title: Enhancement of the uptake and cytotoxic activity of doxorubicin in cancer cells by novel cRGD-semipeptide-anchoring liposomes.
abstract: Novel liposemipeptides hanging cyclic azabicycloalkane-RGD or aminoproline-RGD terminals were synthesized and incorporated into liposomal nanoparticles cAba/cAmpRGD-LNP5 3C/3D. Liposomes with similar composition and lacking semipeptide conjugates were constructed for comparison (LNP, 3A), and physical encapsulation of the anticancer doxorubicin drug in both targeted and untargeted liposomes was accomplished. Microstructural analysis performed by dynamic light scattering (DLS), small-angle neutron scattering (SANS), and electron paramagnetic resonance (EPR) revealed that the conjugated nanoparticles presented an average size of 80 nm and were constituted by 5 nm thick unilamellar liposome bilayer. Flow cytometry and fluorescent microscopy studies showed that 3C-DOXO and 3D-DOXO efficiently delivered the drug into the nuclei of both quiescent and proliferating cells even in a high serum concentration environment. The uptake of doxorubicin when carried by liposomes was faster than that of the free drug, and 30 min incubation was sufficient to load cell nuclei with doxorubicin. Targeted liposomes significantly induced cell death of human breast adenocarcinoma MCF7 cells (IC50 = 144 nM, 3C-DOXO; IC50 = 274 nM, 3D-DOXO), about 2- to 6-fold more potent than free doxorubicin or 3A-DOXO controls (IC50 = 527 and 854 nM, respectively). These results suggest that cAba/cAmpRGD liposomal nanoparticles hold promise for the rapid and efficient delivery of chemotherapeutic agents to αVβ3-expressing tumor cells.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parma 43124, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Battistini
authors.forename: Paola
authors.initials: P
authors.lastname: Burreddu
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartori
authors.forename: Daniela
authors.initials: D
authors.lastname: Arosio
authors.forename: Leonardo
authors.initials: L
authors.lastname: Manzoni
authors.forename: Luigi
authors.initials: L
authors.lastname: Paduano
authors.forename: Gerardino
authors.initials: G
authors.lastname: D'Errico
authors.forename: Roberto
authors.initials: R
authors.lastname: Sala
authors.forename: Laura
authors.initials: L
authors.lastname: Reia
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bonomini
authors.forename: Gloria
authors.initials: G
authors.lastname: Rassu
authors.forename: Franca
authors.initials: F
authors.lastname: Zanardi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000494:pharmacology*; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin