The systemic delivery of siRNAs by a cell penetrating peptide, low molecular weight protamine

Choi, Youngsok; Lee, Jue Yeon; Suh, Jeong‐Yong; Kwon, Young Min; Lee, Seung Jin; Chung, Jun Key; Lee, Dong Hoon; Yang, Victor C.; Chung, Chong Pyoung; Park, Yoon Jeong

doi:10.1016/j.biomaterials.2009.11.001

Cited by 116 publications

(89 citation statements)

References 44 publications

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“…Previous studies have demonstrated that LMWP itself has no effect on cells. 34,35,37,38 Next, we determined the transduction kinetics for the LMWP-SOD1 conjugate. The SOD1 and LMWP-SOD1 conjugate was added to the culture medium of DPSCs at a concentration of 2 µM for various time periods.…”

Section: Transduction Of Lmwp-sod1 Into Human Dpscsmentioning

confidence: 99%

Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

Lee¹,

Chung²,

Park³

2012

IJN

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Background Human dental pulp stem cells (DPSCs) have potential applications in tissue regeneration because of their convenient cell harvesting procedures and multipotent capacity. However, the tissue regenerative potential of DPSCs is known to be negatively regulated by aging in long-term culture and under oxidative stress. With an aim of reducing cellular senescence and oxidative stress in DPSCs, an intracellular delivery system for superoxide dismutase 1 (SOD1) was developed. We conjugated SOD1 with a cell-penetrating peptide known as low-molecular weight protamine (LMWP), and investigated the effect of LMWP-SOD1 conjugates on hydrogen peroxide-induced cellular senescence and osteoblastic differentiation. Results LMWP-SOD1 significantly attenuated enlarged and flattened cell morphology and increased senescence-associated β-galactosidase activity. Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21 Cip1 , induced by hydrogen peroxide. In addition, LMWP-SOD1 reversed the inhibition of osteoblastic differentiation and downregulation of osteogenic gene markers induced by hydrogen peroxide. However, LMWP-SOD1 could not reverse the decrease in odontogenesis caused by hydrogen peroxide. Conclusion Overall, cell-penetrating LMWP-SOD1 conjugates are effective for attenuation of cellular senescence and reversal of osteoblastic differentiation of DPSCs caused by oxidative stress inhibition. This result suggests potential application in the field of antiaging and tissue engineering to overcome the limitations of senescent stem cells.

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Section: Transduction Of Lmwp-sod1 Into Human Dpscsmentioning

confidence: 99%

Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

Lee¹,

Chung²,

Park³

2012

IJN

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“…Twice weekly, starting on day 1, mice were weighed and solid-tumor volume determined using Vernier calipers based on the equation A × B 2 ×0.52, where A was the longest diameter of the tumor and B the shortest diameter of the tumor. 20 In addition, tumor growth was visualized using the IVIS imaging system. Mice were anesthetized using isoflurane and then intraperitoneally injected with d-luciferin at 50 μg/mL 10 minutes before imaging.…”

Section: In Vivo Tissue Distribution Of Hbpmentioning

confidence: 99%

Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis

Choi¹,

Lee

Suh³

et al. 2016

IJN

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Angiogenesis plays a critical role in the growth and metastasis of cancer, and growth factors released from cancer promote blood-vessel formation in the tumor microenvironment. The angiogenesis is accelerated via interactions of growth factors with the high-affinity receptors on cancer cells. In particular, heparan sulfate proteoglycans (HSPGs) on the surface of cancer cells have been shown to be important in many aspects of determining a tumor’s phenotype and development. Specifically, the regulation of the interactions between HSPGs and growth factors results in changes in tumor progression. A peptide with heparin-binding (HBP) activity has been developed and synthesized to inhibit tumor growth via the prevention of angiogenesis. We hypothesized that HBP could inhibit the interaction of growth factors and HSPGs on the surface of cancer cells, decrease paracrine signaling in endothelial cells (ECs), and finally decrease angiogenesis in the tumor microenvironment. In this study, we found that HBP had antiangiogenic effects in vitro and in vivo. The conditioned media obtained from a breast cancer cell line treated with HBP were used to culture human umbilical vein ECs (HUVECs) to evaluate the antiangiogenic effect of HBP on ECs. HBP effectively inhibited the migration, invasion, and tube formation of HUVECs in vitro. In addition, the expressions of angiogenesis-mediating factors, including ERK, FAK, and Akt, were considerably decreased. HBP also decreased the levels of invasive factors, including MMP2 and MMP9, secreted by the HUVECs. We demonstrated significant suppression of tumor growth in a breast cancer xenograft model and enhanced distribution of HBP at the site of tumors. Taken together, our results show that HBP has antiangiogenic effects on ECs, and suggest that it may serve as a potential antitumor agent through control of the tumor microenvironment.

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“…29,30 Naturally derived LMWP, developed by the authors, possess high arginine content and carries significant sequence similarity to TAT, by far the most potent protein-transduction domain peptide. In our previous study, LMWPs demonstrated their capability of transducing a nonpenetrating protein toxin and small interfering RNA (siRNA; vascular endothelial 25,31 In this study, the LMWP-TAZ fusion protein was produced using bacterial expression, a frequently used method for the production of recombinant proteins.…”

Section: Internalization Of Lmwp-taz Fusion Protein Into Hmscsmentioning

confidence: 99%

Intracellular delivery of cell-penetrating peptide-transcriptional factor fusion protein and its role in selective osteogenesis

Suh¹,

Lee²,

You³

et al. 2014

IJN

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Protein-transduction technology has been attempted to deliver macromolecular materials, including protein, nucleic acids, and polymeric drugs, for either diagnosis or therapeutic purposes. Herein, fusion protein composed of an arginine-rich cell-penetrating peptide, termed low-molecular-weight protamine (LMWP), and a transcriptional coactivator with a PDZ-binding motif (TAZ) protein was prepared and applied in combination with biomaterials to increase bone-forming capacity. TAZ has been recently identified as a specific osteogenic stimulating transcriptional coactivator in human mesenchymal stem cell (hMSC) differentiation, while simultaneously blocking adipogenic differentiation. However, TAZ by itself cannot penetrate the cells, and thus needs a transfection tool for translocalization. The LMWP-TAZ fusion proteins were efficiently translocalized into the cytosol of hMSCs. The hMSCs treated with cell-penetrating LMWP-TAZ exhibited increased expression of osteoblastic genes and protein, producing significantly higher quantities of mineralized matrix compared to free TAZ. In contrast, adipogenic differentiation of the hMSCs was blocked by treatment of LMWP-TAZ fusion protein, as reflected by reduced marker-protein expression, adipocyte fatty acid-binding protein 2, and peroxisome proliferator-activated receptor-γ messenger ribonucleic acid levels. LMWP-TAZ was applied in alginate gel for the purpose of localization and controlled release. The LMWP-TAZ fusion protein-loaded alginate gel matrix significantly increased bone formation in rabbit calvarial defects compared with alginate gel matrix mixed with free TAZ protein. The protein transduction of TAZ fused with cell-penetrating LMWP peptide was able selectively to stimulate osteogenesis in vitro and in vivo. Taken together, this fusion protein-transduction technology for osteogenic protein can thus be applied in combination with biomaterials for tissue regeneration and controlled release for tissue-engineering purposes.

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The systemic delivery of siRNAs by a cell penetrating peptide, low molecular weight protamine

Cited by 116 publications

References 44 publications

Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis

Intracellular delivery of cell-penetrating peptide-transcriptional factor fusion protein and its role in selective osteogenesis

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