Original Article
Doxorubicin-loaded dendritic-Fe3O4 supramolecular nanoparticles for magnetic drug targeting and tumor regression in spheroid murine melanoma model

https://doi.org/10.1016/j.nano.2018.01.005Get rights and content

Highlights

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    Elaborate assessment of drug-loaded dendrimer-functionalized Fe3O4 nanoparticles for in vivo magnetic drug targeting.

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    Comparative biodistribution, biocompatibility, hemocompatibility, histopathology and therapeutic efficacy were thoroughly evaluated post intravenous administration in subcutaneous, syngeneic, spheroid melanoma in C57BL/6 mice.

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    A substantial elevation (6-fold) in tumor localization of drug-nanoparticle was observed in presence of an external permanent magnet.

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    Enhanced drug localization promulgates elevated tumor regression and growth inhibition with ~100% mice survival.

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    As-prepared dendritic-Fe3O4 nanosystem showed precise and enhanced targeted cancer therapy in vivo.

Abstract

This work evaluates the magnetically‐guided delivery of DOX-loaded dendritic-Fe3O4 nanoparticles and their tumor regression efficacy in subcutaneous melanoma in C57BL/6 mice. The hematological, biochemical and histopathological parameters were minimally affected. The nanoparticles localized in lungs, liver and spleen suggesting non-specific uptake. However, in tumor-bearing mice, substantially higher localization in magnetically‐targeted tumor was observed when compared to passive localization in non-targeted tumor. The animals of treated group showed significantly high iron levels (161 μg of Fe/mg dry organ weight) in the tumor against the control (<25 μg of Fe/mg dry organ weight). This high localization led to high concentrations of DOX in the tumor which not only induced significant tumor regression but also arrested further growth. Within 14 days, the average tumor volume was reduced to 55±8.3 mm3 (treated) as compared to 4794±844 mm3 (control), i.e. ~88-fold decrease. The tumor disappeared by the end of 20th day post-treatment and ~100% survival rate was observed.

Graphical Abstract

In addition to excellent drug delivery performances, dendrimer-functionalized Fe3O4 nanoparticles are a promising candidate for magnetic drug targeting in tumor models in vivo. Our drug-loaded dendritic-Fe3O4 nanoparticles show elevated tumor localization under an external permanent magnetic field which results in high drug accumulation in subcutaneous melanoma. The magnetic field facilitates this passive localization as high as 6-fold resulting in substantial tumor regression and growth inhibition. The tumor disappears after 20 days, post-treatment, with no relapse and ~100% mice survival for a study period of 60 days.

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Section snippets

Methods

Synthesis of two types of dendritic-Fe3O4 was undertaken, (a) commercial PAMAM-conjugated and (b) as-prepared KR2-conjugated Fe3O4 (Supplementary Information; SI).

Results

Two types of dendritic-Fe3O4 nanosystems viz. PAMAM-IO and KR2-IO, were successfully synthesized and thoroughly characterized.2

Both the dendritic-Fe3O4 nanoparticles were non-toxic and did not hinder cell proliferation and viable cell population after 24 h (Figure S2 A, B). After 48 h, higher concentrations of the PAMAM-IO showed meager loss in viable cells (~10%) while KR2-IO essentially maintained the same viable cell population as control. The DOX-loaded dendritic-Fe3O4 nanoparticles

Discussion

The dendritic-Fe3O4 nanoparticles have been established as successful delivery vehicles as well as diagnostic platforms in various studies.2, 40, 41, 42, 43 The unique architecture, assembly of monomers and active functional groups of the dendrimers and dendritic structures dictate their biomedical properties, stability, and toxicity.44, 45, 46, 47, 48 The current study evaluated them in vitro towards murine melanoma and subsequently focused on their therapeutic performances in vivo. The

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    Disclosure of conflict of interests: No potential conflict of interests.

    The authors acknowledge (a) Nanomission, Department of Science and Technology, Government of India, and (b) TATA Centre for Technology and Design (TCTD), IIT Bombay for the financial support.

    Author contributions: SN and DB designed and planned the experiments. SN performed the experiments, analyzed the data/results and wrote the manuscript. DB supervised the project and critically edited the manuscript.

    1

    Current Affiliation: Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.

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