title: Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy.
abstract: Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained
  quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.
authors.affiliation: Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Xinpeng
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Moore
authors.affiliation: Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Kilgore
authors.affiliation: Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Suntrea
authors.initials: S
authors.lastname: Hammer
authors.affiliation: Department of Biochemistry, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. Electronic address: david.boothman@utsouthwestern.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. Electronic address: jinming.gao@utsouthwestern.edu.
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D020552:Comet Assay; D004912:Erythrocytes / Q000187:drug effects; D004950:Esterases / Q000378:metabolism*; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007773:Lactates / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D008823:Micelles; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007773:Lactates; D008823:Micelles; D009285:Naphthoquinones; D011355:Prodrugs; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse; D004950:Esterases
keywords: Cancer nanomedicine; Non-small cell lung cancer; Polymeric micelles; Prodrug therapy; β-Lapachone