ABSTRACT
Purpose
To develop novel hybrid paclitaxel (PTX) nanocrystals, in which bioactivatable (MMPSense® 750 FAST) and near infrared (Flamma Fluor® FPR-648) fluorophores are physically incorporated, and to evaluate their anticancer efficacy and diagnostic properties in breast cancer xenograft murine model.
Methods
The pure and hybrid paclitaxel nanocrystals were prepared by an anti-solvent method, and their physical properties were characterized. The tumor volume change and body weight change were evaluated to assess the treatment efficacy and toxicity. Bioimaging of treated mice was obtained non-invasively in vivo.
Results
The released MMPSense molecules from the hybrid nanocrystals were activated by matrix metalloproteinases (MMPs) in vivo, similarly to the free MMPSense, demonstrating its ability to monitor cancer progression. Concurrently, the entrapped FPR-648 was imaged at a different wavelength. Furthermore, when administered at 20 mg/kg, the nanocrystal formulations exerted comparable efficacy as Taxol®, but with decreased toxicity.
Conclusions
Hybrid nanocrystals that physically integrated two fluorophores were successfully prepared from solution. Hybrid nanocrystals were shown not only exerting antitumor activity, but also demonstrating the potential of multi-modular bioimaging for diagnostics.
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Abbreviations
- DLS:
-
Dynamic light scattering
- MMP:
-
Matrix metalloproteinase
- NIR:
-
Near infrared
- PBS:
-
Phosphate buffered saline
- PTX:
-
Paclitaxel
- SEM:
-
Scanning electron microscope
REFERENCES
Al-Jamal WT, Kostarelos K. Liposomes: from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine. Acc Chem Res. 2011;44:1094–104.
Levine DH, Ghoroghchian PP, Freudenberg J, Zhang G, Therien MJ, Greene MI, et al. Polymersomes: a new multi-functional tool for cancer diagnosis and therapy. Methods. 2008;46:25–32.
Caldorera-Moore ME, Liechty WB, Peppas NA. Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers. Acc Chem Res. 2011;44:1061–70.
Blanco E, Kessinger CW, Sumer BD, Gao J. Multifunctional micellar nanomedicine for cancer therapy. Exp Biol Med. 2009;234:123–31.
Weng KC, Noble CO, Papahadjopoulos-Sternberg B, Chen FF, Drummond DC, Kirpotin DB, et al. Targeted tumor cell internalization and imaging of multifunctional quantum dot-conjugated immunoliposomes in vitro and in vivo. Nano Lett. 2008;8:2851–7.
Li S, Goins B, Zhang L, Bao A. Novel multifunctional theranostic liposome drug delivery system: construction, characterization, and multimodality MR, near-infrared fluorescent, and nuclear imaging. Bioconjug Chem. 2012;23:1322–32.
Sanson C, Diou O, Thévenot J, Ibarboure E, Soum A, Brûlet A, et al. Doxorubicin loaded magnetic polymersomes: theranostic nanocarriers for MR imaging and magneto-chemotherapy. ACS Nano. 2011;5:1122–40.
Maeng JH, Lee D-H, Jung KH, Bae Y-H, Park I-S, Jeong S, et al. Multifunctional doxorubicin loaded superparamagnetic iron oxide nanoparticles for chemotherapy and magnetic resonance imaging in liver cancer. Biomaterials. 2010;31:4995–5006.
Guthi JS, Yang SG, Huang G, Li SZ, Khemtong C, Kessinger CW, et al. MRI-visible micellar nanomedicine for targeted drug delivery to lung cancer cells. Mol Pharm. 2010;7:32–40.
Janib SM, Moses AS, MacKay JA. Imaging and drug delivery using theranostic nanoparticles. Adv Drug Deliv Rev. 2010;62:1052–63.
Zhao RS, Hollis CP, Zhang H, Sun LL, Gemeinhart RA, Li TL. Hybrid nanocrystals: achieving concurrent therapeutic and bioimaging functionalities toward solid tumors. Mol Pharm. 2011;8:1985–91.
Singer CF, Kronsteiner N, Marton E, Kubista M, Cullen KJ, Hirtenlehner K, et al. MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions. Breast Cancer Res Treat. 2002;72:69–77.
Poulsom R, Hanby AM, Pignatelli M, Jeffery RE, Longcroft JM, Rogers L, et al. Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin. J Clin Pathol. 1993;46:429–36.
Iwata H, Kobayashi S, Iwase H, Masaoka A, Fujimoto N, Okada Y. Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. Jpn J Cancer Res: Gann. 1996;87:602–11.
Clapper ML, Hensley HH, Chang WC, Devarajan K, Nguyen MT, Cooper HS. Detection of colorectal adenomas using a bioactivatable probe specific for matrix metalloproteinase activity. Neoplasia. 2011;13:685–91.
Vartakand DG, Gemeinhart RA. Matrix metalloproteases: underutilized targets for drug delivery. J Drug Target. 2007;15:1–20.
Kozlowski JM, Fidler IJ, Campbell D, Xu ZL, Kaighn ME, Hart IR. Metastatic behavior of human-tumor cell-lines grown in the nude-mouse. Cancer Res. 1984;44:3522–9.
Meyvisch C. Influence of implantation site on formation of metastases. Cancer Metastasis Rev. 1983;2:295–306.
Morikawa K, Walker SM, Nakajima M, Pathak S, Jessup JM, Fidler IJ. Influence of organ environment on the growth, selection, and metastasis of human-colon carcinoma-cells in nude-mice. Cancer Res. 1988;48:6863–71.
Volpeand JPG, Milas L. Influence of tumor-transplatation methods on tumor-growth rate and metastatic potential of solitary tumors derived from metastases. Clin Exp Metastasis. 1990;8:381–9.
Shafieand SM, Liotta LA. Formation of metastasis by human breast carcinoma cells (MCF-7) in nude mice. Cancer Lett. 1980;11:81–7.
Weissleder R, Tung CH, Mahmood U, Bogdanov A. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat Biotechnol. 1999;17:375–8.
Groves K, Kossodo S, Handy E, Jensen J, Blusztajn A, Cuneo G, et al. In vivo imaging of treatment effects using a novel near infrared labeled agent: MMPSense™ 750 FAST, AACR Annual Meeting, Denver, 2009.
Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res. 1996;56:2112–5.
ACKNOWLEDGMENTS AND DISCLOSURES
The project described was supported by Grant Number R25CA153954 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
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Hollis, C.P., Weiss, H.L., Evers, B.M. et al. In Vivo Investigation of Hybrid Paclitaxel Nanocrystals with Dual Fluorescent Probes for Cancer Theranostics. Pharm Res 31, 1450–1459 (2014). https://doi.org/10.1007/s11095-013-1048-x
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DOI: https://doi.org/10.1007/s11095-013-1048-x