Development of siRNA immunonanovehicles for cancer treatment

GIANNONI F; CERDA MB; LLOYD R; GALLINO J; POLICASTRO L

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2018

Colorectal cancer (CRC) is a high incidence tumor. Patients with CRC are treated mainly with surgery, chemotherapy, radiotherapy, leading to radioquimioresistance of tumors. Consequently, multimodal treatment strategies have a greater probability of success because these therapies affect diverse targets simultaneously. Gene therapy, which involves the use of vectors capable of efficiently directing and transferring genetic material to certain cell populations, in combination with radio or chemotherapy, is an example of this. Within the therapeutic agents for gene therapies, small interfering RNA (siRNA) is an efficient tool for gene silencing. Preliminary studies from our laboratory showed that Peroxirredoxin II (PrxII) enzyme, which is overexpressed in CRC, is involved in radioquimioresistance. Silencing the expression of this enzyme with siRNA produces a radioquimiosensitization and a decrease in cell growth of tumors in vivo. Also, it has been shown that CRC tumor cells overexpress, mostly, the epidermal growth factor receptor (EGFR), which has been associated with radio and chemoresistance, as well as being an indicator of poor prognosis; making it attractive for active targeting of these nanovehicles. The aim of this work is to generate nanoimmunovehicles, in particular immunoliposomes containing a siRNA against PrxII and directed by a VHH against the expression of EGFR, combining this strategy with oxaliplatin. siRNA-PrxII/PEI complexes were obtained, characterized and encapsulated in liposomes in a N/P 3 ratio. VHH against EGFR was synthesized and conjugated to maleimide residues contained in the lipid formulation. Immunoliposomes containing siRNAPrxII/PEI with VHH coupled to its surface generated greater inhibition of proliferation in a CRC line (LoVo) respect to immunoliposomes containing a control siRNA. Likewise, the co-administration of siRNAPrxII/PEI immunonanovehicles combined with oxaliplatin produced even greater inhibition of proliferation respect to the treatments without the addition of the antineoplastic drug; a fact that shows that combined therapies tend to be more efficient than monotherapies.