Evaluation of new bi-functional terpolymeric nanoparticles for simultaneous in vivo optical imaging and chemotherapy of breast cancer
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Successful development of a nanoparticulate system for cancer chemotherapy requires detailed knowledge of its biodistribution, clearance and anti-tumour efficacy in vivo. Herein we developed new bi-functional nanoparticles for simultaneous in vivo optical imaging and delivery of the anticancer drug doxorubicin (Dox) for enhanced chemotherapy. Two types of nanoparticles were synthesized, namely preformed nanoparticles (PF-NPs) and self-assembled nanoparticles (SA-NPs). The PF-NPs were prepared by cross-linking graft polymerization of methacrylic acid and polysorbate 80 with starch (PMAA-PS 80-g-St) and then loading the particles with Dox. The SA-NPs were formed upon addition of Dox to non-cross-linked PMAA-PS 80-g-St. A near infrared fluorescent probe was conjugated with the PMAA unit of the nanoparticles. The biodistribution, tumour targeting and pharmacokinetics of the Dox-loaded nanoparticles in mice were determined by in vivo/ex vivo fluorescence imaging and ex vivo fluorescence microscopy. The anti-tumour efficacy of the nanoparticles was investigated using a murine orthotopic breast cancer model. PF-NPs had an average hydrodynamic diameter and zeta potential of 137 ± 3 nm and −38 ± 1 mV, respectively. These values were measured at 62 ± 5 nm and −35 ± 5 mV for SA-NPs. PF-NPs exhibited a porous morphology while the SA-NPs appeared to have a denser structure. SA-NPs outperformed the PF-NPs in terms of blood circulation, tumour uptake and penetration. PF-NPs and SA-NPs exhibited no systemic toxicity and inhibited tumour growth significantly better than the free Dox solution with SA-NPs being the best, attributable to their excellent tumour uptake and penetration. This work demonstrates the usefulness of these bi-functional nanoparticles as nanotheranostics.
KeywordsBi-functional nanoparticles In vivo fluorescence imaging Doxorubicin Biodistribution Theranostics
The authors are grateful for the support of NSERC Discovery grant and Equipment grant to X.Y. Wu, CIHR/CBCRA operating grant to X.Y. Wu and A.M. Rauth and the Ontario graduate scholarship and the University of Toronto and Ben Cohen Fund scholarships to A. Shalviri. The authors are also thankful to Franky Liu for his assistance in producing diagrams.
All animal handling and procedures were conducted under protocols approved by the Animal Care committee at the Ontario Cancer Institute following guidelines set forth by the Canadian Council on Animal Care.
- 5.Torchilin VP. Passive and active drug targeting: drug delivery to tumors as an example. In: Schafer-Korting M, editor. Handb Exp Pharmacol. New York: Springer; 2010. p. 3–53.Google Scholar
- 7.Wiseman GA, White CA, Sparks RB, Erwin WD, Podoloff DA, Lamonica D, et al. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin (TM) radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Crit Rev Oncol Hematol. 2001;39(1–2):181–94.CrossRefPubMedGoogle Scholar
- 10.Shuhendler AJ, Staruch R, Oakden W, Gordijo CR, Rauth AM, Stanisz GJ, et al. Thermally-triggered ‘off-on-off’ response of gadolinium-hydrogel-lipid hybrid nanoparticles defines a customizable temperature window for non-invasive magnetic resonance imaging thermometry. J Controlled Release. 2011;157(3):478–84.CrossRefGoogle Scholar
- 21.Diagaradjane P, Orenstein-Cardona JM, Colón-Casasnovas NE, Deorukhkar A, Shentu S, Kuno N, et al. Imaging epidermal growth factor receptor expression in vivo: pharmacokinetic and biodistribution characterization of a bioconjugated quantum dot nanoprobe. Clin Cancer Res. 2008;14(3):731–41.CrossRefPubMedGoogle Scholar
- 22.Shalviri A, Chan HK, Raval G, Abdekhodaie MJ, Liu Q, Heerklotz H et al. Design of pH-responsive nanoparticles of terpolymer of poly(methacrylic acid), polysorbate 80 and starch for delivery of doxorubicin. Colloids and Surfaces B: Biointerfaces. 2012;101:405–13. doi: 10.1016/j.colsurfb.2012.07.015.
- 32.Malvern Instruments. Zetasizer nano user manual. 4th ed. Worcestershire: Malvern Instruments; 2008.Google Scholar
- 45.Brun PH, DeGroot JL, Dickson EFG, Farahani M, Pottier RH. Determination of the in vivo pharmacokinetics of palladium-bacteriopheophorbide (WST09) in EMT6 tumour-bearing Balb/c mice using graphite furnace atomic absorption spectroscopy. Photochem Photobiol Sci. 2004;3(11–12):1006–10.CrossRefPubMedGoogle Scholar
- 51.Shuhendler AJ, Prasad P, Leung M, Rauth AM, DaCosta RS, Wu XY. A novel solid lipid nanoparticle formulation for active targeting to tumor αvβ3 integrin receptors reveals cyclic RGD as a double–edged sword. Adv Healthcare Mate’r. 2012. doi: 10.1002/adhm.201200006.