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Na Qu,1 Ke Song,2 Yating Ji,1 Mingxia Liu,1 Lijiang Chen,1 Robert J Lee,3,4 Lesheng Teng3,5 1School of Pharmacy, Liaoning University, Shenyang, 110036, People’s Republic of China; 2MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, 6229 ER, the Netherlands; 3School of Life Sciences, Jilin University, Changchun, 130023, People’s Republic of China; 4College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA; 5State Key Laboratory of Long-Acting and Targeting Drug Delivery System, Yantai, 264000, People’s Republic of ChinaCorrespondence: Lesheng Teng, Email tenglesheng@jlu.edu.cnAbstract: Nanoparticle-based systems are extensively investigated for drug delivery. Among others, with superior biocompatibility and enhanced targeting capacity, albumin appears to be a promising carrier for drug delivery. Albumin nanoparticles are highly favored in many disease therapies, as they have the proper chemical groups for modification, cell-binding sites for cell adhesion, and affinity to protein drugs for nanocomplex generation. Herein, this review summarizes the recent fabrication techniques, modification strategies, and application of albumin nanoparticles. We first discuss various albumin nanoparticle fabrication methods, from both pros and cons. Then, we provide a comprehensive introduction to the modification section, including organic albumin nanoparticles, metal albumin nanoparticles, inorganic albumin nanoparticles, and albumin nanoparticle-based hybrids. We finally bring further perspectives on albumin nanoparticles used for various critical diseases.Plain Language Summary: Albumin appears to be a promising carrier for drug delivery with superior biocompatibility and enhanced targeting capacity. This review focuses on the importance of albumin nanoparticles in drug delivery and concludes the recent fabrication techniques to prepare albumin nanoparticles, the modification strategies to require functional albumin nanoparticles, and critical applications of albumin nanoparticles in various diseases. The aim of this review is to help readers understand the significant potential of albumin nanoparticles in drug delivery. Keywords: albumin nanoparticle, drug delivery, fabrication, modification, application

Yumeng Wei,1– 3,* Mingtang Zeng,1– 4,* Chao Pi,1– 3 Hongping Shen,2,5 Jiyuan Yuan,2,5 Ying Zuo,2,6 Jie Wen,1– 3 Pu Guo,7 Wenmei Zhao,1– 3 Ke Li,1– 3 Zhilian Su,1– 3 Xinjie Song,8,9 Shaozhi Fu,10 Robert J Lee,11 Ling Zhao2,3 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 5Clinical Trial Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 6General Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 7Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 8School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, People’s Republic of China; 9Department of Food Science and Technology, Yeungnam University, Gyeongsan-si, Gyeongsangbuk-do, 38541, Republic of Korea; 10Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 11Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA*These authors contributed equally to this workCorrespondence: Shaozhi Fu, Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel +86 830-3165698, Fax +86 830-3165690, Email shaozhifu513@swmu.edu.cn Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling-998@163.comPurpose: Paclitaxel (PTX) has been widely utilized for the treatment of breast cancer. However, drawbacks, such as poor aqueous solubility, rapid blood clearance and severe toxicity, greatly reduce its efficacy and safety. Herein, a novel self-developed curcumin derivative (CUD) was chosen as the carrier to develop a long-acting PTX nano-delivery system (PTX-Sln@CUD) in order to improve its pharmacokinetic behavior, anti-breast cancer efficacy and safety.Methods: PTX-Sln@CUD was prepared using solid dispersion and ultrasonic technology. Relevant physical and chemical properties, including stability and release behavior, were characterized. The clearance of PTX-Sln@CUD in vivo was studied by pharmacokinetic experiments. The anti-tumor activity of PTX-Sln@CUD was investigated in vitro and in vivo. Hemolysis experiments, acute toxicity and cumulative toxicity studies were performed in mice to determine the safety of PTX-Sln@CUD.Results: The average particle size, PDI, Zeta potential, encapsulation efficiency and loading efficiency of the PTX-Sln@CUD were 238.5 ± 4.79 nm, 0.225 ± 0.011, − 33.8 ± 1.26 mV, 94.20 ± 0.49% and 10.98 ± 0.31%, respectively. PTX-Sln@CUD was found to be stable at room temperature for half a year. The cumulative release rates of PTX-Sln@CUD at 24, 96 and 168 h were 17.98 ± 2.60, 57.09 ± 2.32 and 72.66 ± 4.16%, respectively, which were adherent to zero-order kinetics. T1/2, MRT (0-t) and AUC (0-t) of the PTX-Sln@CUD group were 4.03-fold (44.293 h), 7.78-fold (38.444 h) and 6.18-fold (14.716 mg/L*h) of the PTX group, respectively. PTX-Sln@CUD group demonstrated stronger anti-breast cancer activity than the PTX group. Importantly, the PTX-Sln@CUD group was safer compared to the PTX group both in vitro and in vivo.Conclusion: PTX-Sln@CUD was verified as promising therapeutic nanoparticles for breast cancer and provided a novel strategy to solve the problem of low efficacy and poor safety of clinical chemotherapy drugs.Graphical Abstract: Keywords: breast cancer, long-acting, paclitaxel nanoparticles, curcumin derivative

Yumeng Wei,1– 3,* Ke Li,1– 3,* Wenmei Zhao,1– 3,* Yingmeng He,2,4 Hongping Shen,2,5 Jiyuan Yuan,2,5 Chao Pi,1– 3 Xiaomei Zhang,6 Mingtang Zeng,1– 3 Shaozhi Fu,7 Xinjie Song,8,9 Robert J Lee,10 Ling Zhao2,3 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 4Department of Pharmacy, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 5Clinical Trial Center, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 6Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, Institute of Medicinal Chemistry of Chinese Medicine, Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, People’s Republic of China; 7Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 8School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang, 310023, People’s Republic of China; 9Department of Food Science and Technology, Yeungnam University, Gyeongsan-si, Gyeongsangbuk-do, 38541, Republic of Korea; 10Division of Pharmaceutics and Pharmacology, College of Pharmacy, the Ohio State University, Columbus, OH, 43210, USA*These authors contributed equally to this workCorrespondence: Robert J Lee, The Ohio State University, 500 W 12th Ave, Columbus, OH, 43210, USA, Tel +1-614-292-4172, Fax +1-614-292-4172, Email lee.1339@osu.edu Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182, Chunhui Road, Longmatan District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel +86 830 3160093, Fax +86 830 3160093, Email zhaoling-998@163.comPurpose: The objective of this study was to develop long-circulating solid lipid nanoparticles (LSLN) containing a novel curcumin (CU) derivative (CU1), to improve CU1ʹs pharmacokinetic behavior and its anti-cancer effects in MHCC-97H liver cancer cells.Methods: LSLN loaded with CU1 (CU1-LSLN) was optimized and characterized. The cell biological properties and the anti-cancer mechanism of CU1-LSLN on MHCC-97H cells were evaluated by MTT, flow cytometry, Transwell, and Western blot. CU1-LSLN was further evaluated for pharmacokinetic behavior, biodistribution, and liver toxicity in SD rats.Results: The optimized CU1-LSLN formulation showed the ideal particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE%), and drug loading (DL%) of 122.10 ± 6.63 nm, 0.19 ± 0.02, − 36.30 ± 1.25 mV, 94.98 ± 0.90% and 4.53 ± 0.69%, respectively. X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrometry (FTIR) indicated that CU1 was well encapsulated by LSLN and existed in amorphous form. Storage stability of CU1-LSLN was up to 180 days with a sustained-release of drug over 96 h. The uptake efficiency of CU1-LSLN to MHCC-97H cells was 3.24 and 2.98 times higher than that of CU and CU1 after treatment for 3 h, which helped to enhance the inhibitive effect of CU1-LSLN on the proliferation, migration, and invasion potential of MHCC-97H cells and increased its ability to promote apoptosis. Meanwhile, the expression levels of NF-κB, COX-2, MMP-2, MMP-9, and uPA decreased significantly. In vivo, CU1-LSLN prolonged the retention time of the drug, the area under the curve (AUC) increased significantly (CU: 69.9-fold, CU1: 85.9-fold), and no significant liver toxicity was observed.Conclusion: CU1-LSLN is a novel preparation with great potential for treating liver cancer.Keywords: curcumin derivative, nanoparticle, MHCC-97H, pharmacokinetics

Yan Chen,1 Yao Lu,1 Robert J Lee,2 Guangya Xiang1 1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH, USACorrespondence: Guangya XiangSchool of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, Hubei 430030, People’s Republic of ChinaTel +86 27 83692793Email gyxiang1968@hotmail.comAbstract: Curcumin, a yellow-colored polyphenol extracted from the rhizome of turmeric root, is commonly used as a spice and nutritional supplement. It exhibits many pharmacological activities such as anti-inflammatory, anti-bacterial, anti-cancer, anti-Alzheimer, and anti-fungal. However, the therapeutic application of curcumin is limited by its extremely low solubility in aqueous buffer, instability in body fluids, and rapid metabolism. Nano delivery system has shown excellent potential to improve the solubility, biocompatibility and therapeutic effect of curcumin. In this review, we focus on the recent development of nano encapsulated curcumin and its potential for biomedical applications.Keywords: curcumin, nanoformulations, bioavailability, nanoparticles, therapy

Wenxue Mao,1 Fan Wu,2 Robert J Lee,3 Weigen Lu,4 Jianxin Wang11Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, People’s Republic of China; 2College of Medicine, Des Moines University, Des Moines, IA 50312, USA; 3Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus, OH 43210, USA; 4China State Institute of Pharmaceutical Industry, Shanghai 201203, People’s Republic of ChinaBackground: Vincristine is a potent therapeutic agent with well-defined activity against hematologic malignancies and solid tumors. It is a cell-cycle specific drug with concentration and exposure duration dependent activity. When used by liposomal delivery, it exhibits enhanced anti-tumor activity. However, vincristine liposome formulation in the clinic is supplied as a 3-vial-kit due to lacking sufficient stability. So it has to be prepared in situ prior to use through a multi-step process.Purpose: The purpose here is to develop a more stable and ready-to-use liposomal formulation for vincritstine in one vial.Patients and methods: A series of preparations were investigated based on sphingomyelin/cholesterol/PEG2000-DSPE lipid composition, with different drug/lipid (D/L) ratios (1/10, 1/5, 1/2), using an active sucrose octasulfate triethylamine salt gradient loading method. In this work, compared to generic vincristine sulfate liposome injection (GVM), the stability both in vivo and in vitro and efficacy in vivo of novel vincristine liposomes were investigated.Results: It was shown that the degradation of vincristine during 2–8°C storage was significantly decreased from 8.2% in 1 month (GVM) to 2.9% in 12 months (D/L ratio 1/5). The half-time for sphingomyelin/cholesterol/PEG2000-DSPE liposomes in vivo could be adjusted from 17.4 h (D/L ratio 1/10) to 22.7 h (D/L ratio 1/2) in rats, while the half-time for GVM was only 11.1 h. The increase in drug retention contributed to the lower in vivo toxicity. The antitumor efficacy was evaluated using a human melanoma tumor model and showed remarkable improvement compared to GVM.Conclusion: The study demonstrates that the new formulation with the drug/lipid ratio of 1/5 owns a higher encapsulation efficiency, better stability, lower toxicity and superior antitumor efficacy, which is screened out for further development.Keywords: vincristine sulfate, liposome, TEA-SOS, storage stability, and anti-tumor efficacy

Yating Sun,1 Yarong Zhao,1 Shanshan Teng,1 Fei Hao,1 Huan Zhang,1 Fanchao Meng,1 Xiuting Zhao,1 Xiaolong Zheng,1 Ye Bi,1 Yicheng Yao,2 Robert J Lee,1,3 Lesheng Teng1 1School of Life Sciences, Jilin University, Changchun, Jilin, China; 2Acalanes High School, Lafayette, CA, USA; 3Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA Background: We previously developed cabazitaxel (CTX)-loaded human serum albumin nanoparticles (NPs-CTX) via a self-assembly method, and these NPs showed efficacy in prostate cancer therapy. Many studies have shown that the levels of folic acid (FA) receptor on the surface of various tumor cells are high. Therefore, FA-modified NPs-CTX may have enhanced antitumor effects compared with unmodified NPs-CTX. Methods: NPs-CTX were first prepared via self-assembly, and FA was conjugated on the surface of NPs-CTX through the -NH2 groups of the NPs to produce FA-NPs-CTX. The FA-NPs-CTX were evaluated in tumor cells with high FA receptor (FR) expression in vitro and in vivo. Results: Both NPs-CTX and FA-NPs-CTX exhibited good stability and morphology. Drug release from the NPs was not affected by FA conjugation. Compared with CTX dissolved in a mixture of Tween 80 and 13% ethanol (w/w) at a ratio of 1:4 (v/v) (Tween-CTX), the two nanoformulations had lower lytic activity against normal red blood cells. However, FA-NPs-CTX showed greater inhibition of tumor cells with overexpressed FR, compared with NPs-CTX, in the cytotoxicity experiments. Moreover, the cellular uptake of FA-NPs-CTX was enhanced through FR-mediated endocytosis in HeLa cells in vitro and HeLa xenograft tumors in vivo. Although Tween-CTX exhibited tumor growth inhibition similar to FA-NPs-CTX in vivo, this inhibition also caused adverse side effects; the median lethal dose (LD50) of Tween-CTX to mice was 5.68 mg/kg, while FA-NPs-CTX-treated mice survived at doses exceeding 400 mg/kg. Conclusion: The results showed that FA-NPs-CTX caused inhibition of tumor growth in a manner similar to that of Tween-CTX; however, the safety and tolerability of CTX were greatly improved by FA conjugation compared with those of Tween-CTX. In summary, FA-NPs-CTX have great potential in CTX delivery, and this formulation is a promising candidate for the treatment of cancers with high FR levels. Keywords: folic acid, human serum albumin, nanoparticles, cabazitaxel, folic acid receptor

Ye Bi,1 Robert J Lee,1,2 Xinyu Wang,1 Yating Sun,1 Mengqiao Wang,1 Lianlian Li,1 Chenliang Li,1 Jing Xie,1 Lesheng Teng1 1School of Life Sciences, Jilin University, Changchun, Jilin, People’s Republic of China; 2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA Purpose: A liposome-based siRNA–drug combination was evaluated as a potential therapeutic strategy to improve the curative effect. Methods: A topoisomerase inhibitor SN38 prodrug was combined with a survivin siRNA through codelivery using transferrin (Tf)-L-SN38/P/siRNA. In this combination, SN38 was conjugated to the cell penetrating peptide TAT through a polyethylene glycol (PEG) linker to synthesize TAT-PEG-SN38. The amphiphilic TAT-PEG-SN38 was used as an ingredient of liposomes to improve the cellular uptake. Protamine was added to form an electrostatic complex with siRNA in the core of the liposomes. Tf was introduced to enable tumor cell targeting of liposomes (Tf-L-SN38/P/siRNA). Results: Tf-L-SN38/P/siRNA exhibited a particle size of 148 nm and a ζ-potential of +7.8 mV. The cellular uptake and antitumor activity were dependent on Tf receptor targeting, TAT-PEG-SN38, and siRNA codelivery. Tf-L-SN38/P/siRNA was shown to be considerably more effective than liposomes carrying individual components. This combination induced potent tumor inhibition (76.8%) in HeLa cell xenograft tumor-bearing nude mice. Conclusion: These data indicated that Tf-L-SN38/P/siRNA was an effective system for codelivery of SN38 and a survivin siRNA and that its therapeutic potential deserved further evaluation. Keywords: SN38, survivin, siRNA, transferrin, prodrug

Jinlong Zhao,1 Menghui Zhao,1 Changhui Yu,1 Xueyan Zhang,1 Jiaxin Liu,1 Xinwei Cheng,2 Robert J Lee,1,2 Fengying Sun,1 Lesheng Teng,1 Youxin Li1 1School of Life Sciences, Jilin University, Changchun, China; 2College of Pharmacy, Ohio State University, Columbus, OH, USA Abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive cartilage and bone destruction. Activated macrophages that overexpress folic acid (FA) receptors play an important role in RA, due to their abundance in inflamed synovial membrane and joints. In an effort to deliver drugs to the inflamed tissues, multifunctional FA receptor-targeting and pH-responsive nanocarriers were developed. They were composed of lipids, polyethylene glycol (PEG)–poly(lactic-co-glycolic acid) (PLGA) forming a hydrophilic shell, FA around the hydrophilic shell as a targeting ligand, and poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) and PLGA as a hydrophobic core. PCADK also acts as a pH-responsive material. Methotrexate (Mtx) was encapsulated in the nanoparticles, which exhibited pH-responsive release in vitro. Cellular uptake and cytotoxicity experiments revealed that FA-PEG-PLGA/PCADK–lipid nanoparticles loaded with Mtx (FA-PPLNPs) exhibited superior cellular uptake and higher cytotoxicity to activated macrophages than PPLNPs/Mtx. The therapeutic effect of FA-PPLNPs/Mtx in RA was confirmed in an adjuvant-induced arthritis rat model. These results suggest that the multifunctional folate receptor-targeting and pH-responsive nanocarriers are promising for the treatment of RA. Keywords: rheumatoid arthritis, methotrexate, nanoparticles, folate, pH-responsive, PCADK

Ting Feng,1,* Yumeng Wei,1,* Robert J Lee,2 Ling Zhao1 1Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA *These authors contributed equally to this work Abstract: Curcumin (CUR) is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy. Keywords: curcumin, liposomes, drug delivery, bioavailability, cancer

Huiying Xue,1 Zhaoyang Yu,1 Yong Liu,1 Weigang Yuan,1 Tan Yang,1 Jia You,1 Xingxing He,2 Robert J Lee,3 Lei Li,1 Chuanrui Xu1 1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 2Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 3Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA Abstract: Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been shown that miR-375 inhibits P-gp expression via inhibition of astrocyte elevated gene-1 (AEG-1) expression in HCC, and induces apoptosis in HCC cells by targeting AEG-1 and YAP1. In this study, we prepared lipid-coated hollow mesoporous silica nanoparticles (LH) containing doxorubicin hydrochloride (DOX) and miR-375 (LHD/miR-375) to deliver the two agents into MDR HCC cells in vitro and in vivo. We found that LHD/miR-375 overcame drug efflux and delivered miR-375 and DOX into MDR HepG2/ADR cells or HCC tissues. MiR-375 delivered by LHD/miR-375 was taken up through phagocytosis and clathrin- and caveolae-mediated endocytosis. Following release from late endosomes, it repressed the expression of P-gp in HepG2/ADR cells. The synergistic effects of miR-375 and hollow mesoporous silica nanoparticles (HMSN) resulted in a profound increase in the uptake of DOX by the HCC cells and prevented HCC cell growth. Enhanced antitumor effects of LHD/miR-375 were also validated in HCC xenografts and primary tumors; however, no significant toxicity was observed. Mechanistic studies also revealed that miR-375 and DOX exerted a synergistic antitumor effect by promoting apoptosis. Our study illustrates that delivery of miR-375 using HMSN is a feasible approach to circumvent MDR in the management of HCC. It, therefore, merits further development for potential clinical application. Keywords: hollow mesoporous silica nanoparticle, doxorubicin, miR-375, AEG-1, hepatocellular carcinoma, multidrug resistance

Tan Yang,1,* Ling Xu,1,* Bin Li,1 Weijie Li,1 Xiang Ma,1 Lingling Fan,2 Robert J Lee,3 Chuanrui Xu,1 Guangya Xiang1 1Department of Biopharmaceuticals, School of Pharmacy, 2Stem Cell Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA *These authors contributed equally to this work Abstract: Development of antibody-drug conjugates (ADCs) is a promising therapeutic strategy for cancer therapy. In this study, folate was conjugated via a polyethyleneglycol (PEG) linker to immunoglobulin G (IgG), which was linked to doxorubicin (DOX), to form a novel ADC folate-PEG-IgG-DOX (FA-PEG-IgG-DOX). The FA-PEG-IgG-DOX showed high targeting efficiency in HeLa and KB cells and significantly improved the uptake and retention of DOX compared with IgG-DOX about 10-fold. Subsequently, FA-PEG-IgG-DOX was shown to have at least 8 times higher antitumor activity than IgG-DOX both in HeLa and KB cells and also induced more apoptosis in those cells than IgG-DOX. Moreover, FA-PEG-IgG-DOX had a 2 times longer circulating time than FA-IgG-DOX, but did not increase the DOX distribution in mouse hearts. Importantly, FA-PEG-IgG-DOX treatment significantly inhibited tumor growth in xenograft mice. Together, our results indicate that FA-PEG-IgG is an effective ADC carrier for delivery of chemotherapeutic agents and that conjugating tumor targeting ligands to antibodies is a promising strategy for producing ADC drugs. Keywords: folate, immunoglobulin G, doxorubicin, antibody-drug conjugate, cancer

Xue H, Yu Z, Liu Y, et al. Int J Nanomedicine.2017;12:5271–5287. The authors of this paper have advised that Figure 8E is incorrect. Because of the similar label of groups LHD/miR-375 and LH/miR-375, the authors uploaded the wrong figure by mistake. The authors have confirmed this correction will not make any change to the conclusion of their original research. Read the original article

Na Qu,1 Robert J Lee,1,2 Yating Sun,1 Guangsheng Cai,1 Junyang Wang,1 Mengqiao Wang,1 Jiahui Lu,1 Qingfan Meng,1 Lirong Teng,1 Di Wang,1 Lesheng Teng1,3 1School of Life Sciences, Jilin University, Changchun, People’s Republic of China; 2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA; 3State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, People’s Republic of China Abstract: Cabazitaxel-loaded human serum albumin nanoparticles (Cbz-NPs) were synthesized to overcome vehicle-related toxicity of current clinical formulation of the drug based on Tween-80 (Cbz-Tween). A salting-out method was used for NP synthesis that avoids the use of chlorinated organic solvent and is simpler compared to the methods based on emulsion-solvent evaporation. Cbz-NPs had a narrow particle size distribution, suitable drug loading content (4.9%), and superior blood biocompatibility based on in vitro hemolysis assay. Blood circulation, tumor uptake, and antitumor activity of Cbz-NPs were assessed in prostatic cancer xenograft-bearing nude mice. Cbz-NPs exhibited prolonged blood circulation and greater accumulation of Cbz in tumors along with reduced toxicity compared to Cbz-Tween. Moreover, hematoxylin and eosin histopathological staining of organs revealed consistent results. The levels of blood urea nitrogen and serum creatinine in drug-treated mice showed that Cbz-NPs were less toxic than Cbz-Tween to the kidneys. In conclusion, Cbz-NPs provide a promising therapeutic for prostate cancer. Keywords: cabazitaxel, human serum albumin, nanoparticle, drug delivery, toxicity, pros­tate cancer

Jing Xie,1 Xiaomin Zhang,2 Meiyu Teng,1 Bo Yu,2 Shuang Yang,1 Robert J Lee,1,3 Lesheng Teng1 1College of Life Sciences, Jilin University, Changchun, 2Hangzhou PushiKang Biotechnology Co., Ltd, Hangzhou, People’s Republic of China; 3Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA Abstract: 7-Ethyl-10-hydroxy camptothecin (SN38) is a potent topoisomerase inhibitor and a metabolite of irinotecan. Its clinical development has been hampered by its poor solubility. To address this problem, methoxy poly(ethylene glycol)-2000 (mPEG2K)–SN38 and mPEG2K–poly(lactide) (PLA1.5K)–SN38 conjugates were prepared and then dispersed into an aqueous medium to form micelles. Physicochemical characteristics of SN38–polymer conjugate micelles, for example, micelle diameter, zeta potential, morphology, and drug content, were then evaluated. The results showed that the mean diameters of mPEG2K–SN38 and mPEG2K–PLA1.5K–SN38 micelles were ~130 and 20 nm, respectively. These two micelles had similar drug contents. mPEG2K–PLA1.5K–SN38 micelles were more homogeneous than mPEG2K–SN38 micelles. Moreover, in vitro drug release behavior of the micelles was studied by high performance liquid chromatography. SN38 release from mPEG2K–SN38 micelles was much faster than from mPEG2K–PLA1.5K–SN38 micelles. In vitro cytotoxicity, cellular uptake, and apoptosis assays of the SN38–polymer conjugate micelles were carried out on BEL-7402 human liver cancer cells. In vivo biodistribution and antitumor tumor efficacy studies were carried out in a nude mouse xenograft model derived from BEL-7402 cells. The results showed that mPEG2K–PLA1.5K–SN38 micelles were significantly more effective than mPEG2K–SN38 micelles in tumor inhibition, and the inhibitory effect of mPEG2K–PLA1.5K–SN38 micelles on tumor growth was significantly greater than that of mPEG2K–SN38 micelles (1,042 vs 1,837 mm) at 30 days. In conclusion, mPEG–PLA–SN38 is a promising anticancer agent that warrants further investigation. Keywords: SN38, polymer conjugate, micelles, chemotherapy, liver cancer

Yifei Huang,1,* Tan Yang,2,* Wendian Zhang,2 Yao Lu,2 Peng Ye,2 Guang Yang,2 Bin Li,2 Shibo Qi,2 Yong Liu,2 Xingxing He,3 Robert J Lee,4 Chuanrui Xu,2 Guangya Xiang2 1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 4Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA*These authors contributed equally to this workAbstract: Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents.Keywords: liposome, doxorubicin, folate ligand, FR-targeting, stability

Rebecca J Lee, Anne C Armstrong, Andrew M WardleyDepartment of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UKAbstract: The number of targeted treatments has risen exponentially over the last few years and is an important concept in the fight against cancer. This review will concentrate on some of the main treatments targeting aberrant pathways which have been tested mainly in the Phase I/II setting. These include human epidermal growth factor receptor 2 inhibitors, drug-antibody conjugates, epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors, reticular activating system, mammalian target of rapamycin and multi-kinase inhibitors. Further knowledge of these pathways and the predictors of response to them will enable personalized medicine to become a reality.Keywords: breast cancer, targeted therapy, tyrosine kinase, receptor

Xiaoju Zhou,1,2,* Mengzi Zhang,2,* Bryant Yung,2 Hong Li,2 Chenguang Zhou,2 L James Lee,3,4 Robert J Lee2,41State Key Laboratory of Virology, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, People’s Republic of China; 2Division of Pharmaceutics, 3Department of Chemical and Biomolecular Engineering, 4NSF Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA*These authors contributed equally to this workBackground: N-lactosyl-dioleoylphosphatidylethanolamine (Lac-DOPE) was synthesized and evaluated as a liver-specific targeting ligand via asialoglycoprotein receptors for liposomal delivery of doxorubicin.Methods: Lactosylated liposomes encapsulating calcein (Lac-L-calcein) or doxorubicin (Lac-L-DOX) composed of egg phosphatidylcholine, cholesterol, monomethoxy polyethylene glycol 2000-distearoyl phosphatidylethanolamine, and Lac-DOPE at 50:35:5:10 (mol/mol) were prepared by polycarbonate membrane extrusion and evaluated in human hepatocellular carcinoma HepG2 cells. Cellular uptake of Lac-L-calcein was monitored by confocal microscopy and by flow cytometry. The cytotoxicity of Lac-L-DOX was evaluated by MTT assay. The pharmacokinetic properties of Lac-L-DOX were studied in normal mice, and its biodistribution and antitumor activity were studied in nude mice with HepG2 xenografts.Results: The size of Lac-L-DOX was less than 100 nm and the liposomes demonstrated excellent colloidal stability. In vitro uptake of Lac-L-calcein by HepG2 cells was four times greater than that of non-targeted L-calcein. In the presence of 20 mM lactose, the uptake of Lac-L-calcein was inhibited, suggesting that asialoglycoprotein receptors mediated the observed cellular uptake. Lac-L-DOX exhibited enhanced in vivo cytotoxicity compared with the nontargeted liposomal doxorubicin (L-DOX), and its pharmacokinetic parameters indicate that Lac-L-DOX has a long blood circulation time (t1/2 8.73 hours). Tissue distribution and therapeutic efficacy studies in nude mice bearing HepG2 xenografts show that Lac-L-DOX had significantly stronger tumor inhibitory activity compared with L-DOX and free doxorubicin, along with a higher accumulation of drug within the tumor site and greater cellular uptake by tumor cells.Conclusion: These data suggest that lactosylated liposomes are promising drug delivery vehicles for hepatocellular carcinoma.Keywords: liposomes, hepatocellular carcinoma, asialoglycoprotein receptor, drug targeting

Nan Ding1,2, Yao Lu1, Robert J Lee3, Chang Yang1, Lei Huang1, Jian Liu1, Guangya Xiang1,41School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA; 4Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China The first three authors contributed equally to this work. Rationale and objective: Receptor-targeted delivery of imaging and therapeutic agents can lead to enhanced efficacy for both. Multimodality imaging offers unique advantages over traditional single modality imaging. Tumor marker folate receptor (FR)-targeted fluorescent paramagnetic bimodal liposomes were synthesized to co-deliver paramagnetic and fluorescence agents for magnetic resonance (MR) and optical bimodal imaging contrast enhancement. Materials and methods: Fluorescent and paramagnetic bimodal liposomes were synthesized with a mean diameter of 136 nm and a low polydispersity index. The liposomes incorporated folate-PEG3350-CHEMS for FR targeting, Gd(III)[N,N-Bis-stearylamidomethyl-N’-amidomethyl]diethylenetriamine tetraacetic acid (Gd-DTPA-BSA) for MR contrast, and calcein for fluorescence. To determine the specificity and efficiency of delivery, the liposomes were evaluated in FR-positive KB and HeLa cells and FR-negative A549 cells, which were analyzed by fluorescence microscopy, magnetic resonance imaging (MRI), and flow cytometry (FCM). Results: FR-specific and efficient cellular uptake of the FR-targeted bimodal liposomes was confirmed by fluorescence microscopy and by FCM. The mean fluorescence intensity (MFI) of KB cells treated with FR-targeted liposomes was 45× that of cells treated with nontargeted liposomes, and 18× that of cells treated with FR-targeted liposomes and excess folic acid (FA). The MFI of HeLa cells treated with targeted liposomes was 33× that of nontargeted liposomes, and was 16× that of the mixture of targeted liposomes and free FA. In contrast, the MFI of A549 cells treated with FR-targeted liposomes was nearly the same as those treated with nontargeted liposomes. The T1-weighted MR images of HeLa and KB cells incubated with FR-targeted liposomes had much higher signal intensity than those treated with nontargeted liposomes or free Gd-DTPA. Furthermore, the FR-targeting effect could be blocked by excess free FA. Conclusion: FR-targeted fluorescent paramagnetic bimodal liposomes provided a novel platform for bimodal tumor imaging and theranostic delivery. Keywords: folate receptor, tumor targeting, MRI, fluorescence, bimodal liposomes

© 2015 The Authors. Despite the controversy in mechanism, rodent and clinical studies have demonstrated beneficial effects of stem/progenitor cell therapy after myocardial infarction (MI). In a rat ischaemic reperfusion MI model, we investigated the effect

Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and vascular endothelial growth factor receptor (VEGFR) are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and VEGFR-2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date. [ABSTRACT FROM AUTHOR]

Context: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction.Objective: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.Data Sources: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.Study Selection: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.Data Extraction: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.Results: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.Conclusion: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) may be due to an inherited trait, particularly in lone AF patients. A family history of AF in lone AF patients has not previously been compared with a family history of patients with AF and established risk factors (non-lone AF).Objective: The purpose of this study was to compare the frequency of having a first-degree relative with AF in lone and non-lone AF patients.Methods: We performed a case-control study of consecutive subjects presenting to a single electrophysiology laboratory. A convenience sample of subjects with no known arrhythmias was also enrolled.Results: Four hundred twenty-nine subjects were enrolled: 136 had AF (54 with lone AF), 84 had atrial flutter, 158 had other supraventricular arrhythmias, and 51 had no known arrhythmias. Significantly more subjects with AF reported a first-degree family history of AF compared with the remainder of the cohort (25% vs. 5%; P <.001). In multivariable analysis adjusting for potential confounders, AF patients had a 6-fold greater odds of having a family member with AF (95% confidence interval [CI] 2.93-12.7; P <.001). Lone AF patients had a first-degree family member with AF substantially more often than those with non-lone AF (41% vs. 14%; P <.001). After adjusting for potential confounders, lone AF patients remained significantly more likely than other AF patients to have a first-degree relative with AF (OR 7.2; 95% CI 2.1-24.7; P = .002).Conclusion: Lone AF patients have a first-degree family member with AF substantially more often than other AF patients. This suggests that an inherited trait may be particularly important in this subgroup of patients. [ABSTRACT FROM AUTHOR]

Up to 55% of the homeless population report health problems. They often use the emergency department (ED) to obtain care when the health needs are not urgent. Nurse-managed clinics have the potential to reduce nonurgent ED use and improve the health of the homeless. The purpose of this study was to establish baseline health data on homeless persons prior to attending a nurse-managed clinic. This study was a cross-sectional, retrospective health survey of homeless clients at a nurse-managed clinic. A total of 110 participants completed a baseline health survey. Of these, 61% reported that prior to coming to the clinic, they used the ED as a source of health care. The most frequent medical diagnoses reported were substance use disorders, depression, back pain, hypertension, and asthma. Providing care for chronic conditions at a nurse-managed clinic has the potential to improve health and reduce use of the ED. [ABSTRACT FROM AUTHOR]