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Title: Ligand-targeted theranostic nanomedicines against cancer

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 20 years, 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 amore » 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. As a result, the modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.« less
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [1] ;  [5] ;  [6] ;  [1] ;  [1]
  1. Univ. of New Mexico, Albuquerque, NM (United States)
  2. Univ. of New Mexico, Albuquerque, NM (United States); Univ. of Turin, Candiolo (Italy)
  3. Wayne State Univ., Detroit, MI (United States)
  4. Harvard Medical School, Boston, MA (United States)
  5. Univ. of New Mexico, Albuquerque, NM (United States); Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
  6. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Report Number(s):
SAND-2016-3040J
Journal ID: ISSN 0168-3659; PII: S0168365916300025
Grant/Contract Number:
AC04-94AL85000
Type:
Published Article
Journal Name:
Journal of Controlled Release
Additional Journal Information:
Journal Name: Journal of Controlled Release; Journal ID: ISSN 0168-3659
Publisher:
Controlled Release Society
Research Org:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org:
USDOE National Nuclear Security Administration (NNSA)
Country of Publication:
United States
Language:
English
Subject:
antibody display; phage display; peptide ligands; protocells; tumor targeting
OSTI Identifier:
1236080
Alternate Identifier(s):
OSTI ID: 1249086