Targeted Delivery of Small Interfering RNA Using Reconstituted High-Density Lipoprotein Nanoparticles

Abstract

RNA interference holds tremendous potential as a therapeutic approach, especially in the treatment of malignant tumors. However, efficient and biocompatible delivery methods are needed for systemic delivery of small interfering RNA (siRNA). To maintain a high level of growth, tumor cells scavenge high-density lipoprotein (HDL) particles by overexpressing its receptor: scavenger receptor type B1 (SR-B1). In this study, we exploited this cellular characteristic to achieve efficient siRNA delivery and established a novel formulation of siRNA by incorporating it into reconstituted HDL (rHDL) nanoparticles. Here, we demonstrate that rHDL nanoparticles facilitate highly efficient systemic delivery of siRNA in vivo, mediated by the SR-B1. Moreover, in therapeutic proof-of-concept studies, these nanoparticles were effective in silencing the expression of two proteins that are key to cancer growth and metastasis (signal transducer and activator of transcription 3 and focal adhesion kinase) in orthotopic mouse models of ovarian and colorectal cancer. These data indicate that an rHDL nanoparticle is a novel and highly efficient siRNA carrier, and therefore, this novel technology could serve as the foundation for new cancer therapeutic approaches.

Multifunctional nanoparticles for cancer immunotherapy

“…In fact, to maintain a high level of growth, tumor cells scavenge high-density lipoprotein (HDL) particles by overexpressing of this receptor. 77 For example, breast cancer cells increase uptake of cholesterol esters by increasing SR-B1 expression. 78 Thanks to the role of SR-B1 in HDL homing to tumor cells, Shahzad and coworkers established a novel formulation of reconstituted HDL (rHDL) NPs for selective delivery of therapeutic payloads for gene silencing of STAT3 and focal adhesion kinase (FAK), which is a critical factor for tumor cell survival, migration, and invasion.…”

“…78 Thanks to the role of SR-B1 in HDL homing to tumor cells, Shahzad and coworkers established a novel formulation of reconstituted HDL (rHDL) NPs for selective delivery of therapeutic payloads for gene silencing of STAT3 and focal adhesion kinase (FAK), which is a critical factor for tumor cell survival, migration, and invasion. 77 Over expression of FAK has been reported in colorectal, breast, ovarian, thyroid, and prostate carcinoma. In ovarian cancer patients, FAK overexpression is associated with aggressive tumor features resulting to poor overall survival.…”

“…In ovarian cancer patients, FAK overexpression is associated with aggressive tumor features resulting to poor overall survival. 79 In this regard, systemic targeting of FAK with liposomal NPs or small molecule inhibitors has shown reduction in tumor growth and metastasis, 77,80 but such approaches are not tumor-specific and could result in undesired side effects. This highlights the need for targeted delivery of these therapeutic molecules.…”

“…Hence, in Shahzad and co-workers' study STAT3 or FAK siRNA targeted delivery was achieved using rHDL NPs in mouse models of ovarian and colorectal cancer and resulted in significant reduction in tumor growth and metastasis, reduction in angiogenesis, and decreased tumor cell survival without any obvious effects on other organs. 77 Combination delivery of TGF-b inhibitor and IL-2 by nano liposomal polymeric gels cause the inactivation of DCs, thus abolish their capacity to present antigens and induce Tcell activation. Besides, TGF-b decreases the number and activity of NK cells, and that reduces the activity of CTLs while increasing the number of T regs .…”

Molecular Therapy as a Future Strategy in Endometrial Cancer

“…Understanding biology of cancer cells could lead to developing novel effective treatment strategic approaches against them (Thanapprapasr et al, 2012). Preclinical studies show different genetic materials and pericellular proteins between normal tissues and cancerous tissues (Shahzad et al, 2011). There were revealed some proteins which effectively blocked the cancerous cascades.…”