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In Vivo Distribution of Polymeric Nanoparticles at the Whole-Body, Tumor, and Cellular Levels

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Abstract

Purpose

Block copolymer micelles (BCMs) were functionalized with indium-111 and/or epidermal growth factor (EGF), which enabled investigation of the in vivo transport of passively and actively targeted BCMs. The integration of conventional and image-based techniques afforded novel quantitative means to achieve an in-depth insight into the fate of polymeric nanoparticles in vivo.

Methods

Pharmacokinetics and biodistribution studies were performed in athymic mice bearing human breast xenografts to evaluate the whole-body transport of NT-BCMs (non-targeted, EGF-) and T-BCMs (targeted, EGF+). The intratumoral distribution of BCMs was investigated using MicroSPECT/CT and autoradiographic imaging, complemented with quantitative MATLAB® analyses. Tumors were fractionated for quantifying intracellular uptake of BCMs via γ-counting.

Results

The intratumoral distribution of NT-BCMs and T-BCMs were found to be heterogeneous, and positively correlated with tumor vascularization (r > 0.68 ± 0.04). The enhanced in vivo cell uptake and cell membrane binding of T-BCMs were found to delay their clearance from tumors overexpressing EGFR, and therefore resulted in enhanced tumor accumulation for the T-BCMs in comparison to the NT-BCMs.

Conclusions

Adequate passive targeting is required in order to achieve effective active targeting. Tumor physiology has a significant impact on the transvascular and intratumoral transport of passively and actively targeted BCMs.

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Abbreviations

BCM:

Block copolymer micelle

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptors

h.p.i.:

Hours post-injection

IFP:

Interstitial fluid pressure

NDDS:

Nanoparticle-based drug delivery system

NT:

Non-targeted

PEG-b-PCL:

Poly(ethylene glycol)-block-poly(ε-caprolactone)

SPECT/CT:

Single photon emission computed tomography/Computed tomography

T:

Targeted

TAM:

Tumor-associated macrophages

111In:

Indium-111

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Acknowledgments

This study is supported by funding from Canadian Institutes of Health Research, Canadian Breast Cancer Research Alliance, and Ontario Institute for Cancer Research, awarded to C. Allen and R.M. Reilly. The authors are grateful to the Natural Sciences and Engineering Research Council of Canada, Hoffman-La Roche/Rosemarie Hager, and Lorne F. Lambier for scholarships awarded to H. Lee, as well as the MDS-Nordion Graduate Scholarship in Radiopharmaceutical Sciences awarded to B. Hoang. The authors would like to thank Deborah Scollard for technical assistance with the animal studies, as well as Anton Semechko from David A. Jaffray’s Laboratory and STTARR core IV for technical support on the MATLAB® algorithm for the autoradiography studies.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario, Canada, M5S 3M2

    Helen Lee, Bryan Hoang, Humphrey Fonge, Raymond M. Reilly & Christine Allen

  2. Division of Nuclear Medicine, University Health Network, University of Toronto, 144 College St., Toronto, Ontario, Canada, M5S 3M2

    Raymond M. Reilly

  3. Department of Medical Imaging, Faculty of Medicine, University of Toronto, 144 College St., Toronto, Ontario, Canada, M5S 3M2

    Raymond M. Reilly

  4. Department of Chemistry, Faculty of Arts and Science, University of Toronto, 144 College St., Toronto, Ontario, Canada, M5S 3M2

    Christine Allen

  5. STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

    Christine Allen

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  1. Helen Lee
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  2. Bryan Hoang
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  3. Humphrey Fonge
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  4. Raymond M. Reilly
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  5. Christine Allen
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Correspondence to Christine Allen.

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Lee, H., Hoang, B., Fonge, H. et al. In Vivo Distribution of Polymeric Nanoparticles at the Whole-Body, Tumor, and Cellular Levels. Pharm Res 27, 2343–2355 (2010). https://doi.org/10.1007/s11095-010-0068-z

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  • DOI: https://doi.org/10.1007/s11095-010-0068-z

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