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Hongli Yan,1,2,* Zhifeng Xue,1,2,* Jiarong Xie,1,2 Yixiao Dong,1,2 Zhe Ma,1,2 Xinru Sun,1,2 Dereje Kebebe Borga,1–3 Zhidong Liu,1,2 Jiawei Li2,4 1Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People’s Republic of China; 2Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People’s Republic of China; 3School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia; 4Institute of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhidong LiuTianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 10, Poyang Lake Road, Jinghai, Tianjin 301617, People’s Republic of ChinaTel +86 22 5959 6163Email lonerliuzd@163.comJiawei LiInstitute of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, No. 10, Poyang Lake Road, Jinghai, Tianjin 301617, People’s Republic of ChinaTel +86 22 5959 6352Email lijiawei1981@163.comAbstract: Nanoparticle drug formulations have enormous application prospects owing to achievement of targeted and sustained release drug delivery, improvement in drug solubility and reduction of adverse drug reactions. Recently, a variety of efficient drug nanometer carriers have been developed, among which carbon nanotubes (CNT) have been increasingly utilized in the field of cancer therapy. However, these nanotubes exert various toxic effects on the body due to their unique physical and chemical properties. CNT-induced toxicity is related to surface modification, degree of aggregation in vivo, and nanoparticle concentration. This review has focused on the potential toxic effects of CNTs utilized as anti-tumor drug carriers. The main modes by which CNTs enter target sites, the toxicity expressive types and the factors affecting toxicity are discussed.Keywords: anti-tumor, cancer, CNTs, nanometer preparation, nanometer carrier, toxicity

Dereje Kebebe,1–3,*Yumei Wu,1,2,* Bing Zhang,1,2 Jian Yang,1,2 Yuanyuan Liu,1,2 Xinyue Li,1,2 Zhe Ma,1,2 Peng Lu,1,2 Zhidong Liu,1,2 Jiawei Li1,21Tianjin State Key Laboratory of Modern Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People’s Republic of China; 2Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People’s Republic of China; 3Department of Pharmaceutics, School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia*These authors contributed equally to this workBackground and purpose: Gambogic acid (GA) is a natural compound that exhibited a promising multi-target antitumor activity against several types of cancer. However, the clinical application of this drug is limited due to its poor solubility and low tumor cell-specific delivery. In this study, the monomeric and dimeric Cyclo (Arg-Gly-Asp) c(RGD) tumor targeting peptides (c(RGDfK) and E-[c(RGDfK)2]) were used to modify GA loaded nanostructured lipid carriers (NLC) to reduce the limitations associated with GA and improve its antitumor activity.Methods: GA-NLC was prepared by emulsification and solvent evaporation methods and the surface of the NLC was conjugated with the c(RGD) peptides via an amide bond. The formulations were characterized for particle size, morphology and zeta potential, encapsulation efficiency and drug loading. The in-vitro cytotoxicity and cell uptake studies were conducted using 4T1 cell. Furthermore, the in-vivo antitumor activity and bio-distribution study were performed on female BALB/c nude mice.Results: The c(RGD) peptides modified GA-NLC was successfully prepared with the particles size about 20nm. The HPLC analysis, FT-IR and 1H-NMR spectra confirmed the successful conjugation of the peptides with the NLC. The in-vitro cytotoxicity study on 4T1 cells revealed that c(RGD) peptides modified GA-NLCs showed significantly higher cytotoxicity at 0.25 and 0.5μg/mL as compared to unmodified GA-NLC. Furthermore, the cell uptake study demonstrated that better accumulation of E-[c(RGDfK)2] peptides modified NLC in 4T1 cell after 12h incubation. Moreover, the in-vivo study showed that c(RGD)s functionalized GA-NLC exhibited better accumulation in tumor tissue and tumor growth inhibition. In contrast to the monomeric c(RGD) peptide, the dimeric c(RGD) peptide (E-[c(RGDfK)2]) conjugated GA-NLC showed the improved antitumor activity and tumor targeting ability of GA-NLC.Conclusion: These data provide further support for the potential clinical applications of E-[c(RGDfK)2]-GA-NLC in breast cancer therapy.Keywords: c(RGD) peptides, nanostructured lipid carriers, Gambogic acid, breast cancer, cell uptake, antitumor

Zhe Ma,1,2 Yuqi Fan,2,3 Yumei Wu,1,2 Dereje Kebebe,1,2,4 Bing Zhang,1,2 Peng Lu,1,2 Jiaxin Pi,1,2 Zhidong Liu1,2 1Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; 2Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; 3School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; 4School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia Abstract: Cancer is a major public health problem, and is now the world’s leading cause of death. Traditional Chinese medicine (TCM)-combination therapy is a new treatment approach and a vital therapeutic strategy for cancer, as it exhibits promising antitumor potential. Nanotargeted drug-delivery systems have remarkable advantages and allow the development of TCM-combination therapies by systematically controlling drug release and delivering drugs to solid tumors. In this review, the anticancer activity of TCM compounds is introduced. The combined use of TCM for antitumor treatment is analyzed and summarized. These combination therapies, using a single nanocarrier system, namely codelivery, are analyzed, issues that require attention are determined, and future perspectives are identified. We carried out a systematic review of >280 studies published in PubMed since 1985 (no patents involved), in order to provide a few basic considerations in terms of the design principles and management of targeted nanotechnology-based TCM-combination therapies. Keywords: cancer, codelivery, combination therapy, nanotargeted drug-delivery system, tumor targeting, TCM

Targeted delivery by the folate ligand is an effective way to enhance an anti-breast carcinoma effect, due to its high affinity for the folate receptor, which is overexpressed in many tumor cells. In this study, we firstly synthesized a folic acid (FA)-targeted and polyethylene glycol (PEG)-modified TiO2 nanocarrier. Then, an FA-PEG-TiO2 nanoparticle (NP) codelivery system loaded with curcumin and salvianolic acid B were prepared by emulsion evaporation–solidification at low temperature. The obtained folate-targeted NPs (FA-NPs) showed more cytotoxicity on MCF7 cells and MDA-MB-231 cells than a nontargeted NP group. Apart from a synergistic anti-breast cancer effect with curcumin, salvianolic acid B protects the cardiovascular system from oxidative injury by the TiO2 nanocarrier. With coumarin 6 as a fluorescent probe to observe cellular uptake of NPs, the results of in vitro cellular uptake demonstrated FA-NPs exhibited higher cellular uptake and accumulation in MCF7 cells and MDA-MB-231 cells than nontargeted NPs. Then, in vivo biodistribution of NPs was further qualitatively and quantitatively confirmed by in vivo imaging. More importantly, the animal study further suggested that FA-NPs had significantly stronger antitumor effects via receptor-mediated targeted delivery. Consequently, FA-PEG-TiO2 NPs loaded with curcumin and salvianolic acid B could be a promising drug-delivery system to treat breast cancer.

Dereje Kebebe,1–4 Yuanyuan Liu,1–3 Yumei Wu,1–3 Maikhone Vilakhamxay,1–3 Zhidong Liu,1–3 Jiawei Li1–3 1Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; 2Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; 3Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; 4School of Pharmacy, Institute of Health Sciences, Jimma University, Jimma, Ethiopia Abstract: Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents. Keywords: cancer, nanocarriers, cell-penetrating peptide, targeting drug delivery, herb-based drug, tumor targeting&nbsp