Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer

Abstract

Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein)-coated magnetic iron oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF) of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP) were engineered on this nanoplatform. High drug loading (~25 wt%) and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T₂-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that ATF-CNIO-CDDP can be an effective theranostic platform for active targeting-enhanced and image-guided cancer treatment while simultaneously reducing the systemic toxicity.

Keywords:

• active targeting
• drug delivery
• cisplatin
• magnetic nanoparticles
• magnetic resonance imaging
• pancreatic cancer

Supplementary materials

Figure S1 Representative H&E staining of initial and metastatic tumors from the group treated with PBS only.

Notes: Most of the tumors (T) have obvious boundary along with pancreas (P) (left first panel), while metastatic tumors (MT) were observed invading into deeper pancreas (P) or spleen (S). No such metastasis was observed in the groups treated with free CDDP, CNIO-CDDP, or ATF-CNIO-CDDP.

Abbreviations: ATF, amino-terminal fragment; CDDP, cisplatin; CNIO, milk protein (casein)-coated magnetic iron oxide; H&E, hematoxylin and eosin; PBS, phosphate-buffered saline.

Figure S2 Representative Sirius red and H&E staining of liver and spleen sections.

Notes: As indicated by black arrows, hepatic degeneration and vacuolization with necrotic cells were observed in the group that received free CDDP, while little damage was observed in the groups that received CNIO-CDDP and ATF-CNIO-CDDP, demonstrating reduced systemic toxicity to normal tissues by nanocarriers. The scale bar is 100 and 50 μm, respectively.

Abbreviations: ATF, amino-terminal fragment; CDDP, cisplatin; CNIO, milk protein (casein)-coated magnetic iron oxide; H&E, hematoxylin and eosin.

Acknowledgments

This work is supported by NIH R01CA154846-02 (HM and LY), NCI’s Cancer Nanotechnology Platform Project (CNPP) grant (U01CA151810-02 to LY and HM) and Emory Molecular Translational Imaging Center of NCI’s in vivo Cellular and Molecular Imaging Center grant (ICMIC, P50CA128301-01A10003 to HM and LY).

Disclosure

The authors report no conflicts of interest in this work.