Site-specific delivery of drugs while minimizing unwanted distribution has been one of the pursued goals in cancer therapy. In this endeavor, we have developed targeted polymeric nanoparticles called amphiphilic urethane acrylate nonionomer (UAN) for encapsulation of diverse water-insoluble drugs and diagnostic agents, as well as for simple and reproducible surface conjugation of targeting ligands. Using monoclonal antibodies or lymphocyte function-associated antigen-1 (LFA-1) I domain engineered for varying affinities to intercellular adhesion molecule (ICAM)-1, we were able to deliver UAN nanoparticles to human cancer cells with the efficiency dependent on the strength of the molecular interactions and the degree of ICAM-1 expression on cell surface. Compared to non-specific uptake of free drugs, targeted delivery of UAN nanoparticles carrying equal amount of drugs produced more potent cytotoxicity. Notably, without the targeting ligands attached, UAN nanoparticles were largely precluded from non-specific uptake by the cells, resulting in much lower toxicity. The versatility of our UAN nanoparticles in both payload encapsulation and presentation of targeting ligands may facilitate developing a robust platform for evaluating various combinations of cancer drugs and molecular interactions toward developing effective cancer therapy formulations.
BACKGROUND
The BRAFV600E mutation is present in 62% of radioactive iodine resistant (RAIR) thyroid tumors and is associated with down-regulation of the sodium-iodide-symporter (NIS) and TSH-receptor (TSHr). We sought to evaluate the combined effect of BRAF inhibition and TSH supplementation on 131I uptake of BRAFV600E-mutant human thyroid cancer cells.
MATERIALS AND METHODS
WRO cells (a BRAFV600E-mutant follicular-derived papillary thyroid carcinoma cell line) were transfected with siRNA targeting BRAF for 72 hours in a physiologic TSH environment. NIS and TSHr expression were then evaluated at three levels: gene expression, protein levels, and 131I uptake. These three main outcomes were then reassessed in TSH-depleted media and media supplemented with supratherapeutic concentrations of TSH.
RESULTS
NIS gene expression increased 5.5-fold 36 hours after transfection (p=0.01) and TSHr expression increased 2.8-fold at 24 hours (p=0.02). NIS and TSHr protein levels were similarly increased 48 and 24 hours post-transfection, respectively. Seventy two hours after BRAF inhibition, 131I uptake showed was unchanged in TSH-depleted media, increased by 7.5-fold (p<0.01) in physiologic TSH media, and increased by 9.1-fold (p<0.01) in supratherapeutic TSH media.
CONCLUSIONS
The combined strategy of BRAF inhibition and TSH supplementation results in greater 131I uptake than when either technique is utilized alone. This represents a simple and feasible approach that may improve outcomes in patients with RAIR thyroid carcinomas for which current treatment algorithms are ineffective.
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