Systemic delivery of siRNA by actively targeted polyion complex micelles for silencing the E6 and E7 human papillomavirus oncogenes

Abstract

Human papillomavirus (HPV) E6 and E7 oncogenes are essential for the immortalization and maintenance of HPV-associated cancer and are ubiquitously expressed in cervical cancer lesions. Small interfering RNA (siRNA) coding for E6 and E7 oncogenes is a promising approach for precise treatment of cervical cancer, yet a delivery system is required for systemic delivery to solid tumors. Here, an actively targeted polyion complex (PIC) micelle was applied to deliver siRNAs coding for HPV E6/E7 to HPV cervical cancer cell tumors in immune-incompetent tumor-bearing mice. A cell viability assay revealed that both HPV type 16 and 18 E6/E7 siRNAs (si16E6/E7 and si18E6/E7, respectively) interfered with proliferation of cervical cancer cell lines in an HPV type-specific manner. A fluorescence imaging biodistribution analysis further revealed that fluorescence dye-labeled siRNA-loaded PIC micelles efficiently accumulated within the tumor mass after systemic administration. Ultimately, intravenous injection of si16E6/E7 and si18E6/E7-loaded PIC micelles was found to significantly suppress the growth of subcutaneous SiHa and HeLa tumors, respectively. The specific activity of siRNA treatment was confirmed by the observation that p53 protein expression was restored in the tumors excised from the mice treated with si16E6/E7- and si18E6/E7-loaded PIC micelles for SiHa and HeLa tumors, respectively. Therefore, the actively targeted PIC micelle incorporating HPV E6/E7-coding siRNAs demonstrated its therapeutic potential against HPV-associated cancer.

Biodegradable Nanoparticles for Delivering Drugs and Silencing Multiple Genes or Gene activation in Diabetic Nephropathy

“…Nanoparticle loaded with Notch-1 modulators could be excellent if challenges are met with meticulous study. Several investigation and study have been done and reported by researcher about nano particle methods to increase bioavailability, methods to stabilize nanoparticle, prevent degradation, methods to overcome solubility issues, control release from particle [35][36][37][38][39] and use of biodegradable , non-toxic, biocompatible nanomaterial in drug delivery [3,5,7,9,[11][12][13] one such drug molecules which is well reported in nanoparticle formulation is Resveratrol. So based on application of nanotechnology advances and identification of molecular target, cell signaling pathways in DN is possible to deliver drug or silence gene or deliver gene activator or drug with siRNA combination [40] using Nanoparticle.…”

“…Out of the many nanomaterial investigation report suggested that polymer and calcium phosphate material can be used for delivery drug or to load multiple drug or load siRNA or use combination of drug with siRNA or to induce activator drug or inhibitors of signaling pathway. Silencing mechanism [8][9][10][11][12][13][14][15] : Silencing mechanism can be done by using siRNA (small interfering RNA), which inhibited gene expression in several cells.…”

“…RNA stages and its interaction with RISC (RNA Induced Silencing Complex) [8][9][10][11][12][13][14][15] : Linking of RISC i.e. Multiprotein complex and siRNA Followed by activation of RISC.…”

“…Hurdles in delivering siRNA [8][9][10][11][12][13][14][15] : Nucleases cause rapid degradation of naked siRNA after in vivo condition of intravenous administration. The siRNA has short circulating life because it is rapidly excreted by urinary excretory system and also intracellular uptake by phagocytes.…”

“…Principal hurdle in entry of siRNA is bilayer lipid cell membrane of the cell. Some nanoparticles get disassemble in kidney glomerulus, which makes delivery more difficult and challenging [16] Why the need to target genes and why to use nanoparticles: The following difference will make us clear: Overwhelming the hurdles of siRNA delivery [8][9][10][11][12][13][14][15] : A few methodologies were suggested to cope up with these hurdles. Chemical adjustment of the bases, sugars, or phosphate linkages of siRNA may additionally lessen safe incitement and improve the solidness of siRNA.…”