title: Efficacy and toxicity of peritumoral delivery of nanoconjugated cisplatin in an in vivo murine model of head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  Treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) uses a multidisciplinary approach often limited by the toxicity and drug resistance of platinum agents.
  
  
  OBJECTIVE
  To test whether a nanocarrier-conjugated cisplatin boosting locoregional drug delivery improves tumor efficacy while decreasing systemic toxicity over systemic cisplatin in a murine model of locally advanced HNSCC.
  
  
  METHODS
  A randomized, controlled, in vivo study compared standard cisplatin with nanocarrier (hyaluronan [HA])-conjugated cisplatin (HA-cisplatin) each at 50% of the maximum tolerated doses in a murine model of locally advanced HNSCC (10 mice/arm, each injected with 1 × 106 MDA-1986 HNSCC cells, with phosphate-buffered saline and HA-only control arms). Mice were treated for 3 weeks and observed for 3 additional weeks.
  
  
  METHODS
  Academic medical center.
  
  
  METHODS
  Forty female Nu/Nu mice. Randomization and treatment arms were initiated once tumor volumes reached 30 mm3.
  
  
  METHODS
  Injection with MDA-1986 HNSCC cells followed by 3 weeks of treatment with cisplatin, HA-cisplatin, phosphate-buffered saline, or HA only.
  
  
  METHODS
  Animal weights and tumor volumes were measured 3 times each week (modified RECIST [Response Evaluation Criteria in Solid Tumors]). At necropsy, animal kidneys were examined for nephrotoxic effects and cochleae were examined for ototoxic effects.
  
  
  RESULTS
  The mice treated with HA-cisplatin showed superior tumor efficacy (1 with complete clinical response, 3 with partial response, 1 with stable disease, and 5 with progressive disease) compared with standard cisplatin (no animals with complete clinical response, 1 with partial response, 1 with stable disease, and 8 with progressive disease), which was statistically significant (P = .003). All control animals developed progressive disease. Weight loss and body score were surrogate measures of treatment toxicity. The HA-cisplatin group had the least weight loss (mean [SD], 10.8% [4.7%]) compared with the cisplatin group (13.6% [5.6%]; P = .25). Body score dropped to 2 or less in all cisplatin-treated mice but not in any HA-cisplatin-treated mice, which also lacked any histologic signs of nephrotoxic or ototoxic effects.
  
  
  CONCLUSIONS
  Nanoconjugated HA-cisplatin significantly improves tumor efficacy with lower toxicity compared with standard cisplatin in locally advanced HNSCC in vivo, justifying additional translational studies.
authors.affiliation: Departments of Surgery, The University ofKansas Medical Center, KansasCity, KS, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Nick
authors.initials: N
authors.lastname: Rockefeller
authors.forename: Ridhwi
authors.initials: R
authors.lastname: Mukerji
authors.forename: Dianne
authors.initials: D
authors.lastname: Durham
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
authors.forename: Shuang
authors.initials: S
authors.lastname: Cai
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Yelizaveta
authors.initials: Y
authors.lastname: Shnayder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin