Engineered fusion protein-loaded gold nanocarriers for targeted co-delivery of doxorubicin and erbB2-siRNA in human epidermal growth factor receptor-2+ ovarian cancer

Kotcherlakota, Rajesh; Srinivasan, Durga Jeyalakshmi; Mukherjee, Sudip; Haroon, Mohamed Mohamed; Dar, G. H.; Venkatraman, Uthra; Patra, Chitta Ranjan; Gopal, Vijaya

doi:10.1039/c7tb01587a

Cited by 47 publications

(42 citation statements)

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“…The increased absorbance of the Au-CGKRK nanoconjugate and the observed red shift at the saturation point (Figure 2) were fully consistent with a recently reported red shift of protein-conjugated AuNPs. 44 The percent of added CGKRK peptide (at the saturation point, 10 μg/mL) conjugated to the surface of the AuNPs was found to be 42% by quantitative HPLC analysis of the supernatant after separating the Au-CGKRK nanoconjugates by centrifugation (using the standard HPLC calibration graph for CGKRK, data not shown).…”

Section: Resultsmentioning

confidence: 99%

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Au-CGKRK Nanoconjugates for Combating Cancer through T-Cell-Driven Therapeutic RNA Interference

et al. 2018

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Numerous prior studies on fighting cancer have been based on using inhibitors of JAK-STAT pathway (signal transducer and activator of transcription 3 (STAT3) inhibitor in particular), a signaling pathway responsible for progression of many types of cancer cells. However, recent studies have shown that STAT3 activation leads to upregulation of program death receptor-ligand 1 (PD-L1, an immune checkpoint protein that plays a major role behind evasion of immune systems by growing tumors) expression levels in tumor cells, leading to enhanced immune suppression. This is why global efforts are being witnessed in combating cancer through use of immune checkpoint inhibitors. Herein, we report on the design, synthesis, physicochemical characterizations, and bioactivity evaluation of novel tumor- and tumor-vasculature-targeting noncytotoxic Au-CGKRK nanoconjugates (17–80 nm) for combating tumor. Using a syngeneic mouse tumor model, we show that intraperitoneal (i.p.) administration of the Au-CGKRK nanoparticles (NPs) complexed with both PD-L1siRNA (the immune checkpoint inhibitor) and STAT3siRNA (the JAK-STAT pathway inhibitor) results in significant (>70%) enhancement in overall survivability (OS) in melanoma-bearing mice ( n = 5) when compared to the OS in the untreated mice group. The expression levels of CD8 and CD4 proteins in the tumor lysates of differently treated mice groups (by Western blotting) are consistent with the observed OS enhancement being a T-cell-driven process. Biodistribution study using near-infrared dye-loaded Au-CGKRK nanoconjugates revealed selective accumulation of the dye in mouse tumor. Notably, the overall survival benefits were significantly less (∼35%) when melanoma-bearing mice were treated (i.p.) with Au-CGKRK NPs complexed with only PD-L1siRNA or with STAT3siRNA alone. The presently described Au-CGKRK nanoconjugates are expected to find future use in therapeutic RNA-interference-based cancer immunotherapy.

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Section: Resultsmentioning

confidence: 99%

“…Such size difference of AuNPs measured by DLS and TEM has also been reported in our earlier study. 44…”

Section: Resultsmentioning

confidence: 99%

Au-CGKRK Nanoconjugates for Combating Cancer through T-Cell-Driven Therapeutic RNA Interference

et al. 2018

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“…, tumors treated with the Dox-DNA-AuNP had a significantly lower Ki-67 labeling index (4.04 ± 0.71), compared to the free Dox (8.68 ± 0.67)-treated or control (16.96 ± 0.88) groups, demonstrating the effective tumor growth inhibition of Dox-DNA-AuNP. This result indicates Dox-DNA-AuNP plays a key role in enhancing the inhibition of tumor cell proliferation, induction of tumor cell apoptosis, and shows the potential to support tumor suppression[40,41].…”

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In Vivo and In Vitro Anticancer Activity of Doxorubicin-loaded DNA-AuNP Nanocarrier for the Ovarian Cancer Treatment

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Kim

et al. 2020

Cancers

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In this study, we have determined the anticancer activity of doxorubicin (Dox)-loaded DNA/gold nanoparticle (AuNP) nanocarrier (Dox-DNA-AuNP) for the treatment of ovarian cancer. The anticancer effect of Dox-DNA-AuNP was evaluated in vitro using the EZ-Cytox cell viability assay on three human ovarian cancer cell lines, SK-OV-3, HEY A8, and A2780. Dox-DNA-AuNP exhibited outstanding activity with good IC50 values of 4.8, 7.4, and 7.6 nM for SK-OV-3, HEY A8, and A2780, respectively. In vivo evaluation further demonstrated the superior anticancer effects of Dox-DNA-AuNP by inhibiting tumor growth compared to free Dox in an established SK-OV-3 xenograft mice model. Dox-DNA-AuNP showed about a 2.5 times higher tumor growth inhibition rate than free Dox. Furthermore, the immunohistochemical analysis of Ki67 antigen expression showed the lowest number of proliferative cells in the ovarian tumor tissue treated with Dox-DNA-AuNP. These results suggest Dox-DNA-AuNP might be a potential effective agent in ovarian cancer chemotherapy.

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“…96,97 Rajesh Kotcherlakota and team prepared TDDS (Au-TR-DX-si) to target the same. 98 Pancreatic cancer being one of the dangerous cancers, its prominent cause being perineural invasion has its adverse effects such as increased neurite densities. 99,100 Targeting NGF gene is the most important to tackle pancreatic cancer.…”

Section: Employing Gold Nanoparticles For Gene Delivery In Vitromentioning

confidence: 99%

Functionalized gold nanostructures: promising gene delivery vehicles in cancer treatment

et al. 2019

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Engineered fusion protein-loaded gold nanocarriers for targeted co-delivery of doxorubicin and erbB2-siRNA in human epidermal growth factor receptor-2+ ovarian cancer

Abstract: Gold nanoparticle based targeted drug delivery system (TDDS) for transporting DX and siRNA in HER2+ ovarian cancer.

Cited by 47 publications

References 56 publications

Au-CGKRK Nanoconjugates for Combating Cancer through T-Cell-Driven Therapeutic RNA Interference

Au-CGKRK Nanoconjugates for Combating Cancer through T-Cell-Driven Therapeutic RNA Interference

In Vivo and In Vitro Anticancer Activity of Doxorubicin-loaded DNA-AuNP Nanocarrier for the Ovarian Cancer Treatment

Functionalized gold nanostructures: promising gene delivery vehicles in cancer treatment

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