Block copolymers; Dimerization; Drug delivery; Nanoparticles; Peptide; Targeting
Abstract :
[en] We developed cyclic RGD-tagged polymeric micellar nanoassemblies for sustained delivery of Doxorubicin (Dox) endowed with significant cytotoxic effect against MG63, SAOS-2, and U2-OS osteosarcoma cells without compromising the viability of healthy osteoblasts (hFOBs). Targeted polymeric micellar nanoassemblies (RGD-NanoStar@Dox) enabled Dox to reach the nucleus of MG63, SAOS-2, and U2-OS cells causing the same cytotoxic effect as free Dox, unlike untargeted micellar nanoassemblies (NanoStar@Dox) which failed to reach the nucleus and resulted ineffective, demonstrating the crucial role of cyclic RGD peptide in driving cellular uptake and accumulation mechanisms in osteosarcoma cells. Micellar nanoassemblies were obtained by nanoformulation of three-armed star PLA-PEG copolymers properly synthetized with and without decoration with the cyclic-RGDyK peptide (Arg-Gly-Asp-D-Tyr-Lys). The optimal RGD-NanoStar@Dox nanoformulation obtained by nanoprecipitation method (8% drug loading; 35% encapsulation efficiency) provided a prolonged and sustained drug release with a rate significantly lower than that of the free drug under the same experimental conditions. Moreover, the nanosystem preserved Dox from the natural degradation occurring under physiological conditions (i.e., dimerization and consequent precipitation) serving as a slow-release "drug reservoir" ensuring an extended biological activity over the time.
Disciplines :
Chemistry
Author, co-author :
Oliva, Roberto ; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d'Alcontres 31, 98166 Messina, Italy
Torcasio, Serena ; Université de Mons - UMONS > Faculté des Sciences > Service des Matériaux Polymères et Composites
COULEMBIER, Olivier ; Université de Mons - UMONS > Faculté des Sciences > Service des Matériaux Polymères et Composites
Piperno, Anna; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d'Alcontres 31, 98166 Messina, Italy
Mazzaglia, Antonino ; CNR-ISMN, National Council of Research, Institute for the Study of Nanostructured Materials, URT of Messina c/o Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le, F. Stagno d'Alcontres, 31, 98166 Messina, Italy
Scalese, Silvia ; CNR-IMM, Consiglio Nazionale delle Ricerche - Istituto per la Microelettronica e Microsistemi, Ottava Strada n.5, 95121 Catania, Italy
Rossi, Arianna ; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d'Alcontres 31, 98166 Messina, Italy, CNR-ISSMC, Institute of Science, Technology and Sustainability for Ceramics, Via Granarolo 64, 48018 Faenza, RA, Italy
Bassi, Giada ; CNR-ISSMC, Institute of Science, Technology and Sustainability for Ceramics, Via Granarolo 64, 48018 Faenza, RA, Italy, Department of Neuroscience, Imaging and Clinical Science, University of Studies "G. D'Annunzio", 66100 Chieti, CH, Italy
Panseri, Silvia ; CNR-ISSMC, Institute of Science, Technology and Sustainability for Ceramics, Via Granarolo 64, 48018 Faenza, RA, Italy
Montesi, Monica ; CNR-ISSMC, Institute of Science, Technology and Sustainability for Ceramics, Via Granarolo 64, 48018 Faenza, RA, Italy
Scala, Angela ; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d'Alcontres 31, 98166 Messina, Italy. Electronic address: ascala@unime.it
Language :
English
Title :
RGD-tagging of star-shaped PLA-PEG micellar nanoassemblies enhances doxorubicin efficacy against osteosarcoma.
Agrahari, V., Agrahari, V., Advances and applications of block-copolymer-based nanoformulations. Drug Discov. Today. 23 (2018), 1139–1151, 10.1016/j.drudis.2018.03.004.
Battistini, L., Bugatti, K., Sartori, A., Curti, C., Zanardi, F., RGD peptide-drug conjugates as effective dual targeting platforms: recent advances. Eur. J. Org. Chem. 17 (2021), 2506–2528, 10.1002/ejoc.202100240.
Diou, O., Fattal, E., Delplace, V., Mackiewicz, N., Nicolas, J., Mériaux, S., Valette, J., Robic, C., Tsapis, N., RGD decoration of PEGylated polyester nanocapsules of perfluorooctyl bromide for tumor imaging: Influence of pre or post-functionalization on capsule morphology. Eur. J. Pharm. Biopharm. 87 (2014), 170–177, 10.1016/j.ejpb.2013.12.003.
Dornjak, L., Kovačić, M., Ostojić, K., Angaits, A., Szpunar, J., Urlić, I., Rogina, A., Chitosan-boric acid scaffolds for doxorubicin delivery in the osteosarcoma treatment. Polymers, 14, 2022, 4753, 10.3390/polym14214753.
Fang, Z., Sun, Y., Xiao, H., Li, P., Liu, M., Ding, F., Kan, W., Miao, R., Targeted osteosarcoma chemotherapy using RGD peptide-installed doxorubicin-loaded biodegradable polymeric micelle. Biomed. Pharmacother. 85 (2017), 160–168, 10.1016/j.biopha.2016.11.132.
Fazio, E., Scala, A., Grimato, S., Ridolfo, A., Grassi, G., Neri, F., Laser light triggered smart release of silibinin from a PEGylated–PLGA gold nanocomposite. J. Mater. Chem. B. 3 (2015), 9023–9032, 10.1039/C5TB01076D.
Fukushima, S., Machida, M., Akutsu, T., Shimizu, K., Tanaka, S., Okamoto, K., Mashiba, H., Yokoyama, M., Okano, T., Sakurai, Y., Kataoka, K., Roles of adriamycin and adriamycin dimer in antitumor activity of the polymeric micelle carrier system. Colloids Surf. B. 16 (1999), 227–236, 10.1016/S0927-7765(99)00073-9.
Gianferante, D.W., Mirabello, L., Savage, S.A., Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy. Nat. Rev. Endocrinol. 13 (2017), 480–491, 10.1038/nrendo.2017.16.
Govender, T., Riley, T., Ehtezazi, T., Garnett, M.C., Stolnik, S., Illum, L., Davis, S.S., Defining the drug incorporation properties of PLA–PEG Nanoparticles. Int. J Pharm. 199 (2000), 95–110, 10.1016/S0378-5173(00)00375-6.
Jin, X., Sun, P., Tong, G., Zhu, X., Star polymer-based unimolecular micelles and their application in bio-imaging and diagnosis. Biomaterials 178 (2018), 738–750, 10.1016/j.biomaterials.2018.01.051.
Johnsson, M., Wagenaar, A., Engberts, J.B.F.N., Sugar-based gemini surfactant with a vesicle-to-micelle transition at acidic pH and a reversible vesicle flocculation near neutral pH. J. Am. Chem. Soc. 125 (2003), 757–760, 10.1021/ja028195t.
Kovshova, T., Osipova, N., Alekseeva, A., Malinovskaya, J., Belov, A., Budko, A., Pavlova, G., Maksimenko, O., Nagpal, S., Braner, S., Modh, H., Balabanyan, V., Wacker, M.G., Gelperina, S., Exploring the interplay between drug release and targeting of lipid-like polymer nanoparticles loaded with doxorubicin. Molecules, 26, 2021, 831, 10.3390/molecules26040831.
Kreuzer, H.J., Wang, R.L.C., Grunze, M., Hydroxide ion adsorption on self-assembled monolayers. J. Am. Chem. Soc. 125 (2003), 8384–8389, 10.1021/ja0350839.
Kuperkar, K., Patel, D., Atanase, L.I., Bahadur, P., Amphiphilic block copolymers: their structures, and self-assembly to polymeric micelles and polymersomes as drug delivery vehicles. Polymers, 14, 2022, 4702, 10.3390/polym14214702.
Li, N., Qiu, S., Fang, Y., Wu, J., Li, Q., Comparison of linear vs. cyclic RGD pentapeptide interactions with integrin αvβ3 by molecular dynamics simulations. Biology (Basel), 10, 2021, 688, 10.3390/biology10070688.
Li, C., Wanga, W., Xi, Y., Wang, J., Chen, J.-F., Yun, J., Le, Y., Design, preparation and characterization of cyclic RGDfK peptide modified poly(ethylene glycol)-blockpoly(lactic acid) micelle for targeted delivery. Mater. Sci. Eng. C. 64 (2016), 303–309, 10.1016/j.msec.2016.03.062.
Liénard, R., Montesi, M., Panseri, S., Dozio, S.M., Vento, F., Mineo, P.G., Piperno, A., De Winter, J., Coulembier, O., Scala, A., Design of naturally inspired jellyfish-shaped cyclo-polylactides to manage osteosarcoma cancer stem cells fate. Mater. Sci. Eng. C., 117, 2020, 111291, 10.1016/j.msec.2020.111291.
Liu, J., Lin, S., Dang, J., Wang, S., Cheng, W., Ran, Z., Zhu, H., Deng, H., Xiong, C., Xu, W., Huang, Z., Xu, P., Xu, H., Anticancer and bone-enhanced nano-hydroxyapatite/gelatin/polylactic acid fibrous membrane with dual drug delivery and sequential release for osteosarcoma. Int. J. Biol. Macromol., 240, 2023, 124406, 10.1016/j.ijbiomac.2023.124406.
Lotocki, V., Kakkar, A., Miktoarm star polymers: branched architectures in drug delivery. Pharmaceutics., 12, 2020, 827, 10.3390/pharmaceutics12090827.
Lupusoru, R., Pricop, D.A., Uritu, C.M., Arvinte, A., Coroaba, A., Esanu, I., Zaltariov, M.F., Silion, M., Stefanescu, C., Pinteala, M., Effect of TAT-DOX-PEG irradiated gold nanoparticles conjugates on human osteosarcoma cells. Sci. Rep., 10, 2020, 6591, 10.1038/s41598-020-63245-8.
Mineo, P.G., Foti, C., Vento, F., Montesi, M., Panseri, S., Piperno, A., Scala, A., Salinomycin-loaded PLA nanoparticles: drug quantification by GPC and wave voltammetry and biological studies on osteosarcoma cancer stem cells. Anal. Bioanal. Chem. 412 (2020), 4681–4690, 10.1007/s00216-020-02721-6.
Nandi, S., Kale, N., Patil, A., Banerjee, S., Patil, Y., Khandare, J., A graphene-sandwiched DNA nano-system: regulation of intercalated doxorubicin for cellular localization. Nanoscale Adv. 2 (2020), 5746–5759, 10.1039/D0NA00575D.
Oliva, R., Ginestra, G., Piperno, A., Mazzaglia, A., Nostro, A., Scala, A., Harnessing the power of PLA-PEG nanoparticles for linezolid delivery against methicillin-resistant Staphylococcus aureus. Int. J. Pharm., 642, 2023, 123067, 10.1016/j.ijpharm.2023.123067.
Panez-Toro, I., Muñoz-García, J., Vargas-Franco, J.W., Renodon-Cornière, A., Heymann, M.-F., Lézot, F., Heymann, D., Advances in osteosarcoma. Curr. Osteoporos. Rep. 21 (2023), 330–343, 10.1007/s11914-023-00803-9.
Parchami, M., Haghiralsadat, F., Sadeghian-Nodoushan, F., Hemati, M., Shahmohammadi, S., Ghasemi, N., Sargazi, G., A new approach to the development and assessment of doxorubicin-loaded nanoliposomes for the treatment of osteosarcoma in 2D and 3D cell culture systems. Heliyon., 9, 2023, e15495.
Piorecka, K., Stanczyk, W., Florczak, M., NMR analysis of antitumor drugs: Doxorubicin, daunorubicin and their functionalized derivatives. Tetrahedron Lett. 58 (2017), 152–155, 10.1016/j.tetlet.2016.11.118.
Piperno, A., Sciortino, M.T., Giusto, E., Montesi, M., Panseri, S., Scala, A., Recent advances and challenges in gene delivery mediated by polyester-based nanoparticles. Int. J. Nanomed. 16 (2021), 5981–6002, 10.2147/IJN.S321329.
Rahmani, A., Rahimi, F., Iranshahi, M., Kahroba, H., Zarebkohan, A., Talebi, M., Salehi, R., Mousavi, H.Z., Co-delivery of doxorubicin and conferone by novel pH-responsive β-cyclodextrin grafted micelles triggers apoptosis of metastatic human breast cancer cells. Sci. Rep., 11, 2021, 21425, 10.1038/s41598-021-00954-8.
Riley, T., Stolnik, S., Heald, C.R., Xiong, C.D., Garnett, M.C., Illum, L., Davis, S.S., Physicochemical evaluation of nanoparticles assembled from poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) block copolymers as drug delivery vehicles. Langmuir 17 (2001), 3168–3174, 10.1021/la001226i.
Rios De La Rosa, J.M., Spadea, A., Donno, R., Lallana, E., Lu, Y., Puri, S., Caswell, P., Lawrence, M.J., Ashford, M., Tirelli, N., Microfluidic-assisted preparation of RGD-decorated nanoparticles: exploring integrin-facilitated uptake in cancer cell lines. Sci. Rep., 10, 2020, 14505, 10.1038/s41598-020-71396-x.
Scala, A., Piperno, A., Micale, N., Mineo, P.G., Abbadessa, A., Risoluti, R., Castelli, G., Bruno, F., Vitale, F., Cascio, A., Grassi, G., “Click” on PLGA-PEG and hyaluronic acid: Gaining access to anti-leishmanial pentamidine bioconjugates. J. Biomed. Mater. Res. B Appl. Biomater. 106 (2018), 2778–2785, 10.1002/jbm.b.34058.
Song, X., Yan, T., Tian, F., Li, F., Ren, L., Li, Q., Zhang, S., Aptamer functionalized upconversion nanotheranostic agent with nuclear targeting as the highly localized drug-delivery system of doxorubicin. Front. Bioeng. Biotechnol., 9, 2021, 639487, 10.3389/fbioe.2021.639487.
Sun, Y., Kang, C., Liu, F., Zhou, Y., Luo, L., Qiao, H., RGD peptide-based target drug delivery of doxorubicin nanomedicine. Drug Dev. Res. 78 (2017), 283–291, 10.1002/ddr.21399.
Torcasio, S.M., Oliva, R., Montesi, M., Panseri, S., Bassi, G., Mazzaglia, A., Piperno, A., Coulembier, O., Scala, A., Three-armed RGD-decorated starPLA-PEG nanoshuttle for docetaxel delivery. Biomater. Adv., 140, 2022, 213043, 10.1016/j.bioadv.2022.213043.
Visvader, J.E., Cells of origin in cancer. Nature 469 (2011), 314–322, 10.1038/nature09781.
Wang, S.-Y., Hu, H.-Z., Qing, X.-C., Zhang, Z.-C., Shao, Z.-W., Recent advances of drug delivery nanocarriers in osteosarcoma treatment. J. Cancer. 11 (2020), 69–82, 10.7150/jca.36588.
Wei, H., Chen, F., Chen, J., Lin, H., Wang, S., Wang, Y., Wu, C., Lin, J., Zhong, G., Mesenchymal stem cell derived exosomes as nanodrug carrier of doxorubicin for targeted osteosarcoma therapy via SDF1-CXCR4 axis. Int. J. Nanomed. 17 (2022), 3483–3495, 10.2147/IJN.S372851.
Yamada, Y., Dimerization of doxorubicin causes its precipitation. ACS Omega 5 (2020), 33235–33241, 10.1021/acsomega.0c04925.
Yokoyama, M., Fukushima, S., Uehara, R., Okamoto, K., Kataoka, K., Sakurai, Y., Okano, T., Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor. J. Control. Release. 50 (1998), 79–92, 10.1016/S0168-3659(97)00115-6.
Zunino, F., Gambetta, R.A., Zaccara, A., Carsana, R., A Differential interaction of doxorubicin and daunorubicin with human serum proteins. Tumori J. 67 (1981), 399–403, 10.1177/030089168106700502.
