title: Prevention of tumor recurrence and distant metastasis formation in a breast cancer mouse model by biodegradable implant of 131I-norcholesterol.
abstract: Brachytherapy has many potential roles in cancer therapy. However, major constraints are associated with placement and removal procedures of the brachytherapy machinery. An attractive approach would be the use of a biodegradable implant loaded with a radioisotope, thus enabling targeted radiotherapy, while reducing the need for surgical procedures for the removal of brachytherapy hardware. In this study, crosslinked chitosan (Ct) hydrogels were prepared and loaded with (131)I-norcholesterol ((131)I-NC). The radioactive hydrogels ((131)I-NC-Ct) were implanted adjacent to 4T1 cell-induced tumors in two different xenograft mice models either as primary therapy or surgical adjuvant therapy of breast cancer. Non-treated mice and mice implanted with naive (non-radioactive) hydrogels served as control groups. In the primary therapy model, the progression rate of the tumor was delayed by two weeks compared with the non-treated and the naive-implant control animals, resulting in a one-week extension in the survival of the treated animals. In the adjuvant therapy model, for the treatment of minimal residual disease, (131)I-NC-Ct implants were able to prevent 69% of tumor recurrence, and to prevent metastatic spread resulting in long-term survival, compared with 0% long-term survival of the non-treated and the naive control groups. Imaging of the hydrogel's in vivo elimination revealed a first order process with a half-life of 14 days. The degradation was caused by oxidation of the Ct as was assessed by in vitro H&E stain. Biodegradable radioactive implants are suggested as a novel platform for the delivery of brachytherapy. This radiotherapy regimen may prevent locoregional recurrence and metastatic spread after tumor resection.
authors.affiliation: Department of Pharmaceutics, The Hebrew University of Jerusalem, School of Pharmacy, Jerusalem, Israel.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Jackie
authors.initials: J
authors.lastname: Kleinstern
authors.forename: Victoria
authors.initials: V
authors.lastname: Doviner
authors.forename: Boris
authors.initials: B
authors.lastname: Orkin
authors.forename: Morris
authors.initials: M
authors.lastname: Srebnik
authors.forename: Aviram
authors.initials: A
authors.lastname: Nissan
authors.forename: Abraham
authors.initials: A
authors.lastname: Rubinstein
mesh_terms: D015071:19-Iodocholesterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D020341:Absorbable Implants; D000818:Animals; D001918:Brachytherapy / Q000379:methods*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry* / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000737:chemistry; D005260:Female; D005976:Glutaral / Q000737:chemistry; D006207:Half-Life; D020100:Hydrogels; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010084:Oxidation-Reduction; D018714:Radiotherapy, Adjuvant; D055502:Secondary Prevention; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D003432:Cross-Linking Reagents; D020100:Hydrogels; C023033:I-norcholesterol; D015071:19-Iodocholesterol; D048271:Chitosan; D005976:Glutaral