Professional Documents
Culture Documents
Chitosan and Chitosan Coating Nanoparticles For The Treatment of Brain Disease
Chitosan and Chitosan Coating Nanoparticles For The Treatment of Brain Disease
Chitosan and Chitosan Coating Nanoparticles for the Treatment of Brain Dis-
ease
PII: S0378-5173(19)30135-8
DOI: https://doi.org/10.1016/j.ijpharm.2019.02.012
Reference: IJP 18150
Please cite this article as: S. Yu, X. Xu, J. Feng, M. Liu, K. Hu, Chitosan and Chitosan Coating Nanoparticles for
the Treatment of Brain Disease, International Journal of Pharmaceutics (2019), doi: https://doi.org/10.1016/
j.ijpharm.2019.02.012
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Chitosan and Chitosan Coating Nanoparticles for the Treatment of
Brain Disease
Shuangwen Yua,b,1, Xiaolu Xua,b,1, Jianfang Fengc, Mei Liub*, Kaili Hua,d,*
a
Murad Research Center for Modernized Chinese Medicine, Institute of
Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional
Chinese Medicine, Shanghai 201203, China
b
Shanghai Innovation Center of TCM Health Service, Shanghai University of
Traditional Chinese Medicine, Shanghai, 201203, China
c
School of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530001,
People’s Republic of China
d
Key Laboratory of Smart Drug Delivery, Fudan University, Ministry of Education,
Shanghai 201203, China
*
Corresponding author.
E-mail address: liumeiy@aliyun.com (Mei Liu), kaili-hu@163.com (Kaili Hu)
Abstract
barrier by affecting the tight junction. And with positive charge on the
1
surface, chitosan nanoparticles can absorb on the negatively charged
cell membrane, thus increase its residence time on the nasal mucosa and
benefit of the delivery of drugs from the nasal cavity to the brain. All
brain delivery. What’s more, the free amino groups on the surface of
Keywords
Blood-brain barrier
1. Introduction
Bickel et al., 2001; Zhao et al., 2017). Over 98% small molecule drugs
2
and almost 100% large molecule drugs like recombinant protein and
structure and the efflux proteins on the BBB surface limit the entry of
drugs into the brain, so one of the major challenges of brain disease
achieving targeted delivery of drugs and reducing the toxic and side
Invasive method could deliver drugs into the brain, which present some
delivery into the brain through specific carrier or receptor on the BBB.
a promising CNS drug delivery system for its brain targeting ability and
dose of chitosan is in the same range as sugar or table salt (Kean and
which are amino groups, primary and secondary hydroxyl groups at the
C-2, C-3, and C-6 positions, respectively. These groups allow a variety
containing a number of free amine groups that are readily available for
4
crosslinking; 4) cationic chitosan can strongly combined with anionic
unique for their positive charged surfaces and good mucosal adhesion.
Ramesh, 2017).
approach direct delivery to the brain and nasal cavity is the only
exposed part of the CNS (Elnaggar et al., 2015; Hanafy et al., 2016; Lin
scavenging action of nasal cilia, which can clear away the delivered
drug and decrease the absorption time. Low drug permeability of nasal
the nasal membrane which prolong the absorption time of drugs and
polymer, it can extend its retention time at the target and increase
6
absorption through the interaction with negative charged cell membrane
discussed.
2. Brain glioma
Brain glioma accounts for 80% of all malignant brain tumors, and
astrocytoma.
to about 100% relapse and a median survival of only 12-14 months after
diagnosis (Rizvi et al., 2010). What’s more, the special structure of BBB
micelles have a particle size of 16.12 ± 2.2 nm, a zeta potential of - 1.11
after 48 h were 2.89-fold and 4.08-fold higher than that of free DTX,
herbal medicines for glioma treatment (Chirio et al., 2014). Yang et al.
of 25.37 mV. The encapsulation efficiency and drug loading are 89.9%
alkylating damage of DNA and further inhibit its replications (Qiu et al.,
the main carrier material, chitosan is not only used to carry BG, but also
profile of NPCP-BG-CTX.
inability to concentrated in the tumor site. Qian et al. (Qian et al., 2013)
coating shell loaded with BG. The diameter of the NPs is around 177
nm and the average zeta potential is 19.6 ± 4.8 mV, with a loading
efficiency of 3.05% and 8.97% for BCNU and BG, respectively. After
which will reduce the level of MGMT in tumor cell thus increase the
solution group. In addition, safety studies have shown that the carrier
delivers TRAIL into human T98G GBM cells and induces secretion of
diameter of 111.9 ± 52.4 nm, with a zeta potential of+19.6 ± 5.7 mV,
drugs, siRNAs and natural products to brain (Chen et al., 2017; Chirio
et al., 2014; Danhier et al., 2015; Messaoudi et al., 2014). The chitosan
particle size of about 100 nm. However, much smaller micelles can be
chitosan derivative, and modified with PEG can enhance the aqueous
chitosan can strongly combined with anionic cell surface and mucous
glioma cell uptake, and assist loadings escape from endosome and
delivery into the cytosol after modified with PEI (Yezhelyev et al.,
conjugated to tumor targeting peptide like CTX and Tf, which further
to the nature of the drug and the need of the delivery carrier. After
nanoparticles into the nasal mucosa. The CS and derivatives coating can
Moreover, the free amino groups can also bind to probes such as
et al., 2016).
cognitive impairment is not yet clear. The current strategy for treating
2017) .
2003). However, due to the first pass effect, the absolute bioavailability
of tacrine is only about 17% ± 13%. To solve this problem, Wilson et al.
in heart and blood. While its hydrophilicity limits its oral delivery and
intranasal route for the treatment of AD. The results indicated that the
reduced the level and activity of AChE protein in the rat brain compared
neurodegenerative diseases. This study revealed for the first time the
the escape latency from the second day of treatment compared with the
normalized MDA, GSH-Px and CAT levels also confirmed the good
apoptosis (Beilina and Cookson, 2016; Van Den Eeden SK et al., 2003).
size of 161.3 ± 4.7 nm, a zeta potential of +40.3 ± 2.7 mV, and a loading
amount can reach the target site due to incomplete absorption and
outside the brain tissue by the BBB. The prepared BRC-loaded chitosan
nanoparticles can carry the drug across the nasal mucosal and to protect
the drug from degradation in the nasal cavity. Furthermore, the mucosa
min, while the value is 152.7 ± 17.5 s in the BRC solution treated group,
and 47.7 ± 8.6 s in the BRC loaded CS-NPs group. The BRC solution
GDNF has been limited in clinical due to its short half-life and rapid
weight and the charge (Gao et al., 2013; Hernando et al., 2018).
decrease in the number of rotations per minute and the number was
reduced by 80% until the end of the study. What’s more, the density of
body posture and balance (Ashizawa et al., 2018). One of the hallmarks
delivery siRNA to the target gene, Malhotra et al. (Malhotra et al., 2013)
the neuronal cells with liposomes that contained the Ataxin-1 plasmid.
the fact that the positive chitosan nanoparticle can effectively penetrate
the nasal mucosa and directly enter the brain region. Compared with
the intravenous delivery because it can directly enter the brain along the
olfactory nerve or trigeminal nerve thus bypass the BBB (Agrawal et al.,
2018).
6. Cerebral ischemia
one of the most leading causes of disability and mortality (Nazam et al.,
pass the BBB and diffuse into the brain tissue. Therefore, it is necessary
solution was only 19.01%. The interaction between the positive charged
greatly enhanced the drug permeability compared to free RUT. And the
cavity and increases its penetration and continuing delivery to the brain
RUT-CS-NPs into the brain was three times higher than that of the free
increased compared with that of the free RUT. This also results in a
group compared with the cerebral ischemia model group (Fig. 5).
inhibits the release of aspartic acid and glutamic acid in rat cortical
and so on. It is the only available drug for the treatment of motor neuron
disease. However, its application has been limited because of the poor
aqueous solubility, short half-life and side effects such as lung toxicity
showed that the infarct size treated with NR was significantly decreased
riluzole.
molecular weights of chitosan were 150-370 kDa, but all had higher
30
deacetylation degree. However, because of the difference in the drug
Despite the difference in size, they all benefit on the cationic surface of
7. Conclusion
for treatment of brain disease has been highlighted. Due to the presence
time and uptake by nasal mucosal due to the positively charged surface.
which have good effects in the treatment of brain disease like tumor and
active compounds are water-soluble and are difficult to infiltrate into the
chitosan is favorable, which not only protects the stability of the drug,
but also effectively improves the concentration of the drug in the brain.
Funding
Fudan University & The Open Project Program of Key Lab of Smart
China.
References
11,825-833.
Agrawal, M., Saraf, S., Saraf, S., Antimisiaris, S.G., Chougule, M.B., Shoyele, S.A.,
Release. 281,139-177.
Agrawal, P., Sonali, Singh, R.P., Sharma, G., Mehata, A.K., Singh, S., Rajesh, C.V.,
33
152,277-288.
Ahmad, N., Ahmad, R., Naqvi, A.A., Alam, M.A., Ashafaq, M., Samim, M., Iqbal,
91,640-655.
Aktaş, Y., Yemisci, M., Andrieux, K., Gürsoy, R.N., Alonso, M.J., Fernandez-Megia,
E., Novoa-Carballal, R., Quiñoá, E., Riguera, R., Sargon, M.F., Celik, H.H.,
Demir, A.S., Hincal, A.A., Dalkara, T., Capan, Y., Couvreur, P., 2005.
16,1503-1511.
Ashizawa, T., Öz, G., Paulson, H.L., 2018. Spinocerebellar ataxias: prospects and
84,31-34.
Babu, A., Ramesh, R., 2017. Multifaceted Applications of Chitosan in Cancer Drug
Beilina, A., Cookson, M.R., 2016. Genes associated with Parkinson's disease:
Betsholtz, C., 2014. Physiology: Double function at the blood-brain barrier. Nature.
509,432-433.
34
Bickel, U., Yoshikawa, T., Pardridge, W.M., 2001. Delivery of peptides and proteins
Chen, Y., Feng, S., Liu, W., Yuan, Z., Yin, P., Gao, F., 2017. Vitamin E
Micelles Loaded with Paclitaxel for U87MG Tumor Therapy. Mol. Pharm..
14,1190-1203.
Chirio, D., Gallarate, M., Peira, E., Battaglia, L., Muntoni, E., Riganti, C., Biasibetti,
E., Capucchio, M.T., Valazza, A., Panciani, P., Lanotte, M., Annovazzi, L.,
Caldera, V., Mellai, M., Filice, G., Corona, S., Schiffer, D., 2014.
Chung, Y.I., Kim, J.C., Kim, Y.H., Tae, G., Lee, S.Y., Kim, K., Kwon, I.C., 2010.
143,374-382.
Contestabile, A., 2011. The history of the cholinergic hypothesis. Behav. Brain Res..
221,334-340.
Corapi, E., Carrizo, G., Compagno, D., Laderach, D., 2018. Endogenous Galectin-1
35
9,2190.
Dalpiaz, A., Gavini, E., Colombo, G., Russo, P., Bortolotti, F., Ferraro, L.,
Tanganelli, S., Scatturin, A., Menegatti, E., Giunchedi, P., 2008. Brain
Danhier, F., Messaoudi, K., Lemaire, L., Benoit, J.P., Lagarce, F., 2015. Combined
Pharm. 481,154-161.
Dardevet, L., Rani, D., Aziz, T.A., Bazin, I., Sabatier, J.M., Fadl, M., Brambilla, E.,
Dorsey, E.R., Constantinescu, R., Thompson, J.P., Biglan, K.M., Holloway, R.G.,
Kieburtz, K., Marshall, F.J., Ravina, B.M., Schifitto, G., Siderowf, A.,
Dyrba, M., Grothe, M.J., Mohammadi, A., Binder, H., Kirste, T., Teipel, S.J., 2018.
El, K.H., Belaabed, R., Addaou, A., Laajeb, A., Lahsini, A., 2018. Extraction,
36
Biol. Macromol.. 120,1181-1189.
Elnaggar, Y., Etman, S.M., Abdelmonsif, D.A., Abdallah, O.Y., 2015. Intranasal
Fang, F., Zou, D., Wang, W., Yin, Y., Yin, T., Hao, S., Wang, B., Wang, G., Wang, Y.,
2017. Non-invasive approaches for drug delivery to the brain based on the
76,1316-1327.
Fazil, M., Md, S., Haque, S., Kumar, M., Baboota, S., Sahni, J.K., Ali, J., 2012.
Gao, H., 2016. Progress and perspectives on targeting nanoparticles for brain drug
Gao, H., 2017. Perspectives on Dual Targeting Delivery Systems for Brain Tumors.
Gao, H., Pang, Z., Jiang, X., 2013. Targeted delivery of nano-therapeutics for major
Gartziandia, O., Herrán, E., Ruiz-Ortega, J.A., Miguelez, C., Igartua, M., Lafuente,
37
Lesion Model of Parkinson's Disease. J Biomed Nanotechnol. 12,2220-2230.
Target. 20,291-300.
Hanafy, A.S., Farid, R.M., Helmy, M.W., ElGamal, S.S., 2016. Pharmacological,
Hernando, S., Herran, E., Figueiro-Silva, J., Pedraz, J.L., Igartua, M., Carro, E.,
55,145-155.
Jose, S., Juna, B.C., Cinu, T.A., Jyoti, H., Aleykutty, N.A., 2016. Carboplatin loaded
Kean, T., Thanou, M., 2010. Biodegradation, biodistribution and toxicity of chitosan.
Lanjhiyana, S.K., Bajpayee, P., Kesavan, K., Lanjhiyana, S., Muthu, M.S., 2013.
Lin, T., Liu, E., He, H., Shin, M.C., Moon, C., Yang, V.C., Huang, Y., 2016.
38
Nose-to-brain delivery of macromolecules mediated by cell-penetrating
Luppi, B., Bigucci, F., Cerchiara, T., Zecchi, V., 2010. Chitosan-based hydrogels for
nasal drug delivery: from inserts to nanoparticles. Expert Opin Drug Deliv.
7,811-828.
Md, S., Haque, S., Fazil, M., Kumar, M., Baboota, S., Sahni, J.K., Ali, J., 2014.
11,827-842.
Md, S., Khan, R.A., Mustafa, G., Chuttani, K., Baboota, S., Sahni, J.K., Ali, J., 2013.
Meng, Q., Wang, A., Hua, H., Jiang, Y., Wang, Y., Mu, H., Wu, Z., Sun, K., 2018.
Messaoudi, K., Saulnier, P., Boesen, K., Benoit, J.P., Lagarce, F., 2014.
39
Anti-epidermal growth factor receptor siRNA carried by
Mistry, A., Stolnik, S., Illum, L., 2015. Nose-to-Brain Delivery: Investigation of the
Muntimadugu, E., Dhommati, R., Jain, A., Challa, V.G., Shaheen, M., Khan, W.,
potential brain targeting strategy for Alzheimer's disease. Eur J Pharm Sci.
92,224-234.
Nazam, A.M., Bhandari, U., Islam, F., Tripathi, C.D., 2008. Evaluation of
Ouyang, Q.Q., Zhao, S., Li, S.D., Song, C., 2017. Application of Chitosan,
Patel, D., Naik, S., Misra, A., 2012. Improved transnasal transport and brain uptake
Patel, M.P., Patel, R.R., Patel, J.K., 2010. Chitosan mediated targeted drug delivery
40
Prabaharan, M., 2008. Review paper: chitosan derivatives as promising materials
Qian, L., Zheng, J., Wang, K., Tang, Y., Zhang, X., Zhang, H., Huang, F., Pei, Y.,
34,8968-8978.
Qiu, Z.K., Shen, D., Chen, Y.S., Yang, Q.Y., Guo, C.C., Feng, B.H., Chen, Z.P.,
Reichman, W.E., 2003. Current pharmacologic options for patients with Alzheimer's
Rizvi, S., Asghar, A.H., Mehboob, J., 2010. Gliosarcoma: a rare variant of
Rubino, S., Bach, M.D., Schober, A.L., Lambert, I.H., Mongin, A.A., 2018.
Macromol.. 49,747-751.
Sahariah, P., Másson, M., 2017. Antimicrobial Chitosan and Chitosan Derivatives: A
41
Review of the Structure-Activity Relationship. Biomacromolecules.
18,3846-3868.
Sarvaiya, J., Agrawal, Y.K., 2015. Chitosan as a suitable nanocarrier material for
Shevtsov, M., Nikolaev, B., Marchenko, Y., Yakovleva, L., Skvortsov, N., Mazur, A.,
Smith, J., Wood, E., Dornish, M., 2004. Effect of chitosan on epithelial cell tight
Sridhar, V., Gaud, R., Bajaj, A., Wairkar, S., 2018. Pharmacokinetics and
14,2609-2618.
Stephen, Z.R., Kievit, F.M., Veiseh, O., Chiarelli, P.A., Fang, C., Wang, K.,
Toussaint, L.G., Nilson, A.E., Goble, J.M., Ballman, K.V., James, C.D., Lefranc, F.,
Kiss, R., Uhm, J.H., 2012. Galectin-1, a gene preferentially expressed at the
Van Den Eeden SK, Tanner, C.M., Bernstein, A.L., Fross, R.D., Leimpeter, A.,
42
Bloch, D.A., Nelson, L.M., 2003. Incidence of Parkinson's disease: variation
Van Woensel M, Wauthoz, N., Rosière, R., Mathieu, V., Kiss, R., Lefranc, F.,
Steelant, B., Dilissen, E., Van Gool SW, Mathivet, T., Gerhardt, H., Amighi,
Veiseh, O., Kievit, F.M., Fang, C., Mu, N., Jana, S., Leung, M.C., Mok, H.,
Ellenbogen, R.G., Park, J.O., Zhang, M., 2010. Chlorotoxin bound magnetic
nanovector tailored for cancer cell targeting, imaging, and siRNA delivery.
Biomaterials. 31,8032-8042.
Verma, S.K., Arora, I., Javed, K., Akhtar, M., Samim, M., 2016. Enhancement in the
8,19716-19723.
Wahba, S.M., Darwish, A.S., Kamal, S.M., 2016. Ceria-containing uncoated and
Wang, K., Kievit, F.M., Jeon, M., Silber, J.R., Ellenbogen, R.G., Zhang, M., 2015.
43
Wang, X., Chi, N., Tang, X., 2008. Preparation of estradiol chitosan nanoparticles
for improving nasal absorption and brain targeting. Eur J Pharm Biopharm.
70,735-740.
Wang, Z.H., Wang, Z.Y., Sun, C.S., Wang, C.Y., Jiang, T.Y., Wang, S.L., 2010.
Wilson, B., Samanta, M.K., Santhi, K., Kumar, K.P., Ramasamy, M., Suresh, B.,
Xu, Y., Asghar, S., Yang, L., Li, H., Wang, Z., Ping, Q., Xiao, Y., 2017.
Polym. 157,419-428.
Yang, L., Gao, S., Asghar, S., Liu, G., Song, J., Wang, X., Ping, Q., Zhang, C., Xiao,
72,1391-1401.
Yemisci, M., Caban, S., Gursoy-Ozdemir, Y., Lule, S., Novoa-Carballal, R., Riguera,
R., Fernandez-Megia, E., Andrieux, K., Couvreur, P., Capan, Y., Dalkara, T.,
44
Yezhelyev, M.V., Qi, L., O'Regan, R.M., Nie, S., Gao, X., 2008. Proton-sponge
coated quantum dots for siRNA delivery and intracellular imaging. J. Am.
Zhao, X., Chen, R., Liu, M., Feng, J., Chen, J., Hu, K., 2017. Remodeling the
45
46
47
48
49
Dise Co-us Chito Preparat Modifi Siz Zeta EE (%) Adminis Outcome
ase ed san ion cation e pote tration
carrier mole method (n ntial method
materi cular m) (mV
al weig )
ht
50
Iron 5 kDa Co-prec PEG, 76 4± 50 CED Threefold
oxide ipitate CTX ±4 7.4 molecu increase in
core lar BG median
/ overall
nanopa survival of
rticle NPCP-BG-C
TX/TMZ
treated in
comparison
with the
control group
PLGA 50 Emulsio - 17 19.6 3.05 i.v. Targeted
kDa n 7 ± 4.8 for delivery to
solvent BCNU glioma,
evaporat and reversed
ion 8.97 drug
for BG resistance,
and
improved
anti-tumor
Brai
efficacy
n
- 50 Ionic - 14 32 81± 3 i.n. Down-regula
glio
kDa gelation 1± ted the
ma
5 protein level
and
expression of
Gal-1 in
GBM
Iron - Co-prec PEI, 11 19.6 3.8 - Enhanced
oxide ipitate PEG, 1.9 ± 5.7 molecu internalizatio
core CTX ± lar n and
52. siRNA knockdown
4 / of targeted
nanopa gene
rticle expression in
tumor cells
51
with control
group, and
resulted in
near-zero
tumor
growth and
induced
apoptosis in
tumor tissue
TPGS - Solvent Tf 16. 1.1 ± 98.9 i.v. 248 folds
casting 12 0.6 effective than
method ± free DTX in
2.2 C6 glioma
cells, and
improved the
relative
bioavailabilit
y by
4.08-fold
compare
with free
DTX
Hyalu 50 - - 20 25.4 89.9 - Increased
ronic kDa 7 uptake and
acid killing effect
on C6 tumor
cells
52
targeting
- 750 Ionic - 185.4 38.4 85. 43. i.n. Improved
kDa gelation ± 8.4 ± 3 37 nasal
2.9 ± ± delivery
3.5 3.9 efficiency
- 200 Ionic - - - - - i.n. Reduced
kDa gelation the level
and
activity of
acetylcholi
nesterase
protein
- 100- Ionic - 248.5 56.3 81. 43. i.n. Improved
300 gelation 0 0 70 37 cognitive
kDa ± functions
3.9 and
cognitive
ability
PL 100 nano- - 146.7 21.0 8.8 - i.v. Improved
GA kDa precipitati ± 5.1 ± memory
/ on method 2.9 impairmen
10k t and
Da enhanced
the spatial
memory
ability,
decreased
senile
plaques in
brain and
normalized
MDA,
GSH-Px
and CAT
levels
- Medi Ionic 161.3 40.3 84. 37. i.n. Reduced
um gelation ± 4.7 ± 2 8 catalepsy
mole 2.7 ± ± and
cular 3.5 1.8 akinesia
PD weig
ht
NL - melt-emul 136.7 30.0 98. i.n. Significant
C sification ±14.1 10 ly
technique ± improved
53
0.3 the density
6 of tyrosine
hydroxylas
e (TH+)
fibers in
the
striatum
and
substantia
nigra
- Low Ionic PEG, 50-10 - - - - Successfull
mole gelation TAT 0 y and
cular efficiently
weig transfected
ht functional
siRNA
SC
causing
A
suppressio
n of ataxin
protein in
neuronal
cells in
vitro
Tab.2 Chitosan-based nanoparticles for treatment of neurodegenerative disease
54
t
N-isopr - - Tween8 50 - - - i.v. Decreas
opyl 0 ed
acryla infarct
mide size and
the
expressi
on of
NOS-2,
NF-kB
and
COX-2
- Medi Ionic - 92.3 31.0 84 39. i.n. Reduce
um gelation ± ± 1.9 .9 5 d the
molec 2.9 ± ± volume
ular 4. 3.2 of
weigh 2 cerebral
t infarctio
n
- 160 Spray-d - 196 - - - i.v.; i.p. Increase
kDa rying 0± d the
50 concentr
CI
ation of
CPA in
the CSF
- < 150 Ionic PEG, 149. 16.1 - 31. i.v. Facilitat
kDa gelation OX26 7± ± 3.4 1 ed
1.8 ± nanopar
1.6 ticle
transloc
ation
into the
brain
tissue
- Ionic PEG, 747 - - - i.v. Promote
gelation TfRMA ±42 d
b nanopar
ticles
across
the BBB
and
reduced
the
infarct
55
volume
Tab.3 Chitosan-based nanoparticles for treatment of cerebral ischemia
Graphical abstract
56