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pH-controllable cell-penetrating polypeptide that exhibits cancer targeting
Lee, DaeYong,Noh, Ilkoo,Yoo, Jisang,Rejinold, N. Sanoj,Kim, Yeu-Chun Elsevier 2017 ACTA BIOMATERIALIA Vol.57 No.-
<P><B>Abstract</B></P> <P>Helical peptides were naturally-occurring ordered conformations that mediated various biological functions essential for biotechnology. However, it was difficult for natural helical polypeptides to be applied in biomedical fields due to low bioavailability. To avoid these problems, synthetic alpha-helical polypeptides have recently been introduced by further modifying pendants in the side chain. In spite of an attractive biomimetic helical motif, these systems could not be tailored for targeted delivery mainly due to nonspecific binding events. To address these issues, we created a conformation-transformable polypeptide capable of eliciting a pH-activated cell-penetrating property solely at the cancer region. The developed novel polypeptide showed that the bare helical conformation had a function at physiological conditions while the pH-induced helical motif provided an active cell-penetrating characteristic at a tumor extracellular matrix pH. The unusual conformation-transformable system can elicit bioactive properties exclusively at mild acidic pH.</P> <P><B>Statement of Significance</B></P> <P>We developed pH-controllable cell-penetrating polypeptides (PCCPs) undergoing pH-induced conformational transitions. Unlike natural cell-penetrating peptides, PCCPs was capable of penetrating the plasma membranes dominantly at tumor pH, driven by pH-controlled helicity. The conformation of PCCPs at neutral pH showed low helical propensity because of dominant electrostatic attractions within the side chains. However, the helicity of PCCPs was considerably augmented by the balance of electrostatic interactions, thereby inducing selective cellular penetration. Three polypeptides undergoing different conformational transitions were prepared to verify the selective cellular uptake influenced by their structures. The PCCP undergoing low-to-high helical conformation provided the tumor specificity and enhanced uptake efficiency. pH-induced conformation-transformable polypeptide might provide a novel platform for stimuli-triggered targeting systems.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Lee, DaeYong,Lee, Soo-Hwan,Na, Youjin,Noh, Ilkoo,Ha, JongHoon,Yoo, Jisang,Bang, Hyun Bae,Park, Jong Hyun,Jeong, Ki Jun,Yun, Chae-Ok,Kim, Yeu-Chun Elsevier Science Publishers 2017 Journal of controlled release Vol.264 No.-
<P><B>Abstract</B></P> <P>Artificial cationic helical peptides possess an enhanced cell-penetrating property. However, their cell-penetrability is not converted by cellular environmental changes resulting in nonspecific uptake. In this study, pH-sensitive anion-donating groups were added to a helical polypeptide to simultaneously achieve tumor targeting and pro-apoptotic activity. The mitochondria-destabilizing helical polypeptide undergoing pH-dependent conformational transitions selectively targeted cancer cells consequently disrupting mitochondrial membranes and subsequently inducing apoptosis. This work presents a promising peptide therapeutic system for cancer therapy.</P> <P><B>Graphical abstract</B></P> <P>Mitochondria-destabilizing helical polypeptide undergoing a pH-activated conformational transition selectively perturbed the mitochondrial outer membranes thereby inducing pro-apoptosis.</P> <P>[DISPLAY OMISSION]</P>
Yun, Dayeon,Kim, Hyun-Ouk,Son, Hye Young,Choi, Yuna,Noh, Ilkoo,Lim, Jong-Woo,Kim, Jihye,Chun, Haejin,Park, Geunseon,Lee, Dong Ki,Jang, Sung Il,Jang, Eunji,Huh, Yong-Min,Haam, Seungjoo Royal Society of Chemistry 2017 Journal of Materials Chemistry B Vol. No.
<P>The use of drug-eluting stents (DESs) is a promising strategy for non-vascular diseases, especially human biliary cancer. However, the implementation of DESs suffers from two major obstacles: the side effects of drugs and the difficulty of controlling the drug release. These problems can be overcome if the stent elutes targeting nanoparticles that release drugs at time intervals that are dictated by the mechanisms of those drugs. We designed temporally controlled polymeric multi-prodrug nanoparticles (TCMPNs) that can be eluted from stents comprising polyurethane (PU) nanofiber as a polymeric matrix and paclitaxel (PTX)-loaded, CD44-targeting, hyaluronic acid-conjugated poly(lactic-<I>co</I>-glycolic acid) and gemcitabine (GEM) (P-H-G). TCMPNs enable two different types of drugs to be released temporally; PTX is released first owing to the collapse of the structure in the endosomes, and GEM, which induces synergistic anticancer activities, is hydrolyzed from P-H-G later in response to low pH. Embedded in the PU nanofiber, the TCMPNs demonstrate low initial burst behavior and sustainable release of the prodrug <I>in vitro</I>. Furthermore, TCMPN-eluting stents (TESs) exhibit continuous synergistic efficacy as available targeted cellular uptake prodrug delivery systems in tumor-bearing mice. These results demonstrate that this technology will open up cancer therapy by combining localized delivery and functional multi-drug-loaded nanoparticles.</P>
Bae, Seo Ryung,Choi, Jihye,Kim, Hyun-Ouk,Kang, Byunghoon,Kim, Myeong-Hoon,Han, Seungmin,Noh, Ilkoo,Lim, Jong-Woo,Suh, Jin-Suk,Huh, Yong-Min,Haam, Seungjoo The Royal Society of Chemistry 2015 Journal of materials chemistry. B, Materials for b Vol.3 No.3
<P>The integration of contrast-enhanced diagnostic imaging and therapy could utilize image guided therapy to plan treatment strategy. Toward this goal, a unique construction and operation of a pseudo metal based photothermal therapeutic agent (PPAM) is introduced by polyaniline (PANI) generation templated on iron oxide metal nanoclusters (MNCs). Notably, MNC core interferes as a catalytic agent and enables aniline polymerization under ambient acidic conditions. The intrusion of transition metal enhanced the proton sensitivity of PANI, which led to pH responsive conversion even at dilute proton concentrations (pH 5, 6) compared to the PANI particles prepared by conventional methods. Under physiological pH, PPAM reveals no special features; however, under low pH conditions, which is a notable characteristic of the cancer microenvironment, PPAM automatically converts into its emeraldine salt (ES) state and thus activates as a photothermal therapeutic agent. Utilizing this specific redox responsive switched off-on behavior of PPAM, precise and systemized photothermal therapy is demonstrated, proving itself as a smart and efficient photothermal therapeutic agent.</P>