Neuroblastoma-targeted nanocarriers improve drug delivery and penetration, delay tumor growth and abrogate metastatic diffusion.
Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation.
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
Irene
I
Cossu
Nuclear Medicine Unit, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Gianluca
G
Bottoni
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
Monica
M
Loi
Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Laura
L
Emionite
Laboratory of Tumor Microenvironment, Candiolo Cancer Institute-IRCCS, Candiolo, Italy.
Alice
A
Bartolini
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
Daniela
D
Di Paolo
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
Chiara
C
Brignole
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
Francesca
F
Piaggio
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy.
Patrizia
P
Perri
Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
Angelina
A
Sacchi
Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
Flavio
F
Curnis
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Maria Cristina
MC
Gagliani
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Silvia
S
Bruno
Genoa Section, CNR Institute of Bioimages and Molecular Physiology, Milan, Italy.
Cecilia
C
Marini
Istituto di Chimica del Riconoscimento Molecolare, CNR, Milan, Italy.
Alessandro
A
Gori
Istituto di Chimica del Riconoscimento Molecolare, CNR, Milan, Italy.
Renato
R
Longhi
Department of Pathology, Istituto G. Gaslini, Genoa, Italy.
Daniele
D
Murgia
Department of Pathology, Istituto G. Gaslini, Genoa, Italy.
Angela Rita
AR
Sementa
Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Michele
M
Cilli
Department of Experimental Medicine, University of Genoa, Genoa, Italy; Experimental Imaging Center, Scientific Institute San Raffaele, Milan, Italy.
Carlo
C
Tacchetti
Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
Angelo
A
Corti
Nuclear Medicine Unit, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Gianmario
G
Sambuceti
Laboratory of Tumor Microenvironment, Candiolo Cancer Institute-IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Italy.
Serena
S
Marchiò
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy. Electronic address: mircoponzoni@ospedale-gaslini.ge.it.
Mirco
M
Ponzoni
Laboratorio di Oncologia, Istituto G. Gaslini, Genoa, Italy. Electronic address: fabiopastorino@ospedale-gaslini.ge.it.
Fabio
F
Pastorino
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D009447:Neuroblastoma / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D053769:Nanocapsules; D004317:Doxorubicin
Drug delivery; Micro-PET; Neuroblastoma; Targeted therapy; Tumor penetration