The following work describes the development of a novel noninvasive transmucosal drug delivery system, the chitosan sponge matrix (CSM). It is composed of cationic chitosan (CS) nanoparticles (NPs) that encapsulate cisplatin (CDDP) embedded within a polymeric mucoadhesive CS matrix. CSM is designed to swell up when exposed to moisture, facilitating release of the NPs via diffusion across the matrix. CSM is intended to be administered topically and locally to mucosal tissues, with its initial indication being oral cancer (OC). Currently, intravenous (IV) administered CDDP is the gold standard chemotherapeutic agent used in the treatment of OC. However, its clinical use has been limited by its renal and hemotoxicity profile. We aim to locally administer CDDP via encapsulation in CS NPs and deliver them directly to the oral cavity with CSM. It is hypothesized that such a delivery device will greatly reduce any systemic toxicity and increase antitumor efficacy. This paper describes the methods for developing CSM and maintaining the integrity of CDDP NPs embedded in the CSM.

References

1.
Ceschel
,
G. C.
,
Maffei
,
P.
,
Sforzini
,
A.
,
Borgia
,
S. L.
,
Yasin
,
A.
, and
Ronchi
,
C.
,
2002
, “
In Vitro Permeation Through Porcine Buccal Mucosa of Caffeic Acid Phenetyl Ester (CAPE) From a Topical Mucoadhesive Gel Containing Propolis
,”
Fitoterapia
,
73
, pp.
S44
S52
.10.1016/S0367-326X(02)00190-9
2.
Mura
,
P.
,
Corti
,
G.
,
Cirri
,
M.
,
Maestrelli
,
F.
,
Mennini
,
N.
, and
Bragagni
,
M.
,
2010
, “
Development of Mucoadhesive Films for Buccal Administration of Flufenamic Acid: Effect of Cyclodextrin Complexation
,”
J. Pharm. Sci.
,
99
(
7
), pp.
3019
3029
.10.1002/jps.22068
3.
Ceschel
,
G. C.
,
Maffei
,
P.
,
Borgia
,
S. L.
, and
Ronchi
,
C.
,
2001
, “
Design and Evaluation of Buccal Adhesive Hydrocortisone Acetate (HCA) Tablets
,”
Drug Delivery
,
8
(
3
), pp.
161
171
10.1080/107175401316906937.
4.
Odukoya
,
O.
,
Hawach
,
F.
, and
Shklar
,
G.
,
1985
, “
Retardation of Experimental Oral Cancer by Topical Vitamin E
,”
Nutr. Cancer
,
6
(
2
), pp.
98
104
.10.1080/01635588509513813
5.
Senel
,
S.
,
Kremer
,
M.
,
Nagy
,
K.
, and
Squier
,
C.
,
2001
, “
Delivery of Bioactive Peptides and Proteins Across Oral (Buccal) Mucosa
,”
Curr. Pharm. Biotechnol.
,
2
(
2
), pp.
175
186
.10.2174/1389201013378734
6.
Van Roey
,
J.
,
Haxaire
,
M.
,
Kamya
,
M.
,
Lwanga
,
I.
, and
Katabira
,
E.
,
2004
, “
Comparative Efficacy of Topical Therapy With a Slow-Release Mucoadhesive Buccal Tablet Containing Miconazole Nitrate Versus Systemic Therapy With Ketoconazole in HIV-Positive Patients With Oropharyngeal Candidiasis
,”
JAIDS J. Acquired Immune Defic. Syndr.
,
35
(
2
), pp.
144
150
.10.1097/00126334-200402010-00007
7.
Wong
,
H. L.
,
Bendayan
,
R.
,
Rauth
,
A. M.
,
Li
,
Y.
, and
Wu
,
X. Y.
,
2007
, “
Chemotherapy With Anticancer Drugs Encapsulated in Solid Lipid Nanoparticles
,”
Adv. Drug Delivery Rev.
,
59
(
6
), pp.
491
504
.10.1016/j.addr.2007.04.008
8.
Illum
,
L.
,
1998
, “
Chitosan and Its Use as a Pharmaceutical Excipient
,”
Pharm. Res.
,
15
(
9
), pp.
1326
1331
.10.1023/A:1011929016601
9.
Santiago de Alvarenga
,
E.
,
2011
, “
Characterization and Properties of Chitosan
,”
Material Science Biotechnology of Bipolymers
, pp.
91
108
10.5772/17020.
10.
Garcia-Fuentes
,
M.
, and
Alonso
,
M. J.
,
2012
, “
Chitosan-Based Drug Nanocarriers: Where Do We Stand?
,”
J. Controlled Release
,
161
(
2
), pp.
496
504
.10.1016/j.jconrel.2012.03.017
11.
Simeonova
,
M.
,
Velichkova
,
R.
,
Ivanova
,
G.
,
Enchev
,
V.
, and
Abrahams
,
I.
,
2003
, “
Poly (Butylcyanoacrylate) Nanoparticles for Topical Delivery of 5-Fluorouracil
,”
Int. J. Pharm.
,
263
(
1
), pp.
133
140
.10.1016/S0378-5173(03)00373-9
12.
Giannola
,
L. I.
,
De Caro
,
V.
,
Giandalia
,
G.
,
Siragusa
,
M. G.
,
Paderni
,
C.
,
Campisi
,
G.
, and
Florena
,
A. M.
,
2010
, “
5-Fluorouracil Buccal Tablets for Locoregional Chemotherapy of Oral Squamous Cell Carcinoma: Formulation, Drug Release and Histological Effects on Reconstituted Human Oral Epithelium and Porcine Buccal Mucosa
,”
Curr. Drug Delivery
,
7
(
2
), pp.
109
117
.10.2174/156720110791011792
13.
Westra
,
W. H.
,
2009
, “
The Changing Face of Head and Neck Cancer in the 21st Century: The Impact of HPV on the Epidemiology and Pathology of Oral Cancer
,”
Head Neck Pathol.
,
3
(
1
), pp.
78
81
.10.1007/s12105-009-0100-y
14.
National Cancer Institute
,
2015
,
Cancer of the Oral Cavity and Pharynx
, Surveillance, Epidemiology, and End Results Program Turning Cancer Data Into Discovery, http://seer.cancer.gov/statfacts/html/oralcav.html, Last accessed January 2, 2015.
15.
Rischin
,
D.
,
2005
, “
Induction Chemotherapy in Head and Neck Cancer
,”
Squamous Cell Head and Neck Cancer
,
Humana Press
,
New York
, pp.
165
170
10.1007/978-1-59259-938-7_11.
16.
Bachaud
,
J. M.
,
Cohen-Jonathan
,
E.
,
Alzieu
,
C.
,
David
,
J. M.
,
Serrano
,
E.
, and
Daly-Schveitzer
,
N.
,
1996
, “
Combined Postoperative Radiotherapy and Weekly Cisplatin Infusion for Locally Advanced Head and Neck Carcinoma: Final Report of a Randomized Trial
,”
Int. J. Radiat. Oncol. Biol. Phys.
,
36
(
5
), pp.
999
1004
.10.1016/S0360-3016(96)00430-0
17.
Ihde
,
D. C.
,
Mulshine
,
J. L.
,
Kramer
,
B. S.
,
Steinberg
,
S. M.
,
Linnoila
,
R. I.
,
Gazdar
,
A. F.
,
Edison
,
M.
,
Phelps
,
R. M.
,
Lesar
,
M.
, and
Phares
,
J. C.
,
1994
, “
Prospective Randomized Comparison of High-Dose and Standard-Dose Etoposide and Cisplatin Chemotherapy in Patients With Extensive-Stage Small-Cell Lung Cancer
,”
J. Clin. Oncol.
,
12
(
10
), pp.
2022
2034
10.1093/jnci/djg017.
18.
Studer
,
U. E.
,
Bacchi
,
M.
,
Biedermann
,
C.
,
Jaeger
,
P.
,
Kraft
,
R.
,
Mazzucchelli
,
L.
,
Markwalder
,
R.
,
Senn
,
E.
, and
Sonntag
,
R. W.
,
1994
, “
Adjuvant Cisplatin Chemotherapy Following Cystectomy for Bladder Cancer: Results of a Prospective Randomized Trial
,”
J. Urol.
,
152
(
1
), pp.
81
84
10.1016/j.eururo.2013.08.033.
19.
Pearcey
,
R.
,
Brundage
,
M.
,
Drouin
,
P.
,
Jeffrey
,
J.
,
Johnston
,
D.
,
Lukka
,
H.
,
MacLean
,
G.
,
Souhami
,
L.
,
Stuart
,
G.
, and
Tu
,
D.
,
2002
, “
Phase III Trial Comparing Radical Radiotherapy With and Without Cisplatin Chemotherapy in Patients With Advanced Squamous Cell Cancer of the Cervix
,”
J. Clin. Oncol.
,
20
(
4
), pp.
966
972
.10.1200/JCO.20.4.966
20.
Blair
,
B. G.
,
Larson
,
C. A.
,
Adams
,
P. L.
,
Abada
,
P. B.
,
Pesce
,
C. E.
,
Safaei
,
R.
, and
Howell
,
S. B.
,
2011
, “
Copper Transporter 2 Regulates Endocytosis and Controls Tumor Growth and Sensitivity to Cisplatin In Vivo
,”
Mol. Pharmacol.
,
79
(
1
), pp.
157
166
.10.1124/mol.110.068411
21.
Sharp
,
S. Y.
,
Rogers
,
P. M.
, and
Kelland
,
L. R.
,
1995
, “
Transport of Cisplatin and Bis-Acetato-Ammine-Dichlorocyclohexylamine Platinum (IV)(JM216) in Human Ovarian Carcinoma Cell Lines: Identification of a Plasma Membrane Protein Associated With Cisplatin Resistance
,”
Clin. Cancer Res.
,
1
(
9
), pp.
981
989
10.3892/or.2014.3257.
22.
Fuertes
,
M. A.
,
Castilla
,
J.
,
Alonso
,
C.
, and
Perez
,
J. M.
,
2003
, “
Cisplatin Biochemical Mechanism of Action: From Cytotoxicity to Induction of Cell Death Through Interconnections Between Apoptotic and Necrotic Pathways
,”
Curr. Med. Chem.
,
10
(
3
), pp.
257
266
.10.2174/0929867033368484
23.
Hamers
,
F. P. T.
,
Gispen
,
W. H.
, and
Neijt
,
J. P.
,
1991
, “
Neurotoxic Side-Effects of Cisplatin
,”
Eur. J. Cancer Clin. Oncol.
,
27
(
3
), pp.
372
376
.10.1016/0277-5379(91)90549-S
24.
Von Hoff
,
D. D.
,
Schilsky
,
R.
,
Reichert
,
C. M.
,
Reddick
,
R. L.
,
Rozencweig
,
M.
,
Young
,
R. C.
, and
Muggia
,
F. M.
,
1978
, “
Toxic Effects of Cis-Dichlorodiammineplatinum (II) in Man
,”
Cancer Treat. Rep.
,
63
(
9–10
) pp.
1527
1531
10.1007/BF00254137742.
25.
Lau
,
J. K.
, and
Deubel
,
D. V.
,
2005
, “
Loss of Amine From Platinum (II) Complexes: Implications for Cisplatin Inactivation, Storage, and Resistance
,”
Chem.- Eur. J.
,
11
(
9
), pp.
2849
2855
.10.1002/chem.200401053
26.
Jain
,
R. K.
,
2001
, “
Normalizing Tumor Vasculature With Anti-Angiogenic Therapy: A New Paradigm for Combination Therapy
,”
Nat. Med.
,
7
(
9
), pp.
987
989
.10.1038/nm0901-987
27.
Lin
,
J.
, and
Alexander-Katz
,
A.
,
2013
, “
Cell Membranes Open ‘Doors' for Cationic Nanoparticles/Biomolecules: Insights Into Uptake Kinetics
,”
ACS Nano.
,
7
(
12
), pp.
10799
10808
.10.1021/nn4040553
28.
Fernandez-Urrusuno
,
R.
,
Calvo
,
P.
,
Remunan-Lopez
,
C.
,
Vila-Jato
,
L.
, and
Alonso
,
M.
,
1999
, “
Enhancement of Nasal Absorption of Insulin Using Chitosan Nanoparticles
,”
Pharm. Res.
,
16
(
10
), pp.
1576
1581
.10.1023/A:1018908705446
29.
Shojaei
,
A. H.
,
1998
, “
Buccal Mucosa as a Route for Systemic Drug Delivery: A Review
,”
J. Pharm. Pharm. Sci.
,
1
(
1
), pp.
15
30
10.5138/ijdd.v3i4.426.
30.
Nakamura
,
T.
, and
Kinoshita
,
S.
,
2003
, “
Ocular Surface Reconstruction Using Cultivated Mucosal Epithelial Stem Cells
,”
Cornea
,
22
(
7
), pp.
S75
S80
.10.1097/00003226-200310001-00011
31.
Berners-Price
,
S. J.
,
Frenkiel
,
T. A.
,
Frey
,
U.
,
Ranford
,
J.
, and
Sadler
,
P. J.
,
1992
, “
Hydrolysis Products of Cisplatin: pKa Determinations Via [1H, 15N] NMR Spectroscopy
,”
J. Chem. Soc., Chem. Commun.
,
1992
(
10
), pp.
789
791
.10.1039/c39920000789
32.
Corden
,
B. J.
,
1987
, “
Reaction of Platinum (II) Antitumor Agents With Sulfhydral Compounds and the Implications for Nephrotoxicity
,”
Inorg. Chim. Acta
,
137
(
1
), pp.
125
130
.10.1016/S0020-1693(00)87131-5
33.
Galluzzi
,
L.
,
Senovilla
,
L.
,
Vitale
,
I.
,
Michels
,
J.
,
Martins
,
I.
,
Kepp
,
O.
,
Castedo
,
M.
, and
Kroemer
,
G.
,
2012
, “
Molecular Mechanisms of Cisplatin Resistance
,”
Oncogene
,
31
(
15
), pp.
1869
1883
.10.1038/onc.2011.384
34.
Long
,
D. F.
, and
Repta
,
A. J.
,
1981
, “
Review Article Cisplatin: Chemistry, Distribution and Biotransformation
,”
Biopharm. Drug Dispos.
,
2
(
1
), pp.
1
16
.10.1002/bdd.2510020102
35.
Bose
,
R. N.
,
Cornelius
,
R. D.
, and
Viola
,
R. E.
,
1985
, “
Kinetics and Mechanisms of Platinum (II)-Promoted Hydrolysis of Inorganic Polyphosphates
,”
Inorg. Chem.
,
24
(
24
), pp.
3989
3996
.10.1021/ic00218a006
36.
Shafee
,
N.
,
Smith
,
C. R.
,
Wei
,
S.
,
Kim
,
Y.
,
Mills
,
G. B.
,
Hortobagyi
,
G. N.
,
Stanbridge
,
E. J.
, and
Lee
,
E. Y.-H. P.
,
2008
, “
Cancer Stem Cells Contribute to Cisplatin Resistance in Brca1/p53–Mediated Mouse Mammary Tumors
,”
Cancer Res.
,
68
(
9
), pp.
3243
3250
.10.1158/0008-5472.CAN-07-5480
37.
Dass
,
C. R.
, and
Choong
,
P. F. M.
,
2008
, “
The Use of Chitosan Formulations in Cancer Therapy
,”
J. Microencapsulation
,
25
(
4
), pp.
275
279
.10.1080/02652040801970461
38.
Huang
,
M.
,
Khor
,
E.
, and
Lim
,
L.-Y.
,
2004
, “
Uptake and Cytotoxicity of Chitosan Molecules and Nanoparticles: Effects of Molecular Weight and Degree of Deacetylation
,”
Pharm. Res.
,
21
(
2
), pp.
344
353
.10.1023/B:PHAM.0000016249.52831.a5
39.
Agnihotri
,
S. A.
,
Mallikarjuna
,
N. N.
, and
Aminabhavi
,
T. M.
,
2004
, “
Recent Advances on Chitosan-Based Micro-and Nanoparticles in Drug Delivery
,”
J. Controlled Release
,
100
(
1
), pp.
5
28
.10.1016/j.jconrel.2004.08.010
40.
Freier
,
T.
,
Koh
,
H. S.
,
Kazazian
,
K.
, and
Shoichet
,
M. S.
,
2005
, “
Controlling Cell Adhesion and Degradation of Chitosan Films by N-Acetylation
,”
Biomaterials
,
26
(
29
), pp.
5872
5878
.10.1016/j.biomaterials.2005.02.033
41.
Pan
,
Y.
,
Li
,
Y. J.
,
Zhao
,
H. Y.
,
Zheng
,
J. M.
,
Xu
,
H.
,
Wei
,
G.
,
Hao
,
J. S.
, and
Cui
,
F. D.
,
2002
, “
Bioadhesive Polysaccharide in Protein Delivery System: Chitosan Nanoparticles Improve the Intestinal Absorption of Insulin In Vivo
,”
Int. J. Pharm.
,
249
(
1
), pp.
139
147
.10.1016/S0378-5173(02)00486-6
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