Mechanism and Efficacy of Sub–50-nm Tenfibgen Nanocapsules for Cancer Cell–Directed Delivery of Anti-CK2 RNAi to Primary and Metastatic Squamous Cell Carcinoma

Abstract

Improved survival for HNC patients with recurrent and metastatic disease warrants that cancer therapy is specific with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub-50 nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell-specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA induced silencing complex (Ago2/RISC) pathway to target the CK2αα' mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft head and neck squamous cell carcinoma (HNSCC) models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise.

Evaluation of NIN/RPN12 binding protein inhibits proliferation and growth in human renal cancer cells

“…Given the prevalence and availability of RNAi technology in cancer research or cancer therapy [27], we used a RNAi system that can effectively knock down the expression of NOB1 at both the RNA and protein levels [28,29]. As shown in Fig.…”

Simultaneous blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme

“…Additionally, acquisition of tumor resistance to CX-4945 has been reported [13]. Recently, tenfibgen nanoparticles for the delivery of CK2 siRNA to head and neck cancers have been developed [14]. In a xenograft model of hypopharyngeal squamous cell carcinoma, 50% of treated mice survived for more than 6 months after 2 systemic administrations of the nanoparticles at a dose of 0.01 mg/kg.…”

Targeting CK2 for Cancer Therapy Using a Nanomedicine Approach

“…Immunoblot analysis of spleens from control-treated mice showed the presence of keratin-14 signal indicating metastases, as well as stronger CK2αα′ signal than spleens from naïve, non-tumor mice. In contrast, the expression of CK2αα′ mRNA and protein and of keratin-14 protein was signifi cantly reduced in the mice treated with TBG-RNAi-CK2 [ 88 ]. Moreover, hematological profi le and serum chemistry analyses indicated no changes between 25 mg/kg TBG-RNAi-CK2-treated and TBG-sense-CK2 control mice.…”

“…At 200 days posttreatment, 25 of 46 TBG-RNAi-CK2-treated mice survived without local recurrence, whereas only 12 of 53 control mice survived. Survival for more than 6 months was statistically signifi cant for two of the three models [ 88 ].…”