title: Ligand-targeted theranostic nanomedicines against cancer.
abstract: Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors.forename: Virginia J
authors.initials: VJ
authors.lastname: Yao
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors.forename: Sara
authors.initials: S
authors.lastname: D'Angelo
authors.affiliation: Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Butler
authors.affiliation: Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Christophe
authors.initials: C
authors.lastname: Theron
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Smith
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Oncology, University of Turin, Candiolo, 10060, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Marchiò
authors.affiliation: Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, MI 48201.
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.affiliation: Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Dobroff
authors.affiliation: Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131; Center for Micro-Engineered Materials, University of New Mexico, Albuquerque, NM 87131; Cancer Research and Treatment Center, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131; Self-Assembled Materials Department, Sandia National Laboratories, Albuquerque, NM 87185.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.affiliation: Bioscience Division, Los Alamos National Laboratories, Los Alamos, NM, 87545.
authors.forename: Andrew R M
authors.initials: ARM
authors.lastname: Bradbury
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131. Electronic address: warap@salud.unm.edu.
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131. Electronic address: rpasqual@salud.unm.edu.
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
mesh_terms: D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D049329:Nanostructures / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D000068936:Theranostic Nanomedicine / Q000379:methods*
chemical_list: D004337:Drug Carriers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D004364:Pharmaceutical Preparations
keywords: Antibody display; Peptide ligands; Phage display; Protocells; Tumor targeting