title: Nanotechnology combined therapy: tyrosine kinase-bound gold nanorod and laser thermal ablation produce a synergistic higher treatment response of renal cell carcinoma in a murine model.
abstract: OBJECTIVE
  To investigate tyrosine kinase inhibitors (TKI) and gold nanorods (AuNRs) paired with photothermal ablation in a human metastatic clear cell renal cell carcinoma (RCC) mouse model. Nanoparticles have been successful as a platform for targeted drug delivery in the treatment of urological cancers. Likewise, the use of nanoparticles in photothermal tumour ablation, although early in its development, has provided promising results. Our previous in vitro studies of nanoparticles loaded with both TKI and AuNRs and activated with photothermal ablation have shown significant synergistic cell kill greater than each individual arm alone. This study is a translation of our initial findings to an in vivo model.
  
  
  METHODS
  Immunologically naïve nude mice (athymic nude-Foxn1nu) were injected subcutaneously bilaterally in both flanks (n = 36) with 2.5 × 106cells of a human metastatic renal cell carcinoma cell line (RCC 786-O). Subcutaneous xenograft tumours developed into 1-cm palpable nodules. AuNRs encapsulated in human serum albumin protein (HSA) nanoparticles were synthesised with or without a TKI and injected directly into the tumour nodule. Irradiation was administered with an 808-nm light-emitting diode laser for 6 min. Mice were humanely killed 14 days after irradiation; tumours were excised, formalin fixed, paraffin embedded, and evaluated for size and the percentage of necrosis by a genitourinary pathologist. The untreated contralateral flank tumours were used as controls.
  
  
  RESULTS
  In mice that did not receive irradiation, TKI alone yielded 4.2% tumour necrosis on the injected side and administration of HSA-AuNR-TKI alone yielded 11.1% necrosis. In the laser-ablation models, laser ablation alone yielded 62% necrosis and when paired with HSA-AuNR there was 63.4% necrosis. The combination of laser irradiation and HSA-AuNR-TKI had cell kill rate of 100%.
  
  
  CONCLUSIONS
  In the absence of laser irradiation, TKI treatment alone or when delivered via nanoparticles produced moderate necrosis. Irradiation with and without gold particles alone also improves tumour necrosis. However, when irradiation is paired with gold particles and drug-loaded nanoparticles, the combined therapy showed the most significant and synergistic complete tumour necrosis of 100% (P < 0.05). This study illustrates the potential of combination nanotechnology as a new approach in the treatment of urological cancers.
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Caleb
authors.initials: C
authors.lastname: Abshire
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Carry
authors.affiliation: Department of Pathology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Sholl
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Sree Harsha
authors.initials: SH
authors.lastname: Mandava
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Datta
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Ranjan
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Callaghan
authors.affiliation: Department of Chemistry, University of New Orleans, New Orleans, LA, USA.
authors.forename: Donna V
authors.initials: DV
authors.lastname: Peralta
authors.affiliation: Department of Chemistry, University of New Orleans, New Orleans, LA, USA.
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Williams
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Weil R
authors.initials: WR
authors.lastname: Lai
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Asim B
authors.initials: AB
authors.lastname: Abdel-Mageed
authors.affiliation: Department of Chemistry, University of New Orleans, New Orleans, LA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tarr
authors.affiliation: Division of Urology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Lee
mesh_terms: D055011:Ablation Techniques; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D006046:Gold / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000628:therapy*; D053685:Laser Therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D036103:Nanotechnology; D043942:Nanotubes; D011505:Protein-Tyrosine Kinases / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D006046:Gold; D011505:Protein-Tyrosine Kinases
keywords: #KidneyCancer; #kcsm; gold nanorods; nanotechnology; photo thermal ablation; renal cell carcinoma; sorafenib; tyrosine kinase inhibitors