title: Actively Targeted Nanoparticles for Drug Delivery to Tumor.
abstract: BACKGROUND
  Nanomedicine is an emerging therapeutic modality. Nanoparticles (NPs) are potential vehicles for delivery of anticancer therapeutics. NPs can be designed to facilitate tumor drug delivery both by passive and active targeting mechanisms. Passive targeting of NPs to tumors can be achieved through the enhanced permeability and retention (EPR) effect. Meanwhile, actively targeted NPs can be designed based on two different targeting mechanisms, ligand-directed targeting to the tumor cells and tumor microenvironment (TME)-directed targeting.
  
  
  METHODS
  We searched for and reviewed recently published literature on actively targeted NPs. Progress in this field was summarized in several focus areas, including methods for targeting of tumor cells and for targeting TME. Advantages and limitations of each approach were discussed.
  
  
  RESULTS
  This article covers data from 240 recent publications and provided numerous examples of ligand-directed NPs targeting tumor cell-selective surface receptors. Targeting ligands discussed include proteins such as transferrin and antibodies, as well as low molecular weight agents, such as peptides, aptamers, carbohydrates, and folate. In addition, extensive discussions of TME targeting NPs, designed to release drug in response to TME-specific stimuli, such as low pH, tumor-selective enzymes, and unique characteristics of tumor neovasculature, are also included in this review. In general, many novel actively targeting strategies have been developed and encouraging data have been reported in numerous settings, both in vitro and in animal studies.
  
  
  CONCLUSIONS
  Active targeting of NPs has experienced rapid growth as a field of research and is continuously expanding. There are now some early examples of efforts on clinical translation and reported clinical trials on these NPs. Future development of actively targeted NPs depends on better understanding of the many factors affecting the behavior of NPs in vivo and likely involves combining the approaches of targeting the tumor cells and of targeting components of the TME.
authors.forename: Ye
authors.initials: Y
authors.lastname: Bi
authors.forename: Fei
authors.initials: F
authors.lastname: Hao
authors.forename: Guodong
authors.initials: G
authors.lastname: Yan
authors.forename: Lesheng
authors.initials: L
authors.lastname: Teng
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA. lee.1339@osu.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: College of Life Sciences, Jilin University, 2699 Qianjin Avenue, Changchun, Jilin, China. xiejing@jlu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006801:Humans; D008024:Ligands; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands