Prevention of tumor recurrence and distant metastasis formation in a breast cancer mouse model by biodegradable implant of 131I-norcholesterol.
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.
Azab
Abdel Kareem
AK
Department of Pharmaceutics, The Hebrew University of Jerusalem, School of Pharmacy, Jerusalem, Israel.
Kleinstern
Jackie
J
Doviner
Victoria
V
Orkin
Boris
B
Srebnik
Morris
M
Nissan
Aviram
A
Rubinstein
Abraham
A
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
D003432:Cross-Linking Reagents; D020100:Hydrogels; C023033:I-norcholesterol; D015071:19-Iodocholesterol; D048271:Chitosan; D005976:Glutaral