Enhancement of doxorubicin anti-cancer activity by vascular targeting using IsoDGR/cytokine-coated nanogold

Angelo Corti,Anna Maria Gasparri,Angelina Sacchi,Matteo Monieri,Anna Mondino,Barbara Colombo,Alessandro Gori,Flavio Curnis,Giulia Anderluzzi

doi:10.1186/s12951-021-00871-y

Abstract

BackgroundGold nanospheres tagged with peptides containing isoDGR (isoAsp-Gly-Arg), an αvβ3 integrin binding motif, represent efficient carriers for delivering pro-inflammatory cytokines to the tumor vasculature. We prepared bi- or trifunctional nanoparticles bearing tumor necrosis factor-α (TNF) and/or interleukin-12 (IL12) plus a peptide containing isoDGR, and we tested their anti-cancer effects, alone or in combination with doxorubicin, in tumor-bearing mice.ResultsIn vitro biochemical studies showed that both nanodrugs were monodispersed and functional in terms of binding to TNF and IL12 receptors and to αvβ3. In vivo studies performed in a murine model of fibrosarcoma showed that low doses of bifunctional nanoparticles bearing isoDGR and TNF (corresponding to few nanoparticles per cell) delayed tumor growth and increased the efficacy of doxorubicin without worsening its toxicity. Similar effects were obtained using trifunctional nanoparticles loaded with isoDGR, TNF and IL12. Mechanistic studies showed that nanoparticles bearing isoDGR and TNF could increase doxorubicin penetration in tumors a few hours after injection and caused vascular damage at later time points.ConclusionIsoDGR-coated gold nanospheres can be exploited as a versatile platform for single- or multi-cytokine delivery to cells of the tumor vasculature. Extremely low doses of isoDGR-coated nanodrugs functionalized with TNF or TNF plus IL12 can enhance doxorubicin anti-tumor activity.Graphic

Highlights

Gold nanospheres tagged with peptides containing isoDGR, an αvβ3 integrin binding motif, represent efficient carriers for delivering pro-inflammatory cytokines to the tumor vasculature
We show that an extremely low dose of nanogold functionalized with iso1 and tumor necrosis factor-α (TNF) or with iso1, TNF and IL12 can increase the efficacy of doxorubicin without increasing its toxicity
Preparation of bifunctional gold nanoparticles bearing iso1 and IL12 or iso1 and TNF Bifunctional gold Nps loaded with iso1 and IL12 or iso1 and TNF were prepared, as described previously, by incubating 1 ml of 25-nm nanogold (A520nm, ~ 1 unit) with 0.1 ml of solution containing 120 μg of iso1-human serum albumin (HSA) and 2.7 μg of IL12 or 160 μg of iso1-HSA and 16 μg of TNF, respectively [21, 23]

Summary

Introduction

Gold nanospheres tagged with peptides containing isoDGR (isoAsp-Gly-Arg), an αvβ integrin binding motif, represent efficient carriers for delivering pro-inflammatory cytokines to the tumor vasculature. NGR-TNF, a peptide-cytokine conjugate that alters endothelial permeability and enhances the penetration of chemotherapeutic drugs in tumor tissues [3, 7] Low doses of this drug have been tested in various clinical studies in patients with solid tumors, including patients with primary lymphomas of the central nervous system (PCNSL), with evidence of activity and good tolerability [7, 11,12,13,14]. We prepared gold nanoparticles (Nps) bearing TNF and/or IL12 and c(CGisoDGRG) (iso1), a head-to-tail cyclic peptide that recognizes αvβ integrin overexpressed in the tumor vasculature [27, 28] We tested their physicochemical, biochemical and biological properties in vitro and their therapeutic activity in a murine model of fibrosarcoma, alone or combined with doxorubicin (a chemotherapeutic drug). We show that nanogold functionalized with iso and TNF increases doxorubicin penetration in tumors a few hours after injection and causes vascular damage at later time points

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Conclusion