Efficacy and safety of dendrimer nanoparticles with coexpression of tumor necrosis factor-&amp;alpha; and herpes simplex virus thymidine kinase in gene radiotherapy of the human uveal melanoma OCM-1 cell line

Wang, Yingchih; Li, Mo; Wei, Wenbin; Shi, Xi

doi:10.2147/ijn.s48950

Cited by 22 publications

(17 citation statements)

References 39 publications

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“…This results in no net gain in the therapeutic index of radiotherapy. Previous reports have tested nanoparticles as radiosensitizer delivery vehicles (24-27). Here, we have demonstrated the efficacy of ACPP technology to deliver the potent radiosensitizer MMAE specifically to tumors.…”

Section: Discussionmentioning

confidence: 99%

Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

et al. 2015

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Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell penetrating peptide targeting matrix metalloproteinases and RGD binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule and dose dependent manner correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with non-targeted free MMAE or tumor targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell penetrating peptides.

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Section: Discussionmentioning

confidence: 99%

Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

et al. 2015

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“…Choroidal melanoma is a serious metastatic malignant melanoma with poor prognosis. Common treatments for choroidal melanoma offer only temporary relief and are ineffective in inhibiting tumour metastasis or improving the survival rate [17]. Thus, exploring new treatment strategies is important for improving the prognosis of choroidal melanoma patients [7].…”

Section: Discussionmentioning

confidence: 99%

Lithium Chloride Induces Apoptosis in Human Choroidal Melanoma Cells via the NOXA/Mcl-1 Axis and Induction of ER Stress

Zhang¹,

Zhang²,

Li³

et al. 2020

Preprint

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Background: Choroidal melanoma is the most common primary intraocular malignancy that occurs in adults. Lithium chloride (LiCl) has been safely used in the clinic to treat psychiatric disorders for several decades. In this study, we aimed to understand whether LiCl exerts anticancer effects on choroidal melanoma cells and elucidate the underlying molecular mechanisms. Methods: Human choroidal melanoma cells were treated with LiCl, and cell survival was assessed with MTT assays. Cell proliferation was measured by plate colony formation assays. Cell apoptosis was evaluated using flow cytometry, and proteins were detected using western blotting. A human choroidal melanoma xenograft model was established to demonstrate the effect of LiCl on human choroidal melanoma in vivo. An unpaired t-test was used to compare differences between two groups, and one-way ANOVA was used to compare differences among more than two groups.Results: We found that LiCl inhibited cell survival and clonogenic potential and induced apoptosis in human choroidal melanoma cells. LiCl also reduced the proliferation of choroidal melanoma cells in vivo. Moreover, the upregulation of NOXA and downregulation of Mcl-1 were responsible for LiCl-induced apoptosis. Mcl-1 overexpression obviously impaired LiCl-induced apoptosis and cleavage of casp8, casp9, casp3 and PARP. Moreover, the protein expression of endoplasmic reticulum stress markers, including IRE1α, Bip, p-eIF2α, ATF4 and CHOP, was upregulated following treatment with LiCl. Conclusions: In summary, LiCl induced an endoplasmic reticulum stress response while activating intrinsic apoptosis. Furthermore, the NOXA/Mcl-1 axis contributed to LiCl-induced apoptosis both in vitro and in vivo. The present study provides important mechanistic insight into potential cancer treatments involving LiCl and enhances the understanding of human choroidal melanoma.

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“…During the in vivo delivery process, siRNA encounters substantial obstacles while attempting to reach the target cells. For example, ribonucleases may limit the half-life of naked siRNA molecules in the circulation to less than 1 min [34]. The siRNA vectors (Entranster TM -in vivo) used in this study were commercial dendrimer nanoparticles containing many amino groups that protonate at physiological pH.…”

Section: Discussionmentioning

confidence: 99%

“…The protonated amino groups can then neutralize the electric charge on the surface of the siRNA, allowing the siRNA molecules to be compacted into relatively smaller structures to prevent nuclease degradation. The nanometer-scale transfection reagent has unique characteristics, such as providing stronger siRNA protection and lower cytotoxicity [34]. …”

Section: Discussionmentioning

confidence: 99%

A Convenient In Vivo Model Using Small Interfering RNA Silencing to Rapidly Assess Skeletal Gene Function

et al. 2016

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It is difficult to study bone in vitro because it contains various cell types that engage in cross-talk. Bone biologically links various organs, and it has thus become increasingly evident that skeletal physiology must be studied in an integrative manner in an intact animal. We developed a model using local intraosseous small interfering RNA (siRNA) injection to rapidly assess the effects of a target gene on the local skeletal environment. In this model, 160-g male Sprague-Dawley rats were treated for 1–2 weeks. The left tibia received intraosseous injection of a parathyroid hormone 1 receptor (Pth1r) or insulin-like growth factor 1 receptor (Igf-1r) siRNA transfection complex loaded in poloxamer 407 hydrogel, and the right tibia received the same volume of control siRNA. All the tibias received an intraosseous injection of recombinant human parathyroid hormone (1–34) (rhPTH (1–34)) or insulin-like growth factor-1 (IGF-1). Calcein green and alizarin red were injected 6 and 2 days before euthanasia, respectively. IGF-1R and PTH1R expression levels were detected via RT-PCR assays and immunohistochemistry. Bone mineral density (BMD), microstructure, mineral apposition rates (MARs), and strength were determined by dual-energy X-ray absorptiometry, micro-CT, histology and biomechanical tests. The RT-PCR and immunohistochemistry results revealed that IGF-1R and PTH1R expression levels were dramatically diminished in the siRNA-treated left tibias compared to the right tibias (both p<0.05). Using poloxamer 407 hydrogel as a controlled-release system prolonged the silencing effect of a single dose of siRNA; the mRNA expression levels of IGF-1R were lower at two weeks than at one week (p<0.01). The BMD, bone microstructure parameters, MAR and bone strength were significantly decreased in the left tibias compared to the right tibias (all p<0.05). This simple and convenient local intraosseous siRNA injection model achieved gene silencing with very small quantities of siRNA over a short treatment period (≤7 days).

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Efficacy and safety of dendrimer nanoparticles with coexpression of tumor necrosis factor-α and herpes simplex virus thymidine kinase in gene radiotherapy of the human uveal melanoma OCM-1 cell line

Cited by 22 publications

References 39 publications

Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

Lithium Chloride Induces Apoptosis in Human Choroidal Melanoma Cells via the NOXA/Mcl-1 Axis and Induction of ER Stress

A Convenient In Vivo Model Using Small Interfering RNA Silencing to Rapidly Assess Skeletal Gene Function

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