Oral siRNA Delivery to Treat Colorectal Liver Metastases

Kang, Suk Ho; Revuri, Vishnu; Lee, Sang-Joon; Cho, Sungpil; Park, Inkyu; Cho, Kwang Jae; Bae, Woo Kyun; Lee, Yong-Kyu

doi:10.1021/acsnano.7b05547

Cited by 73 publications

(69 citation statements)

References 38 publications

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“…8 Therefore, nonviral carriers have great potential in the application of gene therapy due to their better safety profile. gold NP, 10 and mesoporous silica, 11 have been developed to prepare antitumor nanomedicines with passive tumor-targeting properties due to the "enhanced permeability and retention" effect. 12 Among these nanomaterials, selenium nanoparticles (SeNPs) have attracted increasing attention in the field of drug delivery vehicle in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy

Xia¹,

Guo²,

Xu³

et al. 2018

IJN

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Background Small interfering RNA (siRNA) as a new therapeutic modality holds promise for cancer treatment. However, the traditional viral carriers are prone to immunogenicity and risk of insertional mutagenesis. Methods In order to provide a tumor-targeted delivery carrier of siRNA in cancer therapy, the hyaluronic acid (HA)-selenium (Se)-polyethylenimine (PEI) nanoparticle (NP) was fabricated by decorating SeNP with HA as a tumor-targeting moiety and by linking the polycationic polymers polyethylenimine PEI onto the surface of SeNP. The siRNA was loaded to the surface of SeNP HA-Se-PEI via the electrostatic interaction between siRNA and PEI to prepare the functionalized SeNP HA-Se-PEI@siRNA. Results The HA-Se-PEI@siRNA was internalized into the HepG2 cell mainly in a clathrin-mediated endocytosis manner. Owing to the active tumor-targeted effect mediated by HA, HA-Se-PEI@siRNA achieved the obvious higher transfection efficiency, greater gene silencing ability, and stronger cytotoxicity in the HepG2 cell compared with the passive tumor-targeted NP Se-PEI@siRNA. The knockdown of hairy and enhancer of split 5 by HA-Se-PEI@siRNA induced the HepG2 cell cycle arrest at the G0/G1 phase and apoptosis. Furthermore, the treatment with HA-Se-PEI@siRNA resulted in greater antitumor efficacy compared with the Se-PEI@siRNA in vitro and in vivo. In addition, the HA-Se-PEI@siRNA was almost no toxic to the key organs of mice. Conclusion These findings provided an alternative therapeutic route for targeted cancer treatments.

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Section: Introductionmentioning

confidence: 99%

siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy

Xia¹,

Guo²,

Xu³

et al. 2018

IJN

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“…Therefore, effective strategies for improving oral absorption are urgently needed. Nanocarriers, such as liposomes, 1 nanoparticles, 2,3 nanocrystals, 4 and micelles, 5 have unique physicochemical properties to overcome intestinal epithelial barrier and have attracted more attention in improving the efficiency of oral drug delivery. 6 Nowadays, polymeric micelles (PMs) are promising vehicles to increase the oral absorption of hydrophobic drugs.…”

Section: Introductionmentioning

confidence: 99%

Apically targeted oral micelles exhibit highly efficient intestinal uptake and oral absorption

Wang¹,

Wang²,

Liu³

et al. 2018

IJN

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IntroductionPolymeric micelles (PMs) hold promise for improving solubility and oral absorption of poorly soluble drugs. Unfortunately, the oral absorption of PMs is also limited by intestinal epithelium. To improve the oral delivery efficiency of micelles, transporter-mediated micelles could enhance the transport efficiency across the epithelial barrier, and they have attracted more attention.MethodsPeptide transporter 1 (PepT1)-mediated micelles (Val-PMs/Phe-PMs) were designed by grafting valine (or phenylalanine) onto the surface of curcumin (Cur)-loaded-D-α-tocopheryl polyethylene glycol 1000 succinate micelles (TP-PMs). The oral absorption mechanism and oral bioavailability were further investigated in vitro and in vivo.ResultsThe cellular study showed that Val-PMs/Phe-PMs had a high PepT1 affinity, resulting in a higher drug uptake and transcellular transport than TP-PMs. In rats, Val-PMs/Phe-PMs exhibited higher intestinal accumulation in the apical side of the intestinal epithelium than TP-PMs, promoting drug diffusion across epithelial barrier. The oral bioavailability of Cur was significantly improved by Val-PMs/Phe-PMs, which was about 10.50- and 3.40-fold greater than that of Cur-Sol and TP-PMs, respectively.ConclusionPepT-1-mediated micelles, using PepT1 as a target on intestinal epithelium, have unique functions with intestine and prove promising for oral delivery of poorly water-soluble drugs.

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“…A syngeneic mouse model of colorectal cancer metastasis to the liver was established by infusion of tumor cells into the portal system via intrasplenic injection 24 . Briefly, a left subcostal incision was performed under isoflurane anesthesia, and CT26 cells expressing firefly luciferase (CT26-Fluc) (1 × 10 5 cells) in 50 μL of PBS were inoculated by intrasplenic injection.…”

Section: Methodsmentioning

confidence: 99%

Potassium usnate, a water-soluble usnic acid salt, shows enhanced bioavailability and inhibits invasion and metastasis in colorectal cancer

Yang

Bae

Lee

et al. 2018

Sci Rep

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Usnic acid (UA), a lichen secondary substance, has considerable anticancer activity in vitro, whereas its effect in vivo is limited. Here, potassium usnate (KU) was prepared by the salinization of UA to enhance its water solubility. KU showed increased bioavailability compared with UA in the tumor, liver, and plasma of a CT26 syngeneic mouse tumor xenograft model after oral administration, as determined by LC-MS/MS analysis. KU exhibited potent anticancer effects on colorectal cancer cells and inhibited liver metastasis in an orthotopic murine colorectal cancer model. KU treatment downregulated the epithelial-mesenchymal markers Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in cells and tumor tissues. The present results suggest the potential application of the water-soluble form of UA, KU, in anticancer therapy.

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Oral siRNA Delivery to Treat Colorectal Liver Metastases

Cited by 73 publications

References 38 publications

siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy

siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy

Apically targeted oral micelles exhibit highly efficient intestinal uptake and oral absorption

Potassium usnate, a water-soluble usnic acid salt, shows enhanced bioavailability and inhibits invasion and metastasis in colorectal cancer

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