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The Nasal Delivery Of Nanoencapsulated Statins – An Approach For Brain Delivery
A. Clementino, Mellissa Batger, Gabriela Garrastazu, Michele Pozzoli, E. del Favero, V. Rondelli, B. Gutfilen, Thiago Barboza, M. Sukkar, S. Souza, L. Cantu', F. Sonvico
Published 2016 · Medicine
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Purpose Along with their cholesterol-lowering effect, statins have shown a wide range of pleiotropic effects potentially beneficial to neurodegenerative diseases. However, such effects are extremely elusive via the conventional oral administration. The purpose of the present study was to prepare and characterize the physicochemical properties and the in vivo biodistribution of simvastatin-loaded lecithin/chitosan nanoparticles (SVT-LCNs) suitable for nasal administration in view of an improved delivery of the statins to the brain. Materials and methods Chitosan, lecithin, and different oil excipients were used to prepare nanocapsules loaded with simvastatin. Particle size distribution, surface charge, structure, simvastatin loading and release, and interaction with mucus of nanoparticles were determined. The nanoparticle nasal toxicity was evaluated in vitro using RPMI 2651 nasal cell lines. Finally, in vivo biodistribution was assessed by gamma scintigraphy via Tc99m labeling of the particles. Results Among the different types of nanoparticles produced, the SVT-LCN_MaiLab showed the most ideal physicochemical characteristics, with small diameter (200 nm), positive surface charge (+48 mV) and high encapsulation efficiency (EE; 98%). Size distribution was further confirmed by nanoparticle tracking analysis and electron microscopy. The particles showed a relatively fast release of simvastatin in vitro (35.6%±4.2% in 6 hours) in simulated nasal fluid. Blank nanoparticles did not show cytotoxicity, evidencing that the formulation is safe for nasal administration, while cytotoxicity of simvastatin-loaded nanoparticles (IC50) was found to be three times lower than the drug solution (9.92 vs 3.50 μM). In rats, a significantly higher radioactivity was evidenced in the brain after nasal delivery of simvastatin-loaded nanoparticles in comparison to the administration of a similar dose of simvastatin suspension. Conclusion The SVT-LCNs developed presented some of the most desirable characteristics for mucosal delivery, that is, small particle size, positive surface charge, long-term stability, high EE, and mucoadhesion. In addition, they displayed two exciting features: First was their biodegradability by enzymes present in the mucus layer, such as lysozyme. This indicates a new Trojan-horse strategy which may enhance drug release in the proximity of the nasal mucosa. Second was their ability to enhance the nose-to-brain transport as evidenced by preliminary gamma scintigraphy studies.
This paper references
Involvement of protein kinase C in chitosan glutamate-mediated tight junction disruption.
J. Smith (2005)
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial
Pros and Cons of the Liposome Platform in Cancer Drug Targeting
A. Gabizon (2006)
Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update
M. Schachter (2005)
Sodium hyaluronate as a mucoadhesive component in nasal formulation enhances delivery of molecules to brain tissue.
S. Horvát (2009)
Intranasal delivery: circumventing the iron curtain to treat neurological disorders
Yongjun Jiang (2015)
Current understanding of nasal morphology and physiology as a drug delivery target
J. Suman (2012)
Mucoadhesive properties of carbopol or chitosan-coated liposomes and their effectiveness in the oral administration of calcitonin to rats.
H. Takeuchi (2003)
Quantitative analysis of drug delivery to the brain via nasal route.
L. Kozlovskaya (2014)
Mucus as a barrier to lipophilic drugs.
H. Sigurdsson (2013)
Nasal-nanotechnology: revolution for efficient therapeutics delivery
A. Kumar (2016)
Nanoparticles for direct nose-to-brain delivery of drugs.
Alpesh Mistry (2009)
Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: in vitro and in vivo studies.
U. Seju (2011)
Is nose‐to‐brain transport of drugs in man a reality?
L. Illum (2004)
Innate Antimicrobial Activity of Nasal Secretions
A. M. Cole (1999)
Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip
J. Castile (2013)
Effect of Chitosan on the Permeability of Monolayers of Intestinal Epithelial Cells (Caco-2)
P. Artursson (2004)
Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles.
S. Barbieri (2015)
The brain targeting efficiency following nasally applied MPEG-PLA nanoparticles in rats
Q. Zhang (2006)
Chitosan in nasal delivery systems for therapeutic drugs.
L. Casettari (2014)
Chronic obstructive pulmonary disease: patho-physiology, current methods of treatment and the potential for simvastatin in disease management
L. Marín (2011)
Evaluation of human nasal RPMI 2650 cells grown at an air-liquid interface as a model for nasal drug transport studies.
Shuhua Bai (2008)
The effect of polymer coatings on physicochemical properties of spray-dried liposomes for nasal delivery of BSA.
K. Chen (2013)
MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals : a randomised placebo-controlled trial.
S. Feasson (2008)
Effect of physicochemical properties on intranasal nanoparticle transit into murine olfactory epithelium
Alpesh Mistry (2009)
Antimicrobial peptides and proteins in the innate defense of the airway surface.
S. M. Travis (2001)
Liposome: classification, preparation, and applications
A. Akbarzadeh (2013)
Drug Dev Ind Pharm
Monitoring rheumatoid arthritis synovitis with 99mTc-anti-CD3.
F. P. P. Martins (2008)
Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment.
Sumeet Sood (2014)
Statins: Multiple neuroprotective mechanisms in neurodegenerative diseases
Q. Wang (2011)
Mean square hydrogen fluctuations in chitosan/lecithin nanoparticles from elastic neutron scattering experiments
F. Sonvico (2006)
Study on the conversion of three natural statins from lactone forms to their corresponding hydroxy acid forms and their determination in Pu-Erh tea.
D. Yang (2006)
Intranasal Mucoadhesive Microemulsion of Tacrine to Improve Brain Targeting
Viral V Jogani (2008)
Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: a pharmacoscintigraphic study
Sanjar Alam (2012)
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
G. Bu (2009)
From nose to brain: understanding transport capacity and transport rate of drugs.
H. Wu (2008)
Interlaboratory comparison of size measurements on nanoparticles using nanoparticle tracking analysis (NTA)
P. Hole (2013)
Alzheimer's disease: the cholesterol connection
L. Puglielli (2003)
Anti-inflammatory and immunomodulatory effects of statins.
L. Blanco-Colio (2003)
Use of 99mTc-anti-CD3 scintigraphy in the differential diagnosis of rheumatic diseases.
F. L. Lopes (2010)
Trial of atorvastatin in rheumatoid arthritis (TARA): Double-blind, randomised placebo-controlled trial
D. McCarey (2004)
Doxil®--the first FDA-approved nano-drug: lessons learned.
Y. Barenholz (2012)
Tight junction modulation by chitosan nanoparticles: comparison with chitosan solution.
D. Vllasaliu (2010)
Expanding the therapeutic potential of statins by means of nanotechnology enabled drug delivery systems.
Bilquis Romana (2014)
Determination of drug release kinetics from nanoparticles: overcoming pitfalls of the dynamic dialysis method.
Sweta Modi (2013)
Lecithin/chitosan nanoparticles of clobetasol-17-propionate capable of accumulation in pig skin.
T. Şenyiğit (2010)
Apolipoprotein E 4 Allele, Elevated Midlife Total Cholesterol Level, and High Midlife Systolic Blood Pressure Are Independent Risk Factors for Late-Life Alzheimer Disease
M. Kivipelto (2002)
Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy.
V. Sokolova (2011)
EFFECT OF SIMVASTATIN ON GLIOMA CELL PROLIFERATION, MIGRATION, AND APOPTOSIS
Hongtao Wu (2009)
Transport of drugs from the nasal cavity to the central nervous system.
L. Illum (2000)
Intranasal drug delivery: how, why and what for?
A. Pires (2009)
Simvastatin inhibition of mevalonate pathway induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling pathway.
Archana Gopalan (2013)
Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future.
R. Mueller (2001)
Methods to Assess in Vitro Drug Release from Injectable Polymeric Particulate Systems
Susan Dsouza (2005)
Statin effects beyond lipid lowering — are they clinically relevant ?
P. O. Bonettia (2003)
Structure and organization of phospholipid/polysaccharide nanoparticles
Y. Gerelli (2008)
Intranasal delivery of biologics to the central nervous system.
Jeffrey J Lochhead (2012)
Correlation between epithelial toxicity and surfactant structure as derived from the effects of polyethyleneoxide surfactants on caco-2 cell monolayers and pig nasal mucosa.
K. Ekelund (2005)
Use of 99 mTc - anti - CD 3 scintigraphy in the differential diagnosis of rheumatic diseases
FP Lopes (2010)
Brain uptake of a Zidovudine prodrug after nasal administration of solid lipid microparticles.
A. Dalpiaz (2014)
High cholesterol content in neurons increases BACE, β-amyloid, and phosphorylated tau levels in rabbit hippocampus
O. Ghribi (2006)
Anti-Inflammatory Effects of Statins: Clinical Evidence and Basic Mechanisms
M. Jain (2005)
Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: loading, enzyme-trigger release and cell uptake.
S. Barbieri (2013)
Pleiotropic effects of statins
J. Farmer (2000)
Preliminary results of [99mTc]OKT3 scintigraphy to evaluate acute rejection in renal transplants.
F. P. P. Martins (2004)
Degradation of partially N-acetylated chitosans with hen egg white and human lysozyme
Ragnhild J. Nordtveit (1996)
Preparation, characterization, and anticancer effects of simvastatin-tocotrienol lipid nanoparticles.
Hazem Ali (2010)
Preparation and evaluation of SEDDS of simvastatin by in vivo, in vitro and ex vivo technique
Fahim Tamzeedul Karim (2015)
Unraveling pleiotropic effects of statins on plaque rupture.
W. Palinski (2002)
科技期刊稿件处理的精细化管理——《International Journal of Nanomedicine〉〉投稿体会
Critical Evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the Measurement of Nanoparticles and Protein Aggregates
V. Filipe (2010)
Intranasal drug delivery to the central nervous system: present status and future outlook.
S. Tayebati (2013)
Transmucosal macromolecular drug delivery.
C. Prego (2005)
Dynamics of lipid–saccharide nanoparticles by quasielastic neutron scattering
M. D. Bari (2008)
Chitosan based drug delivery systems
A. Piegat (2016)
Nanoencapsulated statins for brain delivery via nasal route
Nanoparticle tracking analysis for the multiparameter characterization and counting of nanoparticle suspensions.
M. Wright (2012)
Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo
K. Fassbender (2001)
Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems?
L. Illum (2007)
Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
R. Ehehalt (2003)
Biovector™ Nanoparticles Improve Antinociceptive Efficacy of Nasal Morphine
D. Betbeder (2004)
Flexibility and drug release features of lipid/saccharide nanoparticles
Y. Gerelli (2010)
This paper is referenced by
Preparation and Properties of 5-Fluorouracil-Loaded Chitosan Microspheres for the Intranasal Administration.
W. Li (2018)
Coenzyme Q10 protects against β‐cell toxicity induced by pravastatin treatment of hypercholesterolemia
estela Lorza-Gil (2019)
In Vivo Assessment of Clobetasol Propionate-Loaded Lecithin-Chitosan Nanoparticles for Skin Delivery
T. Şenyiğit (2016)
Development and validation of a RP‐HPLC method for the simultaneous detection and quantification of simvastatin's isoforms and coenzyme Q10 in lecithin/chitosan nanoparticles
A. Clementino (2018)
Neem oil nanoemulsions: characterisation and antioxidant activity
F. Rinaldi (2017)
Intranasal tetrandrine temperature-sensitive in situ hydrogels for the treatment of microwave-induced brain injury.
L. Zhang (2020)
Hydrophilic and hydrophobic polymeric benznidazole-loaded nanoparticles: Physicochemical properties and in vitro antitumor efficacy
A. M. D. S. Silva (2019)
Gel-like TPGS-Based Microemulsions for Imiquimod Dermal Delivery: Role of Mesostructure on the Uptake and Distribution into the Skin.
I. Telò (2017)
Bioadhesive Nanoformulations—Concepts and Preclinical Studies: A Critical Review
Monika Joshi (2020)
Self-Assembled Benznidazole-Loaded Cationic Nanoparticles Containing Cholesterol/Sialic Acid: Physicochemical Properties, In Vitro Drug Release and In Vitro Anticancer Efficacy
A. M. Dos Santos-Silva (2019)
Intranasal Nanoparticulate Systems as Alternative Route of Drug Delivery.
Areen Alshweiat (2019)
Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery
F. A. Bruinsmann (2019)
Biomedical Applications of Multifunctional Polymeric Nanocarriers: A Review of Current Literature
Alicja Karabasz (2020)
Preparation and characterisation of PHT-loaded chitosan lecithin nanoparticles for intranasal drug delivery to the brain
A. Yousfan (2020)
1 Surface-modified nanocarriers for nose-to-brain 2 delivery : from bioadhesion to targeting 3
F. Sonvico (2018)
EVALUATION OF CHITOSAN NANOPARTICLES BIODISTRIBUTION USING GROCOTT METHENAMINE SILVER STAINING
S. Zhuravskii (2017)
Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting
F. Sonvico (2018)
Drug delivery to the brain: how can nanoencapsulated statins be used in the clinic?
F. Sonvico (2017)
inPentasomes: An innovative nose-to-brain pentamidine delivery blunts MPTP parkinsonism in mice.
F. Rinaldi (2019)
Preparation and characterization of lamotrigine containing nanocapsules for nasal administration.
P. Gieszinger (2020)
Novel O/W nanoemulsions for nasal administration: Structural hints in the selection of performing vehicles with enhanced mucopenetration.
Emanuela Di Cola (2019)
Formulation Strategies to Improve Nose-to-Brain Delivery of Donepezil
L. Espinoza (2019)
Nose to brain drug delivery - a promising strategy for active components from herbal medicine for treating cerebral ischemia reperfusion.
Y. Long (2020)
Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders
H. Gholizadeh (2019)
An update on the role of nanovehicles in nose-to-brain drug delivery.
Y. Feng (2018)
Self-Assembled chitosan/phospholipid nanoparticles: from fundamentals to preparation for advanced drug delivery
Qingming Ma (2020)