Theranostic multimodular potential of zinc-doped ferrite-saturated metal-binding protein-loaded novel nanocapsules in cancers

Abstract

The present study successfully developed orally deliverable multimodular zinc (Zn) iron oxide (Fe₃O₄)-saturated bovine lactoferrin (bLf)-loaded polymeric nanocapsules (NCs), and evaluated their theranostic potential (antitumor efficacy, magnetophotothermal efficacy and imaging capability) in an in vivo human xenograft CpG-island methylator phenotype (CIMP)-1⁺/CIMP2⁻/chromosome instability-positive colonic adenocarcinoma (Caco2) and claudin-low, triple-negative (ER⁻/PR⁻/HER2⁻; MDA-MB-231) breast cancer model. Mice fed orally on the Zn-Fe-bLf NC diet showed downregulation in tumor volume and complete regression in tumor volume after 45 days of feeding. In human xenograft colon cancer, vehicle-control NC diet-group (n=5) mice showed a tumor volume of 52.28±11.55 mm³, and Zn-Fe-bLf NC diet (n=5)-treated mice had a tumor-volume of 0.10±0.073 mm³. In the human xenograft breast cancer model, Zn-Fe-bLf NC diet (n=5)-treated mice showed a tumor volume of 0.051±0.062 mm³ within 40 days of feeding. Live mouse imaging conducted by near-infrared fluorescence imaging of Zn-Fe-bLf NCs showed tumor site-specific localization and regression of colon and breast tumor volume. Ex vivo fluorescence-imaging analysis of the vital organs of mice exhibited sparse localization patterns of Zn-Fe-bLf NCs and also confirmed tumor-specific selective localization patterns of Zn-Fe-bLf NCs. Dual imaging using magnetic resonance imaging and computerized tomography scans revealed an unprecedented theranostic ability of the Zn-Fe-bLf NCs. These observations warrant consideration of multimodular Zn-Fe-bLf NCs for real-time cancer imaging and simultaneous cancer-targeted therapy.

Keywords:

• theranostic
• multimodular cancer therapy
• nanocapsules
• nanomedicine
• real-time imaging

Supplementary materials

Figure S1 Quantification of tumors by radiant efficiency of fluorescent signal in colon cancer model.

Notes: Near-infrared fluorescence imaging showed that Zn-Fe-bLf NCs exhibited a time-dependent downgrading pattern in colon tumor volume. Radiant efficiency of the fluorescent signal at the tumor site, area (in cm²) of the fluorescent signal at the tumor site, and area (in terms of CCD pixels) of the fluorescent signal at the tumor site were quantified to denote the decrease in tumor volume over the time period. Radiant efficiency presented as (A) area (cm²) and (B) area in terms of CCD pixels. (C) Tumor-reduction trend.

Abbreviations: bLf, bovine lactoferrin; NCs, nanocapsules; CCD, charge-coupled device.

Figure S2 Quantification of tumors by radiant efficiency of fluorescent signal in breast cancer model.

Notes: A time-dependent, consistent decremental pattern in tumor volume was noted, as observed by in vivo near-infrared fluorescence imaging of Zn-Fe-bLf NCs. (A) Radiant efficiency; (B) area in terms of CCD-camera pixels; (C) consistent reduction pattern in tumor volume.

Abbreviations: bLf, bovine lactoferrin; NCs, nanocapsules; CCD, charge-coupled device.

Acknowledgments

The authors would like to thank the Australia–India Strategic Research Fund (AISRF BF030016, BF060042) and the National Health and Medical Research Council (NHMRC APP1050286) for financial support. The authors would like to thank Dr Prasad for the animal work. The authors would also like to thank Dr Nick Branson and Dr Rod Collins from Animal Ethics Committee, Geelong for providing their valuable and necessary help in this study. The authors would also like to thank Dr James Pearson, Dr Qi-Zhu Wu, and Mr Aldo Besmer from the Monash Biomedical Imaging center, Melbourne for their help with the MRI and CT imaging.

Author contributions

SK performed the in vivo study. KR performed the MRI and CT scans. SK and KR wrote the manuscript. SK, RKK, and JRK had substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. JRK, RKK, and RS helped in drafting the article or revising it critically for important intellectual content, and arranged funds for this work. RC performed the characterization of nanocarriers and final approval of the version to be published. All authors have agreed on all aspects of the work. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.