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Gunassekaran, Gowri Rangaswamy,Hong, Chae-Moon,Vadevoo, Sri Murugan Poongkavithai,Chi, Lianhua,Guruprasath, Padmanaban,Ahn, Byung-Cheol,Kim, Ha-Jeong,Kang, Tae Heung,Lee, Byungheon IPC Science and Technology Press 2018 Biomaterials Vol.159 No.-
<P><B>Abstract</B></P> <P>Adoptive transfer of cytotoxic T lymphocytes (CTLs) has been used as an immunotherapy in melanoma. However, the tumor homing and therapeutic efficacy of transferred CTLs against melanoma remain unsatisfactory. Interleukin-4 receptor (IL-4R) is commonly up-regulated in tumors including melanoma. Here, we studied whether IL-4R-targeted CTLs exhibit enhanced tumor homing and therapeutic efficacy against melanoma. CTLs isolated from mice bearing melanomas were non-genetically engineered with IL4RPep-1, an IL-4R-binding peptide, using a membrane anchor composed of dioleylphosphatidylethanolamine. Compared to control CTLs, IL-4R-targeted CTLs showed higher binding to melanoma cells and <I>in vivo</I> tumor homing. They also exerted a more rapid and robust effector response, including increased cytokine secretion and cytotoxicity against melanoma cells and enhanced reprogramming of M2-type macrophages to M1-type macrophages. Moreover, IL-4R-targeted CTLs efficiently inhibited melanoma growth and reversed the immunosuppressive tumor microenvironment. These results suggest that non-genetically engineered CTLs targeting IL-4R have potential as an adoptive T cell therapy against melanoma.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Jung, Hyunkyung,Park, Sungjo,Gunassekaran, Gowri Rangaswamy,Jeon, Mansik,Cho, Young-Eun,Baek, Moon-Chang,Park, Jae Yong,Shim, Gayong,Oh, Yu-Kyoung,Kim, In-San,Kim, Chulhong,Lee, Byungheon American Association for Cancer Research 2019 Cancer Research Vol.79 No.16
<P>These findings present a new tumor-targeting probe for photoacoustic-guided detection and drug delivery.</P><P><B></B></P><P>The lack of molecular targets and targeting probes remains a major drawback for targeted imaging and drug delivery in lung cancer. In this study, we exploited <I>in vivo</I> phage display to identify a novel targeting probe that homes to the tumor in a <I>K-ras<SUP>LA2</SUP></I> mutant mouse lung cancer model. Compared with other candidate peptides selected from 5 rounds of phage display, the CRQTKN peptide homed to tumor nodules in the lung of mutant mice at higher levels. Photoacoustic tomography of mutant mice detected lung tumors via tumor homing of the near-infrared fluorescence dye-labeled CRQTKN peptide. <I>Ex vivo</I> photoacoustic images of isolated organs further demonstrated tumor homing of the CRQTKN peptide, whereas minimal accumulation was observed in control organs, such as the liver. Compared with untargeted liposomes and doxorubicin, doxorubicin-loaded liposomes whose surface was modified with the CRQTKN peptide more efficiently delivered doxorubicin and reduced the number or size of tumor lesions in <I>K-ras<SUP>LA2</SUP></I> mutant mice. Analysis of hematologic parameters and liver and kidney function showed no significant systemic side effects by the treatments. Affinity-based identification was used to detect TNF receptor superfamily member 19L (TNFRSF19L), which was upregulated in lung tumors of mutant mice, as the receptor for the CRQTKN peptide. In conclusion, these results suggest that the CRQTKN peptide is a promising targeting probe for photoacoustic-guided detection and drug delivery to lung cancer, and acts by binding to TNFRSF19L.</P><P><B>Significance:</B></P><P>These findings present a new tumor-targeting probe for photoacoustic-guided detection and drug delivery.</P>
Guruprasath, Padmanaban,Kim, Jihoon,Gunassekaran, Gowri Rangaswamy,Chi, Lianhua,Kim, Soyoun,Park, Rang-Woon,Kim, Sang-Hyun,Baek, Moon-Chang,Bae, Sang Mun,Kim, Sang-Yeob,Kim, Dong-Kyu,Park, In-Kyu,Kim, Elsevier 2017 Biomaterials Vol.142 No.-
<P><B>Abstract</B></P> <P>IL-4 receptor (IL-4R) is commonly up-regulated on tumor cells, and interactions between the receptor and Interleukin-4 (IL-4) can induce the expression of anti-apoptotic proteins, including Bcl-xL. This contributes to tumor cell survival and their resistance to chemotherapy. In this study, we exploited IL-4R-targeted delivery of Bcl-xL siRNA to IL-4R-expressing tumor cells in order to sensitize them to chemotherapy. To target IL-4R, an IL-4R-binding peptide, IL4RPep-1, was attached to branched polyethyleneimine-superparamagnetic iron oxide nanoparticles (BPEI-SPION). These nanoparticles were then complexed with Bcl-xL-targeting siRNA. IL-4R-targeted BPEI-SPION/Bcl-xL siRNA more efficiently reduced Bcl-xL gene expression and enhanced cytotoxicity of doxorubicin in MDA-MB231 breast tumor cells compared to untargeted BPEI-SPION/Bcl-xL siRNA. The siRNA was released from the complexes after 15 h of incubation at pH 5.5 and was stable in the complexes up to 72 h in the serum. The IL-4R-targeted BPEI-SPION/siRNA was internalized by cells through IL-4R, successfully escaped the endosomes, and was dispersed into the cytoplasm. Near-infrared fluorescence and magnetic resonance imaging demonstrated that <I>in vivo</I> tumor homing and accumulation of IL-4R-targeted BPEI-SPION/siRNA were both higher than untargeted BPEI-SPION/siRNA. The IL-4R-targeted BPEI-SPION/Bcl-xL siRNA, in combination with doxorubicin, significantly inhibited tumor growth in mice compared to untargeted BPEI-SPION/Bcl-xL siRNA. These results suggest that the IL-4R-targeted delivery of Bcl-xL siRNA to IL-4R-expressing tumors can sensitize tumors to chemotherapy and enhance the efficacy of anti-tumor therapeutics.</P> <P><B>Graphical abstract</B></P> <P>Interaction between IL-4 and IL-4R provides downstream signaling for the expression of Bcl-xL and inhibits doxorubicin-induced apoptosis. IL4RPep-1-labeled BPEI-SPION/Bcl-xL siRNA selectively binds to IL-4R-expressing tumor cells and is internalized into the cells through the receptor-mediated endocytosis, which contributes to the silencing of the Bcl-xL gene expression. This sensitizes IL-4R-expressing tumor cells to doxorubicin and enhances its therapeutic efficacy.</P> <P>[DISPLAY OMISSION]</P>
Kim, Soyoun,Kim, Gwang Seob,Seo, Junyoung,Gowri Rangaswamy, Gunassekaran,So, In-Seop,Park, Rang-Woon,Lee, Byung-Heon,Kim, In-San American Chemical Society 2016 Biomacromolecules Vol.17 No.1
<P>Ferritin cage nanoparticles are promising platforms for targeted delivery of imaging and therapeutic agents. One of the main advantages of cage nanoparticles is the ability to display multiple functionalities through genetic modification so as to achieve desired therapeutic or diagnostic functions. Ferritin complexes formed from short ferritin (sFt) lacking the fifth helix can accommodate dual peptide and protein functionalities on N- and C-terminal sites in sFt monomers. The resulting double-chambered Nano Cage (DCNC) offers the potential of dual activities; these activities are augmented by the avidity of the ligands, which do not impede each other's function. Here we demonstrated proof-of-concept of DCNCs, loading the tumor-targeting proapoptotic peptide CGKRK(KLAKLAK)(2) onto the N-terminal chamber and green fluorescent protein (GFP) onto the C-terminal chamber. The resulting KLAK-sFt-GFP DCNCs were internalized into the human breast adenocarcinoma cell line MDA-MB-231 and induced apoptosis. These findings suggest that DCNCs containing various combinations of peptides and proteins could be applied as therapeutics in different diseases.</P>
Peptides as multifunctional players in cancer therapy
Vadevoo Sri Murugan Poongkavithai,Gurung Smriti,Lee Hyun-Su,Gunassekaran Gowri Rangaswamy,Lee Seok-Min,Yoon Jae-Won,Lee Yun-Ki,Lee Byungheon 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Peptides exhibit lower affinity and a shorter half-life in the body than antibodies. Conversely, peptides demonstrate higher efficiency in tissue penetration and cell internalization than antibodies. Regardless of the pros and cons of peptides, they have been used as tumor-homing ligands for delivering carriers (such as nanoparticles, extracellular vesicles, and cells) and cargoes (such as cytotoxic peptides and radioisotopes) to tumors. Additionally, tumor-homing peptides have been conjugated with cargoes such as small-molecule or chemotherapeutic drugs via linkers to synthesize peptide–drug conjugates. In addition, peptides selectively bind to cell surface receptors and proteins, such as immune checkpoints, receptor kinases, and hormone receptors, subsequently blocking their biological activity or serving as hormone analogs. Furthermore, peptides internalized into cells bind to intracellular proteins and interfere with protein–protein interactions. Thus, peptides demonstrate great application potential as multifunctional players in cancer therapy.
Peptide-based targeted therapeutics and apoptosis imaging probes for cancer therapy
Vadevoo, Sri Murugan Poongkavithai,Gurung, Smriti,Khan, Fatima,Haque, Md. Enamul,Gunassekaran, Gowri Rangaswamy,Chi, Lianhua,Permpoon, Uttapol,Lee, Byungheon Springer-Verlag 2019 Archives of Pharmacal Research Vol.42 No.2