – without vectors or with empty vectors. At 72
Study of angiogenic gene ointments designed for skin neovascularization
33
Table I. Formula!ons of gene prepara!ons: injec!on – injectable prepara!on, intradermally administered of 0.125
ml of prepara!on; ointment – ointment prepara!on, 1 ml of prepara!on was applied on about 10 cm2 of
the skin; vp – virus par!cle; C1 – control – plasmid pSEC vector without transgene; C1’ – control – rAAV virus
vector without transgene; C2 – control – 0.9% NaCl solu!on; ung. cholesteroli – cholesterol ointment.
Tabela I. Przygotowanie preparatów genowych: iniekcja – preparat iniekcyjny, śródskórnie podawano 0,125 ml
preparatu; maść – preparat maściowy, 1 ml preparatu nakładano na ok. 10 cm2 skóry; vp – liczba cząstek
wirusowych; C1 – kontrola – wektor plazmidowy pSEC bez transgenu; C1’ – kontrola – wektor wirusowy rAAV
bez transgenu; C2 – kontrola – roztwór 0,9% NaCl; ung. cholesteroli – maść cholesterolowa.
Gene prepara!on formula!ons
Preparat genowy: forma i dawka
Injec!on
Ointment
Iniekcja
Maść
Prepara!on
Preparat
pVEGF
pFGF
pSDF
pVIF
C1
rAAV/VEGF
rAAV/SDF
C1’
C2
10 μg/0.125 ml NaCl
100 μg/1ml NaCl + 2 ml ung. cholesteroli
107vp/0.125 ml NaCl
107vp/1ml NaCl + 2 ml ung. cholesteroli
0.125 ml NaCl
1ml NaCl + 2 ml ung. cholesteroli
hours after administration, the animals were anesthetized
using Morbital preparation. The studied sites of injection
or topical application of angiogenic preparations were
analyzed under the light microscope (32x). The new
vessels were counted according to the criteria suggested
by Sidky and Auerbach (16).
All experiments involved in the project were carried
out in accordance with the principles for the care and
use of research animals and approved by the Local Ethic
Committee for Animal Experiments (Medical University
of Warsaw, No. 27/04/08).
RESULTS
The results of the experiments are shown in tables II,
III and in figure 1. Angiogenic gene preparations were
prepared in order to stimulate angiogenesis in the skin.
Studies indicate that all non-viral (pVEGF, pFGF, pSDF,
pVIF) and viral (rAAV/VEGF, rAAV/SDF) vectors strongly
stimulate new vessel formation when administered into
mouse skin as injections. Three days after administration
of angiogenic genes into the skin, new blood vessels
were visible and countable under the light laboratory
Table II. S!mula!on of skin angiogenesis by non-virus gene prepara!ons. The new vessels were counted three
days a#er gene administra!on. injec!on – gene prepara!ons were injected into the skin; ointment – gene
prepara!ons were applied on the skin; C1 – control – plasmid vector without transgene; C2 – control – 0.9%
NaCl solu!on. Results represent the mean ±SD.
Tabela II. Stymulacja angiogenezy skórnej przez niewirusowe preparaty genowe. Nowe naczynia liczono po 3 dniach
od zastosowania preparatu. Iniekcja – preparat podano do skóry w formie iniekcji; maść – preparat nałożono
na skórę w formie maści; C1 – kontrola – wektor plazmidowy bez transgenu; C2 – kontrola – roztwór 0,9%
NaCl. Tabela podaje wartości średnie ±SD.
Prepara!on
Preparat
pVEGF
pFGF
pSDF
pVIF
C1
C2
The number of blood vessels
Liczba nowych naczyń krwionośnych
Injec!on
Ointment
Iniekcja
Maść
14.1±2.1
4.2±0.6
n=6
n=7
12.5±1.9
3.8±0.4
n=6
n=6
23.1±2.6
7.1±0.9
n=6
n=7
19.3±1.3
5.8±0.4
n=6
n=6
4.1±0.6
2.1±0.3
n=6
n=6
3.7±0.3
1.8±0.2
n=5
n=6
Karolina Hajdukiewicz i wsp.
34
Table III. S!mula!on of skin angiogenesis by virus gene prepara!ons. The new vessels were counted three days a#er
gene administra!on. Injec!on – gene prepara!ons were injected into the skin; ointment – gene prepara!ons
were applied on the skin; C1 – control – virus vector without transgene; C2 – control – 0.9% NaCl solu!on.
Results represent the mean ±SD.
Tabela III. Stymulacja angiogenezy skórnej przez wirusowe preparaty genowe. Nowe naczynia liczono po 3 dniach od
zastosowania preparatu. Iniekcja – preparat podano do skóry w formie iniekcji; maść – preparat nałożono
na skórę w formie maści; C1 – kontrola – wektor wirusowy bez transgenu; C2 – kontrola – roztwór 0,9%
NaCl. Tabela podaje wartości średnie ±SD.
Prepara!on
Preparat
rAAV/VEGF
rAAV/SDF
C1
C2
The number of blood vessels
Liczba nowych naczyń krwionośnych
Injec!on
Iniekcja
35.1±4.1
n=7
31.7±3.6
n=8
4.4±0.6
n=6
3.7±0.3
n=5
Ointment
Maść
6.2±2.8
n=7
7.1±2.9
n=7
3.1±0.8
n=6
1.8±0.2
n=6
preparations, the formulation containing the VEGF gene
appears to be the most effective. It is worth noting that
both the injectable preparations that were used, as well
as the ointment ones, did not cause any adverse events
(swelling, redness of the skin, increased body temperature,
etc., the data not shown) in the animals observed.
DISCUSSION AND CONCLUSIONS
Fig. 1. S!mula!on of skin angiogenesis by virus and non-virus
gene prepara!ons. The new vessels were counted three
days a#er gene administra!on. Injec!on – virus (v)
and non-virus (nv) gene prepara!ons were injected to
the skin; ointment – virus (v) and non-virus (nv) gene
prepara!ons were applied on the skin; Results represent
the mean of all tested angiogenic prepara!ons.
Ryc. 1. Stymulacja angiogenezy skórnej przez niewirusowe
i wirusowe preparaty genowe. Nowe naczynia liczono po 3 dniach od zastosowania preparatu. Rycina
pokazuje wartości średnie stymulacji angiogenezy
przez preparaty niewirusowe i wirusowe zastosowane w formie iniekcji i maści. nv, v iniekcja – preparaty niewirusowe (nv) i wirusowe (v) wprowadzane
do skóry w formie iniekcji; nv, v maść – preparaty
niewirusowe (nv) i wirusowe (v) nakładane na skórę
w formie maści.
microscope. On average, in response to the genes applied,
17 new vessels were formed in response to non-viral
vascular preparations, and 33 in response to viral ones
(fig. 1). The most potent stimulators of angiogenesis were
preparations containing SDF and VEGF genes (table II,
III). Analyzing the impact of ointment preparations for
skin angiogenesis shows much weaker stimulation of
the new blood vessel formation. The average number of
new vessels is approximately 6 (fig. 1), which reflects the
low stimulation. In the ointment group of angiogenic
Gene therapy using preparations stimulating skin
angiogenesis is of great interest among scientists and
doctors. Stimulating the formation of new blood vessels
in the skin makes it possible to develop new treatments
for various diseases dependent on angiogenesis, such
as psoriasis, diabetes, cancer (17). Gene ointments that
stimulate neovascularization are directly useful for patients
suffering from wound healing, bedsores, as well as cosmetic
surgery patients and athletes. In this paper, the activity of
proangiogenic non-viral and viral preparations administered
to animals as injection or ointment preparations were
studied. Preparations encoding proangiogenic factors,
namely VEGF, FGF, and SDF were used in the experiments.
Proangiogenic properties of the studied factors are well
documented (18-19). The articles suggest that VEGF,
FGF, SDF strongly stimulate the formation of new blood
vessels, indicating that the direct effect often depends on
the mobilization of endothelial progenitor cells – EPCs
(21-23) by these proteins. In our previous studies it was
also shown that for example VEGF strongly stimulates
dermal neovascularization, and that the inhibition of
the angiogenic activity of tumor cells by gene constructs
encoding antiangiogenic proteins limits their growth (2426). As shown in tables II, III the gene ointments applied to
the skin stimulate neovascularization, but the angiogenic
effect is much weaker than from injectable formulations.
The studied ointments (fig. 1, table II, III) stimulate skin
angiogenesis about 3-5 times less than the injectable forms
(fig. 1). Difficulties with the introduction of genes to the
skin have commonly been known at least since the early
gene therapy clinical trials. Many researchers reported the
Study of angiogenic gene ointments designed for skin neovascularization
inefficient studies (27). They suggest the existence of some
crucial biological limitations due to gene transfer, such as
the presence of intracellular barriers, specific mechanisms
of pDNA removal from the cells or the size of pDNA
that is too large for sufficient penetration of cell barriers
(27). However, the clinical benefits of the development of
gene ointments are broadly visible to researchers, hence
the experimental studies are continued. In the paper of
Badea I. et al. (14) plasmid DNA encoding interferon
(IFN-γ) was administered to the animal skin in the form
of nanoparticles. The authors demonstrated the inhibition
of collagen synthesis and the reduced development of the
disease (14). The team of Foldvari M. et al. (15) published
results demonstrating the high efficiency of plasmid DNA
introduction into the skin using biphasic lipid vesicles.
Research concerning the clinical usefulness of gene ointments
is also carried out on the basis of short dsRNA due to the
discovery of the RNA interference phenomenon (28).
Takanashi M. et al. (11) have shown, for example, that
formulations containing siRNA inhibit the development
of immune diseases such as rheumatoid arthritis.
Searching for gene therapy preparations that regulate
skin angiogenesis is in most cases experimental procedure
and rarely exceeds the thresholds of vascular, cancer or
cosmetic clinics. The clinical utility of gene ointments,
however, is enormous, forcing the need for further research
in basic science laboratories.
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Authors’ contributions/Wkład Autorów
According to the order of the Authorship/Według kolejności
Conflicts of interest/Konflikt interesu
The Authors declare no conflict of interest.
Autorzy pracy nie zgłaszają konfliktu interesów.
Received/Nadesłano: 08.01.2013 r.
Accepted/Zaakceptowano: 16.01.2013 r.
Published online/Dostępne online
Address for correspondence:
Maciej Małecki
Department of Molecular Biology,
Medical University of Warsaw
Banacha 1, 02-097 Warsaw, Poland
tel. (00 48) 572-07-35
e-mail: [email protected]
Informacja własna
Wcześniaki w Sejmie
W Polsce w 2011 r. urodziło się 390 000 dzieci,
6% z nich urodziło się przed planowanym terminem, ale 1,5% to dzieci, które są największym
wyzwaniem dla neonatologów. Ta bowiem grupa
dzieci obarczona jest największą zachorowalnością i umieralnością. To dzieci z ekstremalnie
małą masą urodzeniową, często nie większą niż
800 gramów. Aby takie dzieci mogły wykorzystać wszystkie swoje możliwości uszczuplone
przez poród przedwczesny i nadrobić, to co się
da nadrobić, muszą mieć specjalną opiekę poszpitalną. My neonatolodzy chcemy stworzyć i
podjąć się koordynacji takiej opieki. Mamy już
wstępną akceptację Ministerstwa Zdrowia i NFZ.
– powiedziała prof. dr hab. med. Ewa Helwich,
Konsultant Krajowy w dziedzinie neonatologii,
podczas posiedzenia Sejmowej Komisji Zdrowia
24 stycznia b.r., gdzie zaprezentowano projekt
programu kompleksowej, specjalistycznej opieki
poszpitalnej nad wcześniakami. Po raz pierwszy
parlamentarzyści zechcieli wysłuchać głosu ekspertów medycznych i rodziców w tej sprawie.
Na posiedzeniu nie zabrakło również „Koalicji
dla wcześniaka”.
Problemy wcześniaków pojawiające się
po wypisie ze szpitala dotyczą głównie układu
oddechowego, zakażeń wirusem RS, deficytów
i dysharmonii funkcji poznawczych i motorycznych. Ale, jak podkreśliła prof. dr hab. med. Maria
Katarzyna Borszewska-Kornacka, Prezes Polskiego
Towarzystwa Neonatologicznego, więcej niż 80%
dzieci z powikłaniami ma szanse nadrobić zaległości. Musimy te problemy pokazać społeczeństwu,
bo doskonale je znają neonatolodzy, pediatrzy,
rodzice wcześniaków, ale społeczeństwo jest bardzo
nieświadome. – powiedziała prof. Maria Katarzyna
Borszewska-Kornacka. Co prawda mamy Narodowy
Program Zdrowia na lata 2007-2015, w którym jest
mowa o poprawie opieki zdrowotnej nad matką,
noworodkiem i małym dzieckiem, ale niewiele się
w ramach niego dzieje. „Koalicja dla wcześniaka”,
powołana w ubiegłym roku, chce to zmienić.
Cele Koalicji to przede wszystkim stworzenie
programu kompleksowej opieki nad dziećmi urodzonymi przedwcześnie i zwiększenie dostępności do
nowoczesnej, wielospecjalistycznej opieki zaraz po
narodzinach i po wyjściu ze szpitala, to także uświadamianie społeczeństwa o problemach wcześniaków,
edukacja rodziców w zakresie stymulacji rozwoju i
rehabilitacji, promocja prawidłowego modelu żywienia
dzieci oraz zapobieganie rozwojowi zakażeń.
Rozwiązanie sytuacji wcześniaków, to nie tylko
stworzenie odpowiedniego programu opieki nad
nimi, ale także zapobieganie porodom przedwczesnym, tak, żeby wcześniaków rodziło się jak najmniej.
Podczas posiedzenia Sejmowej Komisji Zdrowia
mowa była również o konieczności stworzenia
programu opieki nad ciężarną oraz o konieczności
przygotowania do zdrowej prokreacji młodzieży,
zarówno grupy przed inicjacją seksualną, jak i grupy,
która prowadzi regularne życie seksualne. Z badań
wynika, że ich wiedza na temat przyczyn porodów
przedwczesnych jest znikoma. Powinno się stworzyć
program edukacyjny mówiący o możliwościach
eliminowania porodów przedwczesnych poprzez
styl życia, czy zachowania prozdrowotne.
Wiceminister zdrowia Aleksander Sopliński
zaznaczył, że ma nadzieję, że system opieki nad
wcześniakami będzie właściwie zorganizowany,
pieniądze będą wydawane racjonalnie i nastąpi
poprawa w opiece nad noworodkami urodzonymi
przed czasem.