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. 2016 Jul 12;113(28):7750-5.
doi: 10.1073/pnas.1605841113. Epub 2016 Jun 24.

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

Yanlan Liu  1 , Viswanath Gunda  2 , Xi Zhu  1 , Xiaoding Xu  1 , Jun Wu  1 , Diana Askhatova  1 , Omid C Farokhzad  3 , Sareh Parangi  4 , Jinjun Shi  3
Affiliations

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

Yanlan Liu et al. Proc Natl Acad Sci U S A. .

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.

Keywords: NIR imaging; anaplastic thyroid cancer; nanoparticle; siRNA delivery; theranostic.

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Conflict of interest statement

Conflict of interest statement: O.C.F. discloses financial interest in BIND Therapeutics, Selecta Biosciences, and Tarveda Therapeutics.

Figures

Fig. 1.
Fig. 1.
NIR NP platform. (A) Schematic illustration of the NIR NPs for siRNA delivery. (B) Excitation and emission of NIR NPs. (C) The TEM image of the NIR NPs. Inset is the digital picture of the NIR NPs in PBS. (D) Confocal imaging of HeLa cells incubated with the NIR NPs loaded with DY547-labeled siRNA. (E) ζ-Potentials of three different NIR NPs loaded with luciferase siRNA (NP#1, NP#2, and NP#3). Silencing efficiency and cytotoxicity of (F) NP#1, (G) NP#2, and (H) NP#3 loaded with luciferase siRNA.
Fig. 2.
Fig. 2.
In vivo NIR imaging. (A) Pharmacokinetics profile of NP#1, NP#2, and NP#3. (B) Time-dependent fluorescence imaging of a BRAFV600E-mutated 8505C tumor-bearing mouse after a single-dose injection of NIR NPs. (C) NIR fluorescence images of organs from B. (D) NIR fluorescence imaging of LNs at 24 h after i.v. injection of NIR NPs: 1, a small piece of muscle; 2 and 3, inguinal LNs; 4–7, neck LNs; 8 and 9, lateral thoracic LNs; and 10 and 11, axillary LNs. (E) SLN mapping 10 min after s.c. injection of NIR NPs into the forepaws.
Fig. 3.
Fig. 3.
NP-mediated BRAF silencing and functional effects in BRAFV600E-mutated 8505C cells. (A) Western blot analysis of BRAF, total ERK1/2 (T-ERK1/2), phosphorylated ERK1/2 (P-ERK1/2), total MEK (T-MEK), and phosphorylated MEK (P-MEK) after treatment of NP(siControl) or NP(siBRAF) with different siBRAF sequences. (B) Immunofluorescence images of BRAFV600E-mutated 8505C cells after treatment of NP(siControl) or NP(siBRAF) with different siBRAF sequences (red, BRAF; green, actin; and blue, nucleus). (C) Cell proliferation of BRAFV600E-mutated 8505C cells after treatment with NP(siControl) or NP(siBRAF) having different siBRAF sequences. (D and E) Migrated and invaded numbers of BRAFV600E-mutated 8505C cells after treatment with NP(siControl) or NP(siBRAF) with different siBRAF sequences, respectively. **P < 0.01 vs. NP(siControl).
Fig. 4.
Fig. 4.
In vivo antitumor effect of NP(siBRAF) in xenograft ATC mouse models. (A) Western blot analysis of BRAF expression in BRAFV600E-mutated 8505C tumor tissue after systemic treatment with NP(siControl) and NP(siBRAF). (B) Immunochemical microphotographs of BRAF expression in BRAFV600E-mutated 8505C tumor tissue after systemic treatment with NP(siControl) or NP(siBRAF). (C) Tumor growth curves of PBS-, NP(siControl)-, and NP(siBRAF)-treated BRAFV600E-mutated 8505C tumor-bearing mice. Three i.v. injections are indicated by arrows. *P < 0.05 vs. NP(siControl). (D) Representative picture of tumors from C. (E) Body weight changes of three groups.
Fig. 5.
Fig. 5.
In vivo inhibition of tumor growth and metastasis in the orthotopic ATC mouse model. (A) In vivo NIR imaging of different organs from nontreated and NP-treated mice (24 h after i.v. injection). (B) Biodistribution of NIR NPs quantified from A. (C) Western blot analysis of the BRAF expression in orthotopic ATC tumors after treatment with NP(siControl) or NP(siBRAF). (D) Therapeutic efficacy of NP(siBRAF) in orthotopic ATC mouse models. (E) Gross lung images from the mice bearing orthotopic ATC tumors with NP(siControl) or NP(siBRAF) treatment 1 month after injection with BRAFV600E-mutated 8505C cells with GFP expression. Bright green spots indicate micrometastases.
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