Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Abstract

Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of ∼100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP) -mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (∼50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies.T hyroid cancer has been continuously increasing in worldwide incidence for the past few decades and is now the fifth most common malignancy in females (1). Notably, the most aggressive form of thyroid cancer, anaplastic thyroid cancer (ATC), has a mortality rate of nearly 100%, with median survival time of 3-5 months, mainly because of local invasion and metastasis to lung, lymph nodes (LNs), and other tissues (2). The mechanisms that mediate metastasis in ATC strongly depend on the activation of genetic mutations, such as V-Raf murine sarcoma viral oncogene homolog B (BRAF), TP53, RAS, PIK3CA, and AKT1 (3). Current treatments for ATC rely on various combinations of surgical resection with adjuvant therapies, such as chemotherapy and radiotherapy, but have shown only limited survival benefits (4). Therefore, there are compelling reasons to establish new strategies for more effective treatment of metastatic ATC.RNAi is a powerful means for specific silencing of virtually any target gene of interest, thus offering an enormous opportunity to treat cancers and suppress metastases (5). By improving the in vivo delivery of RNAi agents (e.g., siRNA) to solid tumor tissues through the enhanced permeability and retention (EPR) effect (6), nanotechnology has drastically facilitated the clinical translation of RNAi for cancer therapy (5). However, RNAi nanoparticles (NPs) at the clinical stage for cancer treatment (7, 8) may still face challenging obstacles, such ...

Tantalum Sulfide Nanosheets as a Theranostic Nanoplatform for Computed Tomography Imaging‐Guided Combinatorial Chemo‐Photothermal Therapy

“…It has also been increasingly recognized that the EPR effect, the dominant mechanism that mediates the tumor accumulation of nanomaterials, varies among patients and tumor types and even within the same patient/tumor type over time, [18] which highlighted the need to incorporate the imaging function into nanomedicines to identify cancer patients with stronger EPR effects and higher tumor accumulation of nanomedicines for more efficient cancer treatment. [19] …”

S100A4 Knockout Sensitizes Anaplastic Thyroid Carcinoma Cells Harboring BRAFV600E/Mt to Vemurafenib

“…ERK1/2) [8]. Using RNA interference (siRNA) to knock down BRAF in human ATC cell lines, preclinical studies showed the importance of BRAF for intracellular MAPK signaling and proliferation, as tumor growth was significantly inhibited [9,10]. These findings suggested that BRAF could be an effective target for thyroid cancer treatment.…”

“…Vemurafenib/PLX4032 is a selective small molecule inhibitor of B-RafV600E, showing a preferential inhibition of cell proliferation, migration, and invasion of BRAFV600E human ATC cell lines [10][11][12][13]. Furthermore, vemurafenib decreased tumor growth and aggressiveness in an animal model using human ATC cell lines [11,13].…”

Solid phase synthesis and self‐assembly of higher‐order siRNAs and their bioconjugates

“…Moreover, the integration of therapy and diagnostics termed “theranostics” has led to the development of new and improved gene therapeutics for the diagnosis and treatment of cancers (Sumer & Gao, ). Specifically, siRNA bioconjugates containing reporter probes such as fluorophores, near‐infrared (near IR) dyes and photosensitizers as well as those containing contrast agents and radiolabels (Figure b) have been extensively applied as theranostic agents in oncology (Liu et al., ; Zhao, Mi, & Feng, ). In spite of the many fruitful examples of siRNA bioconjugation and their applications in cancer gene therapy, a major limitation is the restriction of a single functional moiety on either the 3′ or 5′ ends of the oligonucleotide.…”