Crosslinked chitosan implants as potential degradable devices for brachytherapy: In vitro and in vivo analysis
Introduction
External beam radiation, frequently used in the therapy of solid tumors, has significant toxic effects to normal tissues adjacent to the tumor. Brachytherapy is the treatment of disease, usually cancer, at a short distance with a radioactive isotope placed on, in, or near the lesions or tumor [1]. Compared with conventional external beam therapy, brachytherapy offers a superior therapeutic regimen in which high radiation doses are localized in the tumor bed with less adverse effects to the surrounding healthy tissues. However, the efficacy of brachytherapy in the prevention of tumor recurrence as compared to external beam radiation is still under investigation for most tumor types. Breast conservation therapy includes surgical resection of the tumor with surrounding healthy tissue followed by external beam radiation to the whole breast. In recent years many investigators compared whole breast irradiation with partial breast irradiation, either in the form of intraoperative single dose radiation or brachytherapy applied to the surgical site following surgery. Both were found to have the same effectiveness while brachytherapy had less toxic side effects [2]. The MammoSite RTS™ device was approved by the FDA in 2002 for brachytherapy of breast cancer, where a catheter is used to inflate a balloon loaded with the radioactive material in the post lumpectomy cavity immediately or up to 10 weeks post lumpectomy [3]. Conventional brachytherapy for breast conservation requires the insertion of 14 to 20 catheters per procedure and is much more complex than the breast brachytherapy utilizing the MammoSite RTS™ device [4]. Brachytherapy is also used in soft tissue sarcomas of the extremities, cervical [5] and prostate [6] cancers, where small encapsulated radioactive sources are placed adjacent to the tumor [7].
Despite clear advantages of brachytherapy over conservative radiotherapy in the treatment of cervical cancer and selected soft tissue sarcomas of the extremities, some major constraints are associated with its implementation. These include the need for general anesthesia or intravenous sedation, complicated placement procedures (especially in the case of interstitial brachytherapy) [8], [9], [10], [11] and the need for post treatment re-excision for device removal in both intra-luminal and interstitial brachytherapies [12]. An alternative mode of spatial radiotherapy is therefore warranted. A rational approach would be to use a biodegradable implant that affords radiotherapy at the target site or tumor bed. This implant would erode and eliminate from the implantation site by the time the course of therapy is completed, sparing inconvenient surgical procedures for its removal. Such a device would not only provide a more efficient therapy by virtue of its proximity to the site of surgery, but also contribute to the improvement in the quality of life of the patients. Previous reports on the use of polymeric shuttles for the delivery of radioactives are scarce and focused primarily on microparticulate matrices [13], [14].
Chitosan (Ct) is a polymer of β-(1-4)-linked 2-amino-2-deoxy-d-glucopyranose, obtained by deacetylation of chitin, the main component of crustaceans' exoskeleton[15]. Ct has been documented in a variety of medical uses such as orthopedics [16], tissue engineering [17] and wound healing [18]. In the past decade Ct became popular in the design of drug delivery systems not only for its biocompatibility [19] and biodegradation properties but also because of its aggregation and complexation capabilities. This is due to its ability to form ionic and covalent interactions [20], [21] that can be exploited in preparing Ct hydrogels by its crosslinking, for example, with glutaraldehyde [22]. The most widespread use of Ct in drug delivery is in the preparation of microparticulate systems [23]. A lesser number of studies have been performed on Ct as an implantable drug device[24].
The overall goal of the present study was to examine whether crosslinked Ct can serve as a biodegradable implant in brachytherapy. More specifically, the study aims were to: (a) prepare and characterize two types of Ct hydrogels: fast degrading gel (FDG) and slow degrading gel (SDG); (b) examine the in vivo behavior of the two gels after subcutaneous (SC) and intraperitoneal (IP) implantation in the rat, (c) load the gels with an insoluble marker and study its release rate in vivo (d) load the gels with 131I-norcholesterol (131I-NC) and study its in vivo release in the rat (e) evaluate the safety of the implants by histological examination of the tissue response to the implants.
Section snippets
Materials
Unless stated otherwise, all materials were purchased from Sigma (St. Louis, MO, U.S.A.). Solvents were of analytical grade. Water was double distilled.
Animals, anesthesia and euthanasia
Rat (Sabra, 250 g) studies were conducted in accord with the Principles of Laboratory Animal Care (NIH Publication #85-23, 1985 Revision). The Mutual Committee for Animal Welfare of the Hadassah University Hospital and the Faculty of Medicine of The Hebrew University of Jerusalem approved the study protocol. Anesthesia was performed by an
Results
Increasing amounts of GA were used to prepare a series of Ct hydrogels with different crosslinking densities that were characterized by eosin adsorption. Typically, the adsorption process lasted about three hours (Fig. 1A) and the amount of eosin adsorbed into the gels was inversely proportional to the relative amount of GA used for crosslinking; the higher the ratio of GA : Ct, the lower the amount of eosin adsorbed. Minimal adsorption was observed at GA : Ct ratios of 10–12.5 : 1 (Fig. 1B),
Discussion
A series of crosslinked Ct hydrogels were prepared by reacting the polysaccharide with increasing amounts of GA. From a series of physical examinations of the obtained hydrogels it was possible to identify that the gel that reacted maximally with GA was the product G10 (a GA : Ct ratio of 10 : 1) (Fig. 1, Fig. 2). G10 was further processed to produce fast degrading and slow degrading implants. The different degradation properties of the two implants were accomplished by rinsing the crosslinked
Acknowledgements
The results reported here are included in the dissertation project of A. K. Azab in partial fulfillment of his Ph.D. degree requirements at The Hebrew University of Jerusalem. The study was supported by a research grant # 596/02-1 from the Israeli Science Foundation. The help of Dr. Jackie Kleinstern in editing the manuscript is acknowledged with pleasure.
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Affiliated with the David R. Bloom Center of Pharmacy.