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Liver Cancer Targeting of Doxorubicin with Reduced Distribution to the Heart Using Hematoporphyrin-Modified Albumin Nanoparticles in Rats

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ABSTRACT

Purpose

To evaluate the usefulness of hematoporphyrin (HP)-modification of the surface of doxorubicin (DOX)-loaded bovine serum albumin (BSA) nanoparticles (NPs) in the liver cancer-selective delivery of DOX.

Methods

HP-modified NPs (HP-NPs) were prepared by conjugation of amino groups on the surface of NPs with HP, a ligand for low density lipoprotein (LDL) receptors on the hepatoma cells. In vitro cellular accumulation of DOX, in vivo biodistribution of DOX, safety, and anti-tumor efficacy were evaluated for HP-NPs.

Results

Cytotoxicity and accumulation of DOX were in the order of HP-NPs>NPs>solution form (SOL). Cellular uptake from HP-NPs was proportional to the expression level of LDL receptors on the cells, indicating possible involvement of LDL receptor-mediated endocytosis (RME) in uptake. The “merit index,” an AUC ratio of DOX in liver (target organ) to DOX in heart (major side effect organ) following iv administration of HP-NPs to hepatoma rats, was 132.5 and 4 times greater compared to SOL and NPs, respectively. The greatest suppression of body weight decrease and tumor size increase was observed for iv-administered HP-NPs in tumor-bearing mice.

Conclusions

HP modification appears to be useful in selective delivery of NP-loaded DOX to tumors.

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Abbreviations

25-HC:

25-hydroxycholesterol

BSA:

bovine serum albumin

DOX:

doxorubicin

HP:

hematoporphyrin

HP-NP:

hematoporphyrin-modified, doxorubicin-loaded nanoparticle

NP:

doxorubicin-loaded nanoparticle

SOL:

doxorubicin solution

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ACKNOWLEDGMENTS & DISCLOSURES

This work was supported by a grant from the Korean Ministry of Science and Technology through the National Research Laboratory Program (Grant Number ROA-2006-000-10290-0).

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Authors and Affiliations

  1. National Research Laboratory for Transporters Targeted Drug Design Research Institute of Pharmaceutical Sciences College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea

    Ji-Eun Chang, Eun-Young Kwak & Chang-Koo Shim

  2. Research Institute of Pharmaceutical Sciences College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea

    Saeho Chong, Dae-Duk Kim & Suk-Jae Chung

  3. College of Pharmacy, Gachon University of Medicine and Science, Incheon, 406-799, South Korea

    Won-Sik Shim

  4. Department of Applied Bioscience, College of life science CHA University, Gyeonggi-do, 463-840, South Korea

    Su-Geun Yang

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  1. Ji-Eun Chang
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Chang, JE., Shim, WS., Yang, SG. et al. Liver Cancer Targeting of Doxorubicin with Reduced Distribution to the Heart Using Hematoporphyrin-Modified Albumin Nanoparticles in Rats. Pharm Res 29, 795–805 (2012). https://doi.org/10.1007/s11095-011-0603-6

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  • DOI: https://doi.org/10.1007/s11095-011-0603-6

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