title: Synthetic enzyme inhibitor: a novel targeting ligand for nanotherapeutic drug delivery inhibiting tumor growth without systemic toxicity.
abstract: Unresolved problems associated with ligand-targeting of liposomal nanoparticles (NPs) to solid tumors include variable target receptor expression due to genetic heterogeneity and insufficient target specificity, leading to systemic toxicities. This study addresses these issues by developing a novel ligand-targeting strategy for liposomal NPs using RR-11a, a synthetic enzyme inhibitor of Legumain, an asparaginyl endopeptidase. Cell-surface expression of Legumain is driven by hypoxic stress, a hallmark of solid tumors. Legumain-targeted RR-11a-coupled NPs revealed high ligand-receptor affinity, enhanced solid-tumor penetration and uptake by tumor cells. Treatment of tumor-bearing mice with RR-11a-coupled NPs encapsulating doxorubicin resulted in improved tumor selectivity and drug sensitivity, leading to complete inhibition of tumor growth. These antitumor effects were achieved while eliminating systemic drug toxicity. Therefore, synthetic enzyme inhibitors, such as RR-11a, represent a new class of compounds that can be used for highly specific ligand-targeting of NPs to solid tumors.
  
  
  BACKGROUND
  This study addresses the problems associated with ligand-targeting of liposomal nanoparticles to solid tumors with variable target receptor expression. A novel and efficacious targeting strategy has been developed towards a synthetic enzyme inhibitor of Legumain. The authors demonstrate successful tumor growth inhibiting effect while eliminating systemic drug toxicity in an animal model using this strategy.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Debbie
authors.initials: D
authors.lastname: Liao
authors.forename: Ze
authors.initials: Z
authors.lastname: Liu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: Tingmei
authors.initials: T
authors.lastname: Chen
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008024:Ligands; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D000099240:Asparaginyl Endopeptidase
chemical_list: D000970:Antineoplastic Agents; D003546:Cysteine Endopeptidases; D004317:Doxorubicin; D008024:Ligands; D008081:Liposomes; D011480:Protease Inhibitors; D000099240:Asparaginyl Endopeptidase