title: De novo design of a tumor-penetrating peptide.
abstract: Poor penetration of antitumor drugs into the extravascular tumor tissue is often a major factor limiting the efficacy of cancer treatments. Our group has recently described a strategy to enhance tumor penetration of chemotherapeutic drugs through use of iRGD peptide (CRGDK/RGPDC). This peptide comprises two sequence motifs: RGD, which binds to αvβ3/5 integrins on tumor endothelia and tumor cells, and a cryptic CendR motif (R/KXXR/K-OH). Once integrin binding has brought iRGD to the tumor, the peptide is proteolytically cleaved to expose the cryptic CendR motif. The truncated peptide loses affinity for its primary receptor and binds to neuropilin-1, activating a tissue penetration pathway that delivers the peptide along with attached or co-administered payload into the tumor mass. Here, we describe the design of a new tumor-penetrating peptide based on the current knowledge of homing sequences and internalizing receptors. The tumor-homing motif in the new peptide is the NGR sequence, which binds to endothelial CD13. The NGR sequence was placed in the context of a CendR motif (RNGR), and this sequence was embedded in the iRGD framework. The resulting peptide (CRNGRGPDC, iNGR) homed to tumor vessels and penetrated into tumor tissue more effectively than the standard NGR peptide. iNGR induced greater tumor penetration of coupled nanoparticles and co-administered compounds than NGR. Doxorubicin given together with iNGR was significantly more efficacious than the drug alone. These results show that a tumor-specific, tissue-penetrating peptide can be constructed from known sequence elements. This principle may be useful in designing tissue-penetrating peptides for other diseases.
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Alberici
authors.forename: Lise
authors.initials: L
authors.lastname: Roth
authors.forename: Kazuki N
authors.initials: KN
authors.lastname: Sugahara
authors.forename: Lilach
authors.initials: L
authors.lastname: Agemy
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Kotamraju
authors.forename: Tambet
authors.initials: T
authors.lastname: Teesalu
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
authors.forename: Gian-Paolo
authors.initials: GP
authors.lastname: Rizzardi
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; C526428:NGR peptide; D009842:Oligopeptides; C579134:cysteinyl-arginyl-asparagyl-glycyl-arginyl-glycyl-prolyl-aspartyl-cysteine