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VITAMIN E AND SOLID LIPID NANOPARTICLES (SLNS):
PARTNERS IN DIABETIC WOUND HEALING.
VITAMINA
E E NANOPARTÍCULAS LIPÍDICAS SÓLIDAS (NLSS): PARCEIRAS NA CICATRIZAÇÃO DA FERIDA DIA=
BÉTICA
Ana
Flávia Marçal Pessoa * Bruna
Karla do Amaral * =
span> Maria da Conceição
Baldini Benevides Blanck * Silvia Sousa da Silva * Adelso
Aparecido Pedrosa *
* José
Pinhata Otoch
=
p>
ABSTRACT
Diabetic foot affects 4 to 10% of diabetic patients
per year and has a high rate of amputation and mortality (39-80%). Diabetes
Mellitus (DM) is among the chronic diseases that increase reactive oxygen
species (ROSs) production via glucose oxidation. The use of antioxidants
associated with solid lipid nanocarriers (SLNs) is a promising tool for
treating poor diabetic healing. This literature review aims to present the
impaired diabetic wound healing pathophysiological mechanism and how vitami=
n E
acts to prevent and treat diabetic wounds. Vitamin E-encapsulated SLNs could
accelerate the healing process.
Keywords:=
span> Diabetes; Wound; Vitamin E; Solid Lipid Nanocarri=
ers
(SLN); Oxidative Stress.
=
RESUMO
O pé diabético acomete de 4 a 10% dos pacientes diabéticos por ano, e
apresenta um alto índice de amputação e mortalidade (39-80%). O
diabetes mellius (DM) está dentre as doenças cr=
ônicas
que aumentam a geração das espécies moleculares reativas de oxigênio (EROs ) pela oxidação da glicose. O uso de antioxidantes
associados a nanocarreadores lipídicos é uma
ferramenta promissora no tratamento da cicatrização diabética deficiente. <=
/span>O
objetivo dessa revisão de literatura é apresentar o mecanismo fisiopatológi=
co
da cicatrização diabética deficiente, e como a vitamina E atua na prevenção=
e
tratamento da ferida diabética, assim como os nanocarr=
eadores
lipídicos sólidos (NLS) associados a vitamina E podem auxiliar acelerando o
processo de cicatrização deficiente da ferida diabética.
Palavras-chave: Diabetes; Ferida; Vitamina E; N=
anocarreadores
Lipídicos Sólidos (NLS); Estresse Oxidativo.
=
INTRODUCTION <=
/p>
Chronic diabetic wounds occur in approxim=
ately
25% of patients with untreated diabetes. The "diabetic foot", as =
it
is more commonly known, affects 4 to 10% of this population per year, with a
high rate of amputation and mortality (39-80%). These lesions are character=
ized
by epithelium and dermis loss, which can ultimately reach muscle and bone
tissue. The regions most commonly affected by these types of wounds are the
lower limbs and plantar and other surfaces subjected to repetitive pressure=
. Deformities
(Charcot's foot) or limited joint mobility are common in diabetic foot (1) .
Diabetic neuropathy, vascular diseases and ischemia are
among the leading causes of this wound's appearance. <=
span
style=3D'mso-bookmark:_Hlk64534508'>The heterodimeric transcription factor hypoxia-inducible factor 1
(HIF-1), composed of HIF-1 α and HIF-1 β, plays a significant role in
angiogenesis, metabolic changes, proliferation, migration, and cell surviva=
l . It has been reported that in the diabetic state, hyperglycemia destabilizes HIF-1α,
resulting in functional repression, consequently inhibiting HIF-1-mediated =
signaling
(1,2) . <=
o:p>
Additionally, i=
t has
been demonstrated that Diabetes Mellitus (DM) augments the production of
reactive oxygen and nitrogen species (ROS and RNS, respectively) due to
increased glucose oxidation (5 )=
span> . Rises in ROS and RNS concentrations can eventually overwhelm the
antioxidant defense system and cause oxidative stress (3,4) .
Additionally, DM and oxidative stress can both aggravate the inflammatory
processes ( 6) =
sup>.
The ROS-mediated reactions include lipid
peroxidation, protein carbonylation and nucleic acid oxidation, among other=
s. An
overabundance of these modified biomolecules can activate and/or perturb no=
rmal
metabolic pathways, leading to cell damage, depleted intracellular antioxid=
ant
defenses, and chronic oxidative stress (4,5) . Interestingly, activation of the hexosamine and advanc=
ed
glycoxidation end product (AGE) pathways, which are involved in collagen
degradation, and nuclear transcription factor kappa-B (NF- кB), which upregulates inflammatory cytokine production, are associated
with the persistence of inflammatory cells and more significant ROS product=
ion ( 7,8) .
Antioxidants are
substances that slow or prevent oxidation of a substrate (9) . =
The oral
use of antioxidants such as vitamins C and E, lipoic acid, and N-acetylcyst=
eine
has been shown to improve diabetic wound healing, with notable changes obse=
rved
in extracellular matrix (ECM) synthesis, cytokine production and
re-epithelialization (5, 10) . However, it should be pointed out =
that
in 2011, the authors (11) reported increased mortality in women
after prolonged antioxidant use. Therefore, the effects of long-term
antioxidant supplementation need to be evaluated. <=
/span>
Vitamin E has eight stereoisomers, of whi=
ch α-tocopherol is the most abundant form, with RRR- α =
-tocopherol exhibiting the highest biological activity. Its synthetic
form is composed of a racemic mixture of all eight stereoisomers (all-rac - α-tocopherol) that form vitam=
in E ( 12) . Vitamin E is lipophilic, and it is preferentially stored in cell
membranes. In the membrane, Vitamin E protects against internal and/or exte=
rnal
oxidizing agents. In the present literature review, we found that studies e=
valuating
plasma and tissue vitamin E concentrations in diabetic individuals reported
conflicting results (4,10,12) . It is plausible that these
discrepancies are at least partially due to bioavailability.
The development of new forms and technolo=
gies
for drug administration is a challenge for researchers. One solution for
improving drug delivery involves using nanotechnology to create materials,
devices, and systems at the nanoscale ( 13) . Nanopar=
ticles
or nanocarriers have been shown to act as drug carriers and aid in diagnost=
ic imaging
( 1=
3 ). These systems can i=
mprove
bioavailability, stabilize bioactive agents ( 14 ) , and target drugs, reducing toxicity ( 14, 15=
span> ) .=
The nanometric scale delivery systems are
classified into two general groups: a) Liquids: nanoem=
ulsions
and nanoliposomes, and b) Solids: lipid nanoparticles [solid lipid
nanoparticles (SLNs) and nanostructured lipid carriers (NLCs)], polymeric
nanoparticles (nanospheres and nanocapsules ) and
nanocrystals ( 16) . Among
these, SLNs have attracted considerable attention for cutaneous application=
s.
SLNs are colloidal systems derived from
oil/water (O/W) emulsions created by simply replacing the oil with a solid
lipid, which remains in this state at body temperature (17) . In =
the
1950s, SLN emulsions were introduced into the clinical routine as emulsions=
for
parenteral nutrition. Currently, there is a second generation of SLNs,
represented by NLCs. These systems were developed by blending a solid lipid
with a liquid lipid at room temperature (17) . The second
generation carriers have greater cargo capacity and better cargo
retention during storage than SLNs (18) . The three SLN drug
incorporation models are shown in Figure 1 and depend on their solubility
(Figure 1).
Figur=
e 1 -
Models of drug incorporation into<=
/b>
Solid Lipid Nanoparticles (SLNs).
1.
Solid solution model (left); 2. Casing model enriched with drugs, with lipid
matrix (center); 3. Lipid shell model, with the drug enriching the matrix
(right).
Source: Muller et al. <=
sup>(17).
The development of drug-containing nanoca=
rriers
involves a series of pre-formulation studies aimed at obtaining truly
nanotechnological formulations, with a nanometric particle size, adequate d=
rug
encapsulation efficiency, physical-chemical stability and biocompatibility.=
These
features are fundamental to the optimization of the therapeutic action of <=
span
class=3DSpellE>nanoencapsulated bioactive substances (19,20).
METHODOLOGICAL
APPROACH
The present study is a qualitative systematic review carried out from
2018 to 2019. We searched for articles on the Pubmed data platform published
between 2000 and 2016. Article selection was based on the description of the
molecular and pathophysiological mechanisms of diabetic wounds, the mechani=
sm
of action of vitamin E, and the utility of nanocarriers as a tool to accele=
rate
diabetic wound healing. =
CONCLUSION
Vitamin E supplementation is currently
prescribed for outpatient chronic wound treatment. However, the use of lipid
nanocarriers has not gained traction in this clinical setting. Encapsulating
this potent antioxidant within SLNs is a promising alternative for the topi=
cal
treatment of chronic wounds. Indeed, clinical trials have been carried out =
to
evaluate the effectiveness of this association.
REFERENCES
1. =
Catrina SB, Zheng X. Disturbed Hypoxic Responses a=
s a
Pathogenic Mechanism of Diabetic Foot Ulcers. Diabetes Metab Res Rev. 2016;=
32
Suppl 1:179-85.
2. =
Ladeira et al. Úlceras nos membros
inferiores de pacientes diabéticos: mecanismos moleculares e
celulares. Revista De Medicina 2011, 90(3), 122-27.
=
Johansen JS et
al. Oxidative stress and the use of antioxidants in diabetes: Linking basic
science to clinical practice. Cardiovascular Diabetology. 2005, 4:5. =
=
Maritim AC, Sanders RA, Watkins =
JB.
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cal
and Molecular Toxicology: United States of America. 2003; 1(17):24-38.
=
Scott JA, King
GL. Oxidative Stress and Antioxidant Treatment in Diabetes. Annals of the N=
ew
York Academy of Sciences. 2004; 1031: 204–213.
6. =
Wagner =
S et al. Redox
regulation of sodium and calcium handling. Antio=
xidant
Redox Signal . 2013;
20(8-9):714-8.
7. =
Huebschmann AG, Regensteine=
r
JG, Vlassara H, Reusch JE. Diabet=
es
and advanced glycoxidation end products. Diabetes Care. 2006;29(6):1420-1432.
8. =
Brownlee M. Biochemistry and molecular cell biolog=
y of
diabetic complications. Nature. 2001;414:813-20.
=
Halliwell B, =
Gutteridge JM (Eds): Free Radicals in Biology and Med=
icine.
Oxford University Press. Free radi=
cals
in biology and medicine.1992;12(1):93-5.
=
Pessoa A=
F et
al. Oral ad=
ministration
of antioxidants improves skin wound healing in diabetic mice. =
span> Wound Repair Regen. <=
/span> 2016;24(6):981-93.
=
Mursu J, Robien K, Harna=
ck
LJ, Park K, Jacobs DR. Dietary Supplements and Mortality Rate in Older Wome=
n: Th=
e Iowa
Women's Health Study . Arch
Intern Med. =
2011;171( 18):1625–1633.
=
Azzi A, Stocker A. Vitamin E:
non-antioxidant roles. Progress in Lipid Research. 2000; 39: 231-55.
=
&nb=
sp;
Apuzzo ML et al. The alchemy of ideas. Neurosurgery. 2008; 63:1035-44.
14. =
Devalapally H, Chakilam
A, Amiji MM. Role of nanotechnology in pharmaceutical product
development. J Pharm Sci . 2007 ;96(10):2547-65. Review.
=
Naahidi S =
et al. Biocompatibility=
span> of engineered &nbs=
p; nanoparticles &=
nbsp; for drug delivery=
.
J Control
Release. 2013;166(2):182-94 . =
;
16. =
Borel T ,<=
span
class=3Dapple-converted-space> Sabliov=
span> CM .<=
span
class=3Dhighlight> Nanodelivery of bioactive  =
; components &nbs=
p; for
food &nbs=
p; applications : types of delivery =
systems , =
properties , and their effe=
ct on ADME profiles=
&nbs=
p; and
toxicity =
of nanopart=
icles .
Annu Rev Food Sci Technol. 2014;5:197 -213.
=
&nb=
sp;
Müller RH et al. So=
lid
lipid nanoparticles (SLN) for controlled drug delivery - a review of the st=
ate
of the art. =
European Journal of Pharmaceutics and Biopharmace=
utics.
2000;50(1):161-77.
18. =
Stecová <=
/span> J, Mehnert W, =
Blaschke T, et al. Cyproterone acetate loading to lip=
id
nanoparticles for topical acne treatment: particle cha=
racterisation
and skin uptake. Pharm Res. 2007;24(5):991-1000. <=
/p>
19. =
Mo=
ra-huertas CE et al. Polymer-Based nanocapsules for drug deli=
very.
International Journal of Pharmaceutics. 2009; 385 (1-2): 113-142.
20. =
Schaffazick SR, Guterres SS, Freitas LL, Pohlman AR.=
Caracterização e estabilidade físico-química de sist=
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de
fármacos. Quím. Nova [online]. 2003; 26(5):726-737.
Submission <=
span
style=3D'mso-bookmark:_Hlk64534508'>: =
Approval : =
=
Pharmaceuticals and Biochemistry. Postdoctoral fel=
low
at the Medical School of USP-LIM-26, Coordinator of the specialization in <=
span
class=3DSpellE>Phytotherapics and Medicinal Plants at EEPHC-FMUSP.
Performance themes: Nutrition, Nutraceutical Supplementation, Nanoparticles,
Wound Healing, Natural Products, Inflammation and Oxidative Stress. =
ORCID: https://orc=
id.org/0000-0003-3979-1607 .
Nurse. Master's student in the
Multicenter Physiological Sciences Program at the Pain and Inflammation
Laboratory (LANDI) - UFSC. Operating themes: Medicinal Plants, Skin Injuries
and Intensive Care Unit. ORCID: ht=
tps://orcid.org/0000-0002-9842-5984 .
Technician in
nursing. Acting in the management and care of patients with skin lesions at
Azevedo e Pedrosa Serviço =
Ltda ,
Santarém - Pará.
Vascular Surgeon at t=
he Baixo
Amazonas Regional Hospital - Santarém- PA. Member of the Society =
for
Vascular Surgery .
Nurse. Coordinator of the Dressi=
ng
Commission in the municipality of Corbélia / PR.
Emphasis on the management and care of patients with skin lesions, manageme=
nt
and administration in Nursing and Health Education.
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