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Chaemin Lim,1,* Yuseon Shin,2,* Kioh Kang,2 Patihul Husni,2 Dayoon Lee,2 Sehwa Lee,2 Han-Gon Choi,3 Eun Seong Lee,4 Yu Seok Youn,5 Kyung Taek Oh1,2 1College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea; 2Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Seoul, 06974, Republic of Korea; 3College of Pharmacy, Hanyang University, Ansan, 15588, South Korea; 4Department of Biotechnology, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea; 5School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, Republic of Korea*These authors contributed equally to this workCorrespondence: Kyung Taek Oh, College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul, 06974, Republic of Korea, Tel +82-2-824-5617, Email kyungoh@cau.ac.krIntroduction: Ligand-conjugated liposomes are promising for the treatment of specific receptor-overexpressing cancers. However, previous studies have shown inconsistent results because of the varying properties of the ligand, presence of a polyethylene glycol (PEG) coating on the liposome, length of the linker, and density of the ligand.Methods: Here, we prepared PEGylated liposomes using PEG-linkers of various lengths conjugated with folate and evaluated the effect of the PEG-linker length on the nanoparticle distribution and pharmacological efficacy of the encapsulated drug both in vitro and in vivo.Results: When folate was conjugated to the liposome surface, the cellular uptake efficiency in folate receptor overexpressed KB cells dramatically increased compared to that of the normal liposome. However, when comparing the effect of the PEG-linker length in vitro, no significant difference between the formulations was observed. In contrast, the level of tumor accumulation of particles in vivo significantly increased when the length of the PEG-linker was increased. The tumor size was reduced by > 40% in the Dox

June Yong Park,1,* Yuseon Shin,1,* Woong Roeck Won,1 Chaemin Lim,1,2 Jae Chang Kim,1 Kioh Kang,1 Patihul Husni,1 Eun Seong Lee,3 Yu Seok Youn,4 Kyung Taek Oh1,5 1Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Dongjak-gu, Seoul, 06974, Republic of Korea; 2Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; 3Division of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, Republic of Korea; 4School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, Republic of Korea; 5College of Pharmacy, Chung-Ang University, Dongjak-gu, Seoul, 06974, Republic of Korea*These authors contributed equally to this workCorrespondence: Kyung Taek OhCollege of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul, 06974, Republic of KoreaTel +82-2-824-5617Email kyungoh@cau.ac.krPurpose: An AE147 peptide-conjugated nanocarrier based on PEGylated liposomes was developed in order to target the metastatic tumors overexpressing urokinase-type plasminogen activator receptor (uPAR), which cancer progression via uPA signaling. Therefore, the AE147 peptide-conjugated nanocarrier system may hold the potential for active targeting of metastatic tumors.Methods: The AE147 peptide, an antagonist of uPAR, was conjugated to the PEGylated liposomes for targeting metastatic tumors overexpressing uPAR. Docetaxel (DTX), an anticancer drug, was incorporated into the nanocarriers. The structure of the AE147-conjugated nanocarrier, its physicochemical properties, and in vivo biodistribution were evaluated.Results: The DTX-loaded nanocarrier showed a spherical structure, a high drug-loading capacity, and a high colloidal stability. Drug carrying AE147 conjugates were actively taken up by the uPAR-overexpressing MDA-MB-231 cancer cells. In vivo animal imaging confirmed

June Yong Park,1,* Yuseon Shin,1,* Woong Roeck Won,1 Chaemin Lim,1,2 Jae Chang Kim,1 Kioh Kang,1 Patihul Husni,1 Eun Seong Lee,3 Yu Seok Youn,4 Kyung Taek Oh1,5 1Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Dongjak-gu, Seoul, 06974, Republic of Korea; 2Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; 3Division of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do, 14662, Republic of Korea; 4School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, Republic of Korea; 5College of Pharmacy, Chung-Ang University, Dongjak-gu, Seoul, 06974, Republic of Korea*These authors contributed equally to this workCorrespondence: Kyung Taek OhCollege of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul, 06974, Republic of KoreaTel +82-2-824-5617Email kyungoh@cau.ac.krPurpose: An AE147 peptide-conjugated nanocarrier based on PEGylated liposomes was developed in order to target the metastatic tumors overexpressing urokinase-type plasminogen activator receptor (uPAR), which cancer progression via uPA signaling. Therefore, the AE147 peptide-conjugated nanocarrier system may hold the potential for active targeting of metastatic tumors.Methods: The AE147 peptide, an antagonist of uPAR, was conjugated to the PEGylated liposomes for targeting metastatic tumors overexpressing uPAR. Docetaxel (DTX), an anticancer drug, was incorporated into the nanocarriers. The structure of the AE147-conjugated nanocarrier, its physicochemical properties, and in vivo biodistribution were evaluated.Results: The DTX-loaded nanocarrier showed a spherical structure, a high drug-loading capacity, and a high colloidal stability. Drug carrying AE147 conjugates were actively taken up by the uPAR-overexpressing MDA-MB-231 cancer cells. In vivo animal imaging confirmed

Phuong Thi Thu Pham,1 Xuan Thien Le,1 Hanju Kim,1 Hwang Kyung Kim,1 Eun Seong Lee,2 Kyung Taek Oh,3 Han-Gon Choi,4 Yu Seok Youn1 1School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea; 2Division of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Republic of Korea; 3College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea; 4College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of KoreaCorrespondence: Yu Seok Youn Tel +82-31-290-7785Email ysyoun@skku.eduBackground: Indocyanine green (ICG) has received considerable interest as a biocompatible organic photothermal agent, and curcumin (Cur) is considered an attractive natural chemopreventive and chemotherapeutic compound. However, the in vivo applicability of ICG and Cur is significantly restricted by their poor ability to target tumors and their extremely low solubility.Materials and Methods: To address these problems, ICG/Cur-loaded albumin nanoparticles (ICG-BSA-Cur-NPs) based on the nabTM (nanoparticle albumin-bound) technology were applied to neuroblastomas in vivo.Results: The fabricated ICG-BSA-Cur-NPs were found to be spherical, ∼ 150 nm in size and highly dispersible and stable in aqueous solution. Approximately 80% of the incorporated ICG and Cur were gradually released from the NPs over 48 h. All formulations of ICG-BSA-Cur-NPs (5∼ 20 μg/mL) showed efficient hyperthermia profiles (up to 50– 60°C within 5 min) in response to 808-nm NIR laser irradiation in vitro and in vivo. Notably, ICG-BSA-Cur-NPs illuminated with 808-nm laser irradiation (1.5 W/cm2) showed excellent cytotoxicity toward N2a cells in vitro and undisputable antitumor efficacy in N2a-xenografted mice in vivo, compared to other tested sample groups (tumor volumes for PBS, BSA-Cur-NPs, free ICG, and ICG-BSA-Cur-NPs groups were 1408.6 ± 551.9, 1190.6 ± 343.6, 888.6 ± 566.2

Phuong Thi Thu Pham,1 Xuan Thien Le,1 Hanju Kim,1 Hwang Kyung Kim,1 Eun Seong Lee,2 Kyung Taek Oh,3 Han-Gon Choi,4 Yu Seok Youn1 1School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea; 2Division of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Republic of Korea; 3College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea; 4College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of KoreaCorrespondence: Yu Seok Youn Tel +82-31-290-7785Email ysyoun@skku.eduBackground: Indocyanine green (ICG) has received considerable interest as a biocompatible organic photothermal agent, and curcumin (Cur) is considered an attractive natural chemopreventive and chemotherapeutic compound. However, the in vivo applicability of ICG and Cur is significantly restricted by their poor ability to target tumors and their extremely low solubility.Materials and Methods: To address these problems, ICG/Cur-loaded albumin nanoparticles (ICG-BSA-Cur-NPs) based on the nabTM (nanoparticle albumin-bound) technology were applied to neuroblastomas in vivo.Results: The fabricated ICG-BSA-Cur-NPs were found to be spherical, ∼ 150 nm in size and highly dispersible and stable in aqueous solution. Approximately 80% of the incorporated ICG and Cur were gradually released from the NPs over 48 h. All formulations of ICG-BSA-Cur-NPs (5∼ 20 μg/mL) showed efficient hyperthermia profiles (up to 50– 60°C within 5 min) in response to 808-nm NIR laser irradiation in vitro and in vivo. Notably, ICG-BSA-Cur-NPs illuminated with 808-nm laser irradiation (1.5 W/cm2) showed excellent cytotoxicity toward N2a cells in vitro and undisputable antitumor efficacy in N2a-xenografted mice in vivo, compared to other tested sample groups (tumor volumes for PBS, BSA-Cur-NPs, free ICG, and ICG-BSA-Cur-NPs groups were 1408.6 ± 551.9, 1190.6 ± 343.6, 888.6 ± 566.2

When light illuminates the junction formed between a sharp metal tip and a sample, different mechanisms can contribute to the measured photoinduced force simultaneously. Of particular interest are the instantaneous force between the induced dipoles in the tip and in the sample, and the force related to thermal heating of the junction. A key difference between these 2 force mechanisms is their spectral behavior. The magnitude of the thermal response follows a dissipative (absorptive) Lorentzian line shape, which measures the heat exchange between light and matter, while the induced dipole response exhibits a dispersive spectrum and relates to the real part of the material polarizability. Because the 2 interactions are sometimes comparable in magnitude, the origin of the chemical selectivity in nanoscale spectroscopic imaging through force detection is often unclear. Here, we demonstrate theoretically and experimentally how the light illumination gives rise to the 2 kinds of photoinduced forces at the tip-sample junction in the midinfrared. We comprehensively address the origin of the spectroscopic forces by discussing cases where the 2 spectrally dependent forces are entwined. The analysis presented here provides a clear and quantitative interpretation of nanoscale chemical measurements of heterogeneous materials and sheds light on the nature of light-matter coupling in optomechanical force-based spectronanoscopy.

Ngoc Ha Hoang,1,* Taehoon Sim,1,* Chaemin Lim,1 Thi Ngoc Le,1 Sang Myung Han,1 Eun Seong Lee,2 Yu Seok Youn,3 Kyung Taek Oh11College of Pharmacy, Chung-Ang University, Dongjak-gu, Seoul 06974, Korea; 2Department of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Korea; 3School of Pharmacy, Sungkyunkwan University, Suwon City 16419, Korea*These authors contributed equally to this workBackground: A very common and simple method (known as the blending method) to formulate drug delivery systems with required properties is to physically mix amphiphilic block copolymers with different hydrophobicity. In addition to its simplicity, this blending strategy could help avoid the time and effort involved in the synthesis of block copolymers with the desired structure required for specific drug formulations.Purpose: We used the blending strategy to design a system that could overcome the problem of high hydrophobicity and be a good candidate for drug product development using PEG-PLA-PEG triblock copolymers.Methods: Two types of PEG-PLA-PEG triblock copolymers with similar (long) PLA molecular weights (MWs) and different PEG MWs were synthesized. The micellar formulations were prepared by blending the two block copolymers in various ratios. The size and stability of the blending systems were subsequently investigated to optimize the formulations for further studies. The loading properties of doxorubicin or paclitaxel into the optimized blending system were compared to that in mono systems (systems composed of only a single type of triblock copolymer). In vitro and in vivo anti-cancer effects of the preparations were evaluated to assess the use of the blending system as an optimal nanomedicine platform for insoluble anticancer agents.Results: The blending system (B20 system) with an optimized ratio of the triblock copolymers overcame the drawbacks of mono systems. Drug uptake from the drug-loaded B20 system

When light illuminates the junction formed between a sharp metal tip and a sample, different mechanisms can contribute to the measured photoinduced force simultaneously. Of particular interest are the instantaneous force between the induced dipoles in the tip and in the sample, and the force related to thermal heating of the junction. A key difference between these 2 force mechanisms is their spectral behavior. The magnitude of the thermal response follows a dissipative (absorptive) Lorentzian line shape, which measures the heat exchange between light and matter, while the induced dipole response exhibits a dispersive spectrum and relates to the real part of the material polarizability. Because the 2 interactions are sometimes comparable in magnitude, the origin of the chemical selectivity in nanoscale spectroscopic imaging through force detection is often unclear. Here, we demonstrate theoretically and experimentally how the light illumination gives rise to the 2 kinds of photoinduced forces at the tip-sample junction in the midinfrared. We comprehensively address the origin of the spectroscopic forces by discussing cases where the 2 spectrally dependent forces are entwined. The analysis presented here provides a clear and quantitative interpretation of nanoscale chemical measurements of heterogeneous materials and sheds light on the nature of light-matter coupling in optomechanical force-based spectronanoscopy.

Ngoc Ha Hoang,1,* Taehoon Sim,1,* Chaemin Lim,1 Thi Ngoc Le,1 Sang Myung Han,1 Eun Seong Lee,2 Yu Seok Youn,3 Kyung Taek Oh11College of Pharmacy, Chung-Ang University, Dongjak-gu, Seoul 06974, Korea; 2Department of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Korea; 3School of Pharmacy, Sungkyunkwan University, Suwon City 16419, Korea*These authors contributed equally to this workBackground: A very common and simple method (known as the blending method) to formulate drug delivery systems with required properties is to physically mix amphiphilic block copolymers with different hydrophobicity. In addition to its simplicity, this blending strategy could help avoid the time and effort involved in the synthesis of block copolymers with the desired structure required for specific drug formulations.Purpose: We used the blending strategy to design a system that could overcome the problem of high hydrophobicity and be a good candidate for drug product development using PEG-PLA-PEG triblock copolymers.Methods: Two types of PEG-PLA-PEG triblock copolymers with similar (long) PLA molecular weights (MWs) and different PEG MWs were synthesized. The micellar formulations were prepared by blending the two block copolymers in various ratios. The size and stability of the blending systems were subsequently investigated to optimize the formulations for further studies. The loading properties of doxorubicin or paclitaxel into the optimized blending system were compared to that in mono systems (systems composed of only a single type of triblock copolymer). In vitro and in vivo anti-cancer effects of the preparations were evaluated to assess the use of the blending system as an optimal nanomedicine platform for insoluble anticancer agents.Results: The blending system (B20 system) with an optimized ratio of the triblock copolymers overcame the drawbacks of mono systems. Drug uptake from the drug-loaded B20 system

Chaemin Lim,1,* Junseong Moon,1,* Taehoon Sim,1 Ngoc Ha Hoang,1 Woong Roeck Won,1 Eun Seong Lee,2 Yu Seok Youn,3 Han-Gon Choi,4 Kyungsoo Oh,1 Kyung Taek Oh1 1College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; 2Division of Biotechnology, The Catholic University of Korea, Bucheon, Republic of Korea; 3School of Pharmacy, SungKyunKwan University, Suwon, Republic of Korea; 4College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea *These authors contributed equally to this work Background: Blending micellar systems of different types of polymers has been proposed as an efficient approach for tailor-made drug formulations. The lamellar structure of hydrophobic polymers may provide a high drug loading capacity, and hydrophilic polymers may provide good colloidal stability. Methods: In this study, the anticancer model drug docetaxel was loaded onto a nanosized blending micellar system with two pluronics (L121/F127). To achieve increased antitumor activity, the cyclic arginine-glycine-aspartic acid tripeptide (cRGD) as an active tumor targeting ligand was conjugated to the blending system.Results: The docetaxel-loaded Pluronic blending system exhibited a higher drug loading capacity than that of F127 and showed high colloidal stability with a spherical structure. cRGD conjugates demonstrated enhanced drug cellular uptake and anticancer activity against αvβ3 integrin-overexpressing U87MG cancer cells. In vivo animal imaging also revealed that the prepared cRGD-conjugated nanoparticles effectively accumulated at the targeted tumor site through an active and passive targeting strategy. Conclusion: Accordingly, the prepared nanosized system shows potential as a tailor-made, active targeting, nanomedicinal platform for anticancer therapy. We believe that this novel nanoplatform will provide insights for advancement of tumor therapy. Keywords: blending micellar system, docetaxel, cycli

Chaemin Lim,1,* Junseong Moon,1,* Taehoon Sim,1 Ngoc Ha Hoang,1 Woong Roeck Won,1 Eun Seong Lee,2 Yu Seok Youn,3 Han-Gon Choi,4 Kyungsoo Oh,1 Kyung Taek Oh1 1College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; 2Division of Biotechnology, The Catholic University of Korea, Bucheon, Republic of Korea; 3School of Pharmacy, SungKyunKwan University, Suwon, Republic of Korea; 4College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea *These authors contributed equally to this work Background: Blending micellar systems of different types of polymers has been proposed as an efficient approach for tailor-made drug formulations. The lamellar structure of hydrophobic polymers may provide a high drug loading capacity, and hydrophilic polymers may provide good colloidal stability. Methods: In this study, the anticancer model drug docetaxel was loaded onto a nanosized blending micellar system with two pluronics (L121/F127). To achieve increased antitumor activity, the cyclic arginine-glycine-aspartic acid tripeptide (cRGD) as an active tumor targeting ligand was conjugated to the blending system.Results: The docetaxel-loaded Pluronic blending system exhibited a higher drug loading capacity than that of F127 and showed high colloidal stability with a spherical structure. cRGD conjugates demonstrated enhanced drug cellular uptake and anticancer activity against αvβ3 integrin-overexpressing U87MG cancer cells. In vivo animal imaging also revealed that the prepared cRGD-conjugated nanoparticles effectively accumulated at the targeted tumor site through an active and passive targeting strategy. Conclusion: Accordingly, the prepared nanosized system shows potential as a tailor-made, active targeting, nanomedicinal platform for anticancer therapy. We believe that this novel nanoplatform will provide insights for advancement of tumor therapy. Keywords: blending micellar system, docetaxel, cycli

When light illuminates the junction formed between a sharp metal tip and a sample, different mechanisms can con-tribute to the measured photo-induced force simultaneously. Of particular interest are the instantaneous force be-tween the induced dipoles in the tip and in the sample and the force related to thermal heating of the junction. A key difference between these two force mechanisms is their spectral behaviors. The magnitude of the thermal response follows a dissipative Lorentzian lineshape, which measures the heat exchange between light and matter, while the induced dipole response exhibits a dispersive spectrum and relates to the real part of the material polarizability. Be-cause the two interactions are sometimes comparable in magnitude, the origin of the nanoscale chemical selectivity in the recently developed photo-induced force microscopy (PiFM) is often unclear. Here, we demonstrate theoretically and experimentally how light absorption followed by nanoscale thermal expansion generates a photo-induced force in PiFM. Furthermore, we explain how this thermal force can be distinguished from the induced dipole force by tuning the relaxation time of samples. Our analysis presented here helps the interpretation of nanoscale chemical measure-ments of heterogeneous materials and sheds light on the nature of light-matter coupling in van der Waals materials.

Chaemin Lim,1 Taehoon Sim,1 Ngoc Ha Hoang,2 Chan Eun Jung,1 Eun Seong Lee,3 Yu Seok Youn,4 Kyung Taek Oh1 1Department of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Heukseok-dong, Dongjak-gu, Seoul, South Korea; 2Department of Pharmaceutics, Ha Noi University of Pharmacy, Ha Noi, Vietnam; 3Division of Biotechnology, The Catholic University of Korea, Gyeonggi-do, Bucheon, 4Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, South Korea Abstract: A polyelectrolyte nanoparticle composed of PEG-PLL(-g-Ce6, DMA)-PLA was developed for nanomedicinal application in photodynamic therapy. These nanoparticles formed stable aggregates through the hydrophobic interaction of poly(lactic acid) and demonstrated pH-dependent behaviors such as surface charge conversion and enhanced cellular uptake at acidic pH, resulting in improved phototoxicity. In vivo animal imaging revealed that the prepared PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles effectively accumulated at the targeted tumor site through enhanced permeability and retention effects. Reversible surface charge for PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles allows the nanoparticles to escape the immune system and concentrate on the tumor tissue. Tumor growth in the nude mice treated with the nanoparticles decreased significantly and the hydrophobic interaction in the poly(lactic acid) block could allow the incorporation of multiple drugs. Therefore, the PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles could have considerable potential as a nanomedicinal platform for photodynamic therapy. Keywords: apoptosis, chlorin e6, polyelectrolyte, pH sensitive, charge conversion, nano­medicine&nbsp

When light illuminates the junction formed between a sharp metal tip and a sample, different mechanisms can con-tribute to the measured photo-induced force simultaneously. Of particular interest are the instantaneous force be-tween the induced dipoles in the tip and in the sample and the force related to thermal heating of the junction. A key difference between these two force mechanisms is their spectral behaviors. The magnitude of the thermal response follows a dissipative Lorentzian lineshape, which measures the heat exchange between light and matter, while the induced dipole response exhibits a dispersive spectrum and relates to the real part of the material polarizability. Be-cause the two interactions are sometimes comparable in magnitude, the origin of the nanoscale chemical selectivity in the recently developed photo-induced force microscopy (PiFM) is often unclear. Here, we demonstrate theoretically and experimentally how light absorption followed by nanoscale thermal expansion generates a photo-induced force in PiFM. Furthermore, we explain how this thermal force can be distinguished from the induced dipole force by tuning the relaxation time of samples. Our analysis presented here helps the interpretation of nanoscale chemical measure-ments of heterogeneous materials and sheds light on the nature of light-matter coupling in van der Waals materials.

Chaemin Lim,1 Taehoon Sim,1 Ngoc Ha Hoang,2 Chan Eun Jung,1 Eun Seong Lee,3 Yu Seok Youn,4 Kyung Taek Oh1 1Department of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Heukseok-dong, Dongjak-gu, Seoul, South Korea; 2Department of Pharmaceutics, Ha Noi University of Pharmacy, Ha Noi, Vietnam; 3Division of Biotechnology, The Catholic University of Korea, Gyeonggi-do, Bucheon, 4Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, South Korea Abstract: A polyelectrolyte nanoparticle composed of PEG-PLL(-g-Ce6, DMA)-PLA was developed for nanomedicinal application in photodynamic therapy. These nanoparticles formed stable aggregates through the hydrophobic interaction of poly(lactic acid) and demonstrated pH-dependent behaviors such as surface charge conversion and enhanced cellular uptake at acidic pH, resulting in improved phototoxicity. In vivo animal imaging revealed that the prepared PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles effectively accumulated at the targeted tumor site through enhanced permeability and retention effects. Reversible surface charge for PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles allows the nanoparticles to escape the immune system and concentrate on the tumor tissue. Tumor growth in the nude mice treated with the nanoparticles decreased significantly and the hydrophobic interaction in the poly(lactic acid) block could allow the incorporation of multiple drugs. Therefore, the PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles could have considerable potential as a nanomedicinal platform for photodynamic therapy. Keywords: apoptosis, chlorin e6, polyelectrolyte, pH sensitive, charge conversion, nano­medicine&nbsp

Chaemin Lim,1,* Yu Seok Youn,2,* Kyung Soo Lee,1 Ngoc Ha Hoang,1 Taehoon Sim,1 Eun Seong Lee,3 Kyung Taek Oh1 1Department of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Seoul, 2Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, 3Division of Biotechnology, The Catholic University of Korea, Gyeonggi-do, South Korea *These authors contributed equally to this work Abstract: A polyelectrolyte ionomer complex (PIC) composed of cationic and anionic polymers was developed for nanomedical applications. Here, a poly(ethylene glycol)–poly(lactic acid)–poly(ethylene imine) triblock copolymer (PEG–PLA–PEI) and a poly(aspartic acid) (P[Asp]) homopolymer were synthesized. These polyelectrolytes formed stable aggregates through electrostatic interactions between the cationic PEI and the anionic P(Asp) blocks. In particular, the addition of a hydrophobic PLA and a hydrophilic PEG to triblock copolyelectrolytes provided colloidal aggregation stability by forming a tight hydrophobic core and steric hindrance on the surface of PIC, respectively. The PIC showed different particle sizes and zeta potentials depending on the ratio of cationic PEI and anionic P(Asp) blocks (C/A ratio). The doxorubicin (dox)-loaded PIC, prepared with a C/A ratio of 8, demonstrated pH-dependent behavior by the deprotonation/protonation of polyelectrolyte blocks. The drug release and the cytotoxicity of the dox-loaded PIC (C/A ratio: 8) increased under acidic conditions compared with physiological pH, due to the destabilization of the formation of the electrostatic core. In vivo animal imaging revealed that the prepared PIC accumulated at the targeted tumor site for 24 hours. Therefore, the prepared pH-sensitive PIC could have considerable potential as a nanomedicinal platform for anticancer therapy. Keywords: polyelectrolyte ionomer complex, PEG–PLA–PEI, nanomedicine, pH-sensiti

Chaemin Lim,1,* Yu Seok Youn,2,* Kyung Soo Lee,1 Ngoc Ha Hoang,1 Taehoon Sim,1 Eun Seong Lee,3 Kyung Taek Oh1 1Department of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Seoul, 2Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, 3Division of Biotechnology, The Catholic University of Korea, Gyeonggi-do, South Korea *These authors contributed equally to this work Abstract: A polyelectrolyte ionomer complex (PIC) composed of cationic and anionic polymers was developed for nanomedical applications. Here, a poly(ethylene glycol)–poly(lactic acid)–poly(ethylene imine) triblock copolymer (PEG–PLA–PEI) and a poly(aspartic acid) (P[Asp]) homopolymer were synthesized. These polyelectrolytes formed stable aggregates through electrostatic interactions between the cationic PEI and the anionic P(Asp) blocks. In particular, the addition of a hydrophobic PLA and a hydrophilic PEG to triblock copolyelectrolytes provided colloidal aggregation stability by forming a tight hydrophobic core and steric hindrance on the surface of PIC, respectively. The PIC showed different particle sizes and zeta potentials depending on the ratio of cationic PEI and anionic P(Asp) blocks (C/A ratio). The doxorubicin (dox)-loaded PIC, prepared with a C/A ratio of 8, demonstrated pH-dependent behavior by the deprotonation/protonation of polyelectrolyte blocks. The drug release and the cytotoxicity of the dox-loaded PIC (C/A ratio: 8) increased under acidic conditions compared with physiological pH, due to the destabilization of the formation of the electrostatic core. In vivo animal imaging revealed that the prepared PIC accumulated at the targeted tumor site for 24 hours. Therefore, the prepared pH-sensitive PIC could have considerable potential as a nanomedicinal platform for anticancer therapy. Keywords: polyelectrolyte ionomer complex, PEG–PLA–PEI, nanomedicine, pH-sensiti

Hyeong Jun Byeon,1 Insoo Kim,1 Ji Su Choi,1 Eun Seong Lee,2 Beom Soo Shin,3 Yu Seok Youn11Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 2Division of Biotechnology, The Catholic University of Korea, Bucheon-si, Republic of Korea; 3Department of Pharmacy, College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Republic of KoreaAbstract: The aim of the current study was to investigate the antitumor potential of poly(D,L-lactic-co-glycolic acid) microspheres (PLGA MSs) containing polyethylene glycol (PEG)-conjugated (PEGylated) tumor necrosis factor–related apoptosis-inducing ligand (PEG-TRAIL). PEG-TRAIL PLGA MSs were prepared by using a water-in-oil-in-water double-emulsion method, and the apoptotic activities of supernatants released from the PLGA MSs at days 1, 3, and 7 were examined. The antitumor effect caused by PEG-TRAIL PLGA MSs was evaluated in pancreatic Mia Paca-2 cell-xenografted mice. PEG-TRAIL PLGA MS was found to be spherical and 14.4±1.06 µm in size, and its encapsulation efficiency was significantly greater than that of TRAIL MS (85.7%±4.1% vs 43.3%±10.9%, respectively). The PLGA MS gradually released PEG-TRAIL for 14 days, and the released PEG-TRAIL was shown to have clear apoptotic activity in Mia Paca-2 cells, whereas TRAIL released after 1 day had a negligible activity. Finally, PEG-TRAIL PLGA MS displayed remarkably greater antitumor efficacy than blank or TRAIL PLGA MS in Mia Paca-2 cell-xenografted mice in terms of tumor volume and weight, apparently due to increased stability and well-retained apoptotic activity of PEG-TRAIL in PLGA MS. We believe that this PLGA MS system, combined with PEG-TRAIL, should be considered a promising candidate for treating pancreatic cancer.Keywords: Poly(D,L-lactic-co-glycolic acid), controlled release, PEGylation, TRAIL, pancreatic cancer

Hyeong Jun Byeon,1 Insoo Kim,1 Ji Su Choi,1 Eun Seong Lee,2 Beom Soo Shin,3 Yu Seok Youn11Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 2Division of Biotechnology, The Catholic University of Korea, Bucheon-si, Republic of Korea; 3Department of Pharmacy, College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Republic of KoreaAbstract: The aim of the current study was to investigate the antitumor potential of poly(D,L-lactic-co-glycolic acid) microspheres (PLGA MSs) containing polyethylene glycol (PEG)-conjugated (PEGylated) tumor necrosis factor–related apoptosis-inducing ligand (PEG-TRAIL). PEG-TRAIL PLGA MSs were prepared by using a water-in-oil-in-water double-emulsion method, and the apoptotic activities of supernatants released from the PLGA MSs at days 1, 3, and 7 were examined. The antitumor effect caused by PEG-TRAIL PLGA MSs was evaluated in pancreatic Mia Paca-2 cell-xenografted mice. PEG-TRAIL PLGA MS was found to be spherical and 14.4±1.06 µm in size, and its encapsulation efficiency was significantly greater than that of TRAIL MS (85.7%±4.1% vs 43.3%±10.9%, respectively). The PLGA MS gradually released PEG-TRAIL for 14 days, and the released PEG-TRAIL was shown to have clear apoptotic activity in Mia Paca-2 cells, whereas TRAIL released after 1 day had a negligible activity. Finally, PEG-TRAIL PLGA MS displayed remarkably greater antitumor efficacy than blank or TRAIL PLGA MS in Mia Paca-2 cell-xenografted mice in terms of tumor volume and weight, apparently due to increased stability and well-retained apoptotic activity of PEG-TRAIL in PLGA MS. We believe that this PLGA MS system, combined with PEG-TRAIL, should be considered a promising candidate for treating pancreatic cancer.Keywords: Poly(D,L-lactic-co-glycolic acid), controlled release, PEGylation, TRAIL, pancreatic cancer

Coherent Raman scattering (CRS) microscopy is gaining acceptance as a valuable addition to the imaging toolset of biological researchers. Optimal use of this label-free imaging technique benefits from a basic understanding of the physical principles and technical merits of the CRS microscope. This tutorial offers qualitative explanations of the principles behind CRS microscopy and provides information about the applicability of this nonlinear optical imaging approach for biological research.

Changkyu Lee,1 Ji Su Choi,1 Insoo Kim,1 Kyung Taek Oh,2 Eun Seong Lee,3 Eun-Seok Park,1 Kang Choon Lee,1 Yu Seok Youn11School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 2College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; 3Division of Biotechnology, The Catholic University of Korea, Bucheon-si, Republic of KoreaAbstract: Inhalable glycol chitosan-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing palmitic acid-modified exendin-4 (Pal-Ex4) (chitosan Pal-Ex4 PLGA NPs) were prepared and characterized. The surface morphology, particle size, and zeta potential of chitosan Pal-Ex4 PLGA NPs were investigated, and the adsorption and cytotoxicity of chitosan Pal-Ex4 PLGA NPs were evaluated in human lung epithelial cells (A549). Finally, the lung deposition characteristics and hypoglycemia caused by chitosan Pal-Ex4 PLGA NPs were evaluated after pulmonary administration in imprinting control region (ICR) and type 2 diabetic db/db mice. Results showed that chitosan Pal-Ex4 PLGA NPs were spherical, compact and had a diameter of ~700 nm and a positive surface charge of +28.5 mV. Chitosan-coated PLGA NPs were adsorbed onto A549 cells much more so than non-coated PLGA NPs. Pal-Ex4 release from chitosan-coated PLGA NPs was delayed by as much as 1.5 days as compared with chitosan-coated Ex4 PLGA NPs. In addition, chitosan-coated PLGA NPs remained in the lungs for ~72 hours after pulmonary administration, whereas most non-coated PLGA NPs were lost at 8 hours after administration. Furthermore, the hypoglycemic efficacy of inhaled chitosan Pal-Ex4 PLGA NPs was 3.1-fold greater than that of chitosan Ex4 PLGA NPs in db/db mice. The authors believe chitosan Pal-Ex4 PLGA NPs have considerable potential as a long-acting inhalation delivery system for the treatment of type 2 diabetes.Keywords: chitosan-coating, PLGA nanoparticles, inhalation, exendin-4, type 2 diabetes

Changkyu Lee,1 Ji Su Choi,1 Insoo Kim,1 Kyung Taek Oh,2 Eun Seong Lee,3 Eun-Seok Park,1 Kang Choon Lee,1 Yu Seok Youn11School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 2College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; 3Division of Biotechnology, The Catholic University of Korea, Bucheon-si, Republic of KoreaAbstract: Inhalable glycol chitosan-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing palmitic acid-modified exendin-4 (Pal-Ex4) (chitosan Pal-Ex4 PLGA NPs) were prepared and characterized. The surface morphology, particle size, and zeta potential of chitosan Pal-Ex4 PLGA NPs were investigated, and the adsorption and cytotoxicity of chitosan Pal-Ex4 PLGA NPs were evaluated in human lung epithelial cells (A549). Finally, the lung deposition characteristics and hypoglycemia caused by chitosan Pal-Ex4 PLGA NPs were evaluated after pulmonary administration in imprinting control region (ICR) and type 2 diabetic db/db mice. Results showed that chitosan Pal-Ex4 PLGA NPs were spherical, compact and had a diameter of ~700 nm and a positive surface charge of +28.5 mV. Chitosan-coated PLGA NPs were adsorbed onto A549 cells much more so than non-coated PLGA NPs. Pal-Ex4 release from chitosan-coated PLGA NPs was delayed by as much as 1.5 days as compared with chitosan-coated Ex4 PLGA NPs. In addition, chitosan-coated PLGA NPs remained in the lungs for ~72 hours after pulmonary administration, whereas most non-coated PLGA NPs were lost at 8 hours after administration. Furthermore, the hypoglycemic efficacy of inhaled chitosan Pal-Ex4 PLGA NPs was 3.1-fold greater than that of chitosan Ex4 PLGA NPs in db/db mice. The authors believe chitosan Pal-Ex4 PLGA NPs have considerable potential as a long-acting inhalation delivery system for the treatment of type 2 diabetes.Keywords: chitosan-coating, PLGA nanoparticles, inhalation, exendin-4, type 2 diabetes