Development of thermosensitive chitosan/glicerophospate injectable in situ gelling solutions for potential application in intraoperative fluorescence imaging and local therapy of hepatocellular carcinoma: a preliminary study.
OBJECTIVE
Thermosensitive chitosan/glycerophosphate (C/GP) solutions exhibiting sol-gel transition around body temperature were prepared to develop a class of injectable hydrogel platforms for the imaging and loco-regional treatment of hepatocellular carcinoma (HCC). Indocyanine green (ICG) was loaded in the thermosensitive solutions in order to assess their potential for the detection of tumor nodules by fluorescence.


METHODS
The gel formation of these formulations as well as their gelling time, injectability, compactness and resistance of gel structure, gelling temperature, storage conditions, biodegradability, and in vitro dye release behavior were investigated. Ex vivo studies were carried out for preliminary evaluation using an isolated bovine liver.


RESULTS
Gel strengths and gelation rates increased with the cross-link density between C and GP. These behaviors are more evident for C/GP solutions, which displayed a gel-like precipitation at 4°C. Furthermore, formulations with the lowest cross-link density between C and GP exhibited the best injectability due to a lower resistance to flow. The loading of the dye did not influence the gelation rate. ICG was not released from the hydrogels because of a strong electrostatic interaction between C and ICG. Ex vivo preliminary studies revealed that these injectable formulations remain in correspondence of the injected site.


CONCLUSIONS
The developed ICG-loaded hydrogels have the potential for intraoperative fluorescence imaging and local therapy of HCC as embolic agents. They form in situ compact gels and have a good potential for filling vessels and/or body cavities.
a 1 University of Sassari, Department of Chemistry and Pharmacy , Sassari, Italy.
Andrea
A
Salis
a 1 University of Sassari, Department of Chemistry and Pharmacy , Sassari, Italy.
Giovanna
G
Rassu
b 2 University of Szeged, Department of Pharmaceutical Technology , H-6720, Szeged, Eötvös str. 6, Hungary.
Maria
M
Budai-Szűcs
c 3 IRCCS Policlinico San Matteo Foundation , Pavia, Italy.
Ilaria
I
Benzoni
b 2 University of Szeged, Department of Pharmaceutical Technology , H-6720, Szeged, Eötvös str. 6, Hungary.
Erzsébet
E
Csányi
b 2 University of Szeged, Department of Pharmaceutical Technology , H-6720, Szeged, Eötvös str. 6, Hungary.
Szilvia
S
Berkó
c 3 IRCCS Policlinico San Matteo Foundation , Pavia, Italy.
Marcello
M
Maestri
d 4 University of Pavia, IRCCS Policlinico San Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences , Pavia, Italy.
Paolo
P
Dionigi
e 5 University of Pavia , Pavia, Italy.
Elena P
EP
Porcu
a 1 University of Sassari, Department of Chemistry and Pharmacy , Sassari, Italy.
Elisabetta
E
Gavini
f 6 University of Sassari, Department of Chemistry and Pharmacy , via Muroni 23/a, 07100 Sassari, Italy +39079228754 ; +39079228732 ; pgiunc@uniss.it.
Paolo
P
Giunchedi
D020341:Absorbable Implants; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000188:drug therapy; D002417:Cattle; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry*; D004396:Coloring Agents / Q000008:administration & dosage*; D003952:Diagnostic Imaging; D016503:Drug Delivery Systems; D004343:Drug Implants; D005782:Gels; D005994:Glycerophosphates / Q000737:chemistry*; D007208:Indocyanine Green / Q000008:administration & dosage*; D007269:Injections, Intra-Arterial; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D019999:Pharmaceutical Solutions; D013696:Temperature; D014783:Viscosity
D000970:Antineoplastic Agents; D004396:Coloring Agents; D004343:Drug Implants; D005782:Gels; D005994:Glycerophosphates; D019999:Pharmaceutical Solutions; D048271:Chitosan; D007208:Indocyanine Green
chitosan; glycerophosphate; hepatocellular carcinoma; indocyanine green; stimuli-sensitive hydrogel; transarterial embolization