The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles

Kyung Hyun Min, Hong Jae Lee, Kwang Meyung Kim, Ick Chan Kwon, Seo Young Jeong, Sang Cheon Lee

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

A mineral (calcium phosphate, CaP)-reinforced core-shell-corona micelle was evaluated as a nanocarrier of doxorubicin (DOX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(l-aspartic acid)-b-poly(l-phenylalanine) (PEG-PAsp-PPhe) in the aqueous phase provided the three distinct functional domains: the hydrated PEG outer corona for prolonged circulation, the anionic PAsp middle shell for CaP mineralization, and the hydrophobic PPhe inner core for DOX loading. CaP mineralization was performed by initial electrostatic localization of calcium ions at anionic PAsp shells, and the consequent addition of phosphate anions to trigger the growth of CaP. The mineralization did not affect the micelle size or the spherical morphology. The CaP-mineralized micelles exhibited enhanced serum stability. The DOX release from the DOX-loaded mineralized micelles (DOX-CaP-PM) at physiological pH was efficiently inhibited, whereas at an endosomal pH (pH 4.5), DOX release was facilitated due to the rapid dissolution of the CaP mineral layers in the middle shell domains. The in vivo tissue distribution and tumor accumulation of the DOX-CaP-PM that were labeled with a near-infrared fluorescent (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DOX-CaP-PM exhibited enhanced tumor specificity due to the prolonged stable circulation in the blood and an enhanced permeation and retention (EPR) effect compared with the DOX-loaded non-mineralized polymer micelles (DOX-NPM). The DOX-CaP-PM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DOX and DOX-NPM. The CaP mineralization on assembled nanoparticles may serve as a useful guide for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.

Original languageEnglish
Pages (from-to)5788-5797
Number of pages10
JournalBiomaterials
Volume33
Issue number23
DOIs
Publication statusPublished - 2012 Aug 1
Externally publishedYes

Fingerprint

Calcium phosphate
Nanoparticles
Doxorubicin
Tumors
Polymers
Micelles
Neoplasms
Bearings (structural)
Therapeutics
Polyethylene glycols
Minerals
calcium phosphate
Phosphate minerals
Ethylene Glycol
Blood Circulation
Optical Imaging
Tissue Distribution
Permeation
Static Electricity
Phenylalanine

Keywords

  • Calcium phosphate
  • Cancer therapy
  • Doxorubicin
  • Mineralization
  • Polymer micelle

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

Cite this

The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles. / Min, Kyung Hyun; Lee, Hong Jae; Kim, Kwang Meyung; Kwon, Ick Chan; Jeong, Seo Young; Lee, Sang Cheon.

In: Biomaterials, Vol. 33, No. 23, 01.08.2012, p. 5788-5797.

Research output: Contribution to journalArticle

Min, Kyung Hyun ; Lee, Hong Jae ; Kim, Kwang Meyung ; Kwon, Ick Chan ; Jeong, Seo Young ; Lee, Sang Cheon. / The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles. In: Biomaterials. 2012 ; Vol. 33, No. 23. pp. 5788-5797.
@article{5f5565f4db0f42e6a80e65b5e253a6ca,
title = "The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles",
abstract = "A mineral (calcium phosphate, CaP)-reinforced core-shell-corona micelle was evaluated as a nanocarrier of doxorubicin (DOX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(l-aspartic acid)-b-poly(l-phenylalanine) (PEG-PAsp-PPhe) in the aqueous phase provided the three distinct functional domains: the hydrated PEG outer corona for prolonged circulation, the anionic PAsp middle shell for CaP mineralization, and the hydrophobic PPhe inner core for DOX loading. CaP mineralization was performed by initial electrostatic localization of calcium ions at anionic PAsp shells, and the consequent addition of phosphate anions to trigger the growth of CaP. The mineralization did not affect the micelle size or the spherical morphology. The CaP-mineralized micelles exhibited enhanced serum stability. The DOX release from the DOX-loaded mineralized micelles (DOX-CaP-PM) at physiological pH was efficiently inhibited, whereas at an endosomal pH (pH 4.5), DOX release was facilitated due to the rapid dissolution of the CaP mineral layers in the middle shell domains. The in vivo tissue distribution and tumor accumulation of the DOX-CaP-PM that were labeled with a near-infrared fluorescent (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DOX-CaP-PM exhibited enhanced tumor specificity due to the prolonged stable circulation in the blood and an enhanced permeation and retention (EPR) effect compared with the DOX-loaded non-mineralized polymer micelles (DOX-NPM). The DOX-CaP-PM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DOX and DOX-NPM. The CaP mineralization on assembled nanoparticles may serve as a useful guide for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.",
keywords = "Calcium phosphate, Cancer therapy, Doxorubicin, Mineralization, Polymer micelle",
author = "Min, {Kyung Hyun} and Lee, {Hong Jae} and Kim, {Kwang Meyung} and Kwon, {Ick Chan} and Jeong, {Seo Young} and Lee, {Sang Cheon}",
year = "2012",
month = "8",
day = "1",
doi = "10.1016/j.biomaterials.2012.04.057",
language = "English",
volume = "33",
pages = "5788--5797",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
number = "23",

}

TY - JOUR

T1 - The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles

AU - Min, Kyung Hyun

AU - Lee, Hong Jae

AU - Kim, Kwang Meyung

AU - Kwon, Ick Chan

AU - Jeong, Seo Young

AU - Lee, Sang Cheon

PY - 2012/8/1

Y1 - 2012/8/1

N2 - A mineral (calcium phosphate, CaP)-reinforced core-shell-corona micelle was evaluated as a nanocarrier of doxorubicin (DOX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(l-aspartic acid)-b-poly(l-phenylalanine) (PEG-PAsp-PPhe) in the aqueous phase provided the three distinct functional domains: the hydrated PEG outer corona for prolonged circulation, the anionic PAsp middle shell for CaP mineralization, and the hydrophobic PPhe inner core for DOX loading. CaP mineralization was performed by initial electrostatic localization of calcium ions at anionic PAsp shells, and the consequent addition of phosphate anions to trigger the growth of CaP. The mineralization did not affect the micelle size or the spherical morphology. The CaP-mineralized micelles exhibited enhanced serum stability. The DOX release from the DOX-loaded mineralized micelles (DOX-CaP-PM) at physiological pH was efficiently inhibited, whereas at an endosomal pH (pH 4.5), DOX release was facilitated due to the rapid dissolution of the CaP mineral layers in the middle shell domains. The in vivo tissue distribution and tumor accumulation of the DOX-CaP-PM that were labeled with a near-infrared fluorescent (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DOX-CaP-PM exhibited enhanced tumor specificity due to the prolonged stable circulation in the blood and an enhanced permeation and retention (EPR) effect compared with the DOX-loaded non-mineralized polymer micelles (DOX-NPM). The DOX-CaP-PM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DOX and DOX-NPM. The CaP mineralization on assembled nanoparticles may serve as a useful guide for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.

AB - A mineral (calcium phosphate, CaP)-reinforced core-shell-corona micelle was evaluated as a nanocarrier of doxorubicin (DOX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(l-aspartic acid)-b-poly(l-phenylalanine) (PEG-PAsp-PPhe) in the aqueous phase provided the three distinct functional domains: the hydrated PEG outer corona for prolonged circulation, the anionic PAsp middle shell for CaP mineralization, and the hydrophobic PPhe inner core for DOX loading. CaP mineralization was performed by initial electrostatic localization of calcium ions at anionic PAsp shells, and the consequent addition of phosphate anions to trigger the growth of CaP. The mineralization did not affect the micelle size or the spherical morphology. The CaP-mineralized micelles exhibited enhanced serum stability. The DOX release from the DOX-loaded mineralized micelles (DOX-CaP-PM) at physiological pH was efficiently inhibited, whereas at an endosomal pH (pH 4.5), DOX release was facilitated due to the rapid dissolution of the CaP mineral layers in the middle shell domains. The in vivo tissue distribution and tumor accumulation of the DOX-CaP-PM that were labeled with a near-infrared fluorescent (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DOX-CaP-PM exhibited enhanced tumor specificity due to the prolonged stable circulation in the blood and an enhanced permeation and retention (EPR) effect compared with the DOX-loaded non-mineralized polymer micelles (DOX-NPM). The DOX-CaP-PM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DOX and DOX-NPM. The CaP mineralization on assembled nanoparticles may serve as a useful guide for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.

KW - Calcium phosphate

KW - Cancer therapy

KW - Doxorubicin

KW - Mineralization

KW - Polymer micelle

UR - http://www.scopus.com/inward/record.url?scp=84861343605&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861343605&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2012.04.057

DO - 10.1016/j.biomaterials.2012.04.057

M3 - Article

C2 - 22591612

AN - SCOPUS:84861343605

VL - 33

SP - 5788

EP - 5797

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

IS - 23

ER -