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To evaluate the adverse effects and therapeutic efficacy of our biocompatible polymer platform delivering targeted local therapy of cytokine CCL21 and cisplatin in a partially resected xenograft animal model of head and neck squamous cell carcinoma. In addition, to evaluate the efficacy of cotreatment with radiotherapy and assess the biocompatibility of the cisplatin-eluting polymer in the murine neck.Experimental animal study.Academic research laboratory.SCCVII/SF cell injection established head and neck squamous cell carcinoma tumors in C3H/HeJ mice. Subjects underwent surgery, and a chemokine-eluting polymer was implanted into the resected site. Subjects treated with cisplatin received radiation or no radiation, and tissue was harvested after 8 weeks to assess polymer biocompatibility.Our results with the polymer platform significantly (P < .05) reduced SCCVII/SF tumor size in C3H/HeJ mice with cisplatin (49% ± 8.7%, Δ3.4 ± 0.6 cm3 [95% CI]), CCL21 (42% ± 4.8%, Δ3.5 ± 0.4 cm3), and cisplatin/CCL21 dual-agent polymer (82% ± 4.4%, Δ8.0 ± 0.4 cm3) as compared with controls. Cisplatin polymer with high-dose (16 Gy) and low-dose (4 Gy) radiation reduced tumor mass (respectively, 92% ± 7.2%, Δ6.1 ± 0.5 cm3; 85% ± 7.4%, Δ5.7 ± 0.5 cm3) as compared with the reduction from high-dose radiotherapy alone (70% ± 7.9%, Δ4.7 ± 0.5 cm3). No significant toxicity or inflammation was noted on histopathology after radiotherapy and cisplatin-eluting polymer treatment.Cisplatin, CCL21, and cisplatin/CCL21 dual-agent polymer all exhibit significant antitumor effects and decrease tumor burden. Moreover, combination cisplatin polymer with radiotherapy may permit a decrease in intensity of radiation therapy in patients having received the cisplatin polymer. Histopathologic analysis suggests that the polymer is free from significant adverse effects in this model and warrants clinical trial.