Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after IV administration

Rajesh R. Wakaskar, Sai Praneeth R Bathena, Shailendra B. Tallapaka, Vishakha V. Ambardekar, Nagsen Gautam, Rhishikesh Thakare, Samantha M Simet Chadwick, Stephen M. Curran, Rakesh K Singh, Yuxiang Dong, Joseph A Vetro

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors. Methods: Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo. Results: X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration. Conclusions: Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors.

Original languageEnglish (US)
Pages (from-to)1028-1044
Number of pages17
JournalPharmaceutical Research
Volume32
Issue number3
DOIs
StatePublished - Jan 1 2015

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UCON 50-HB-5100
Micelles
Tumors
Polymers
Blood
Breast Neoplasms
ethylenediamine
Pharmaceutical Preparations
fosbretabulin
Poloxamer
Water
Polyethylene oxides
Dimethyl Sulfoxide
Solubility
Blood Vessels

Keywords

  • drug delivery
  • peripheral shell cross-linking
  • pluronic F127
  • poloxamer 407
  • polymer nanocarriers
  • premature drug release
  • vascular disrupting agents

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Cite this

Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after IV administration. / Wakaskar, Rajesh R.; Bathena, Sai Praneeth R; Tallapaka, Shailendra B.; Ambardekar, Vishakha V.; Gautam, Nagsen; Thakare, Rhishikesh; Simet Chadwick, Samantha M; Curran, Stephen M.; Singh, Rakesh K; Dong, Yuxiang; Vetro, Joseph A.

In: Pharmaceutical Research, Vol. 32, No. 3, 01.01.2015, p. 1028-1044.

Research output: Contribution to journalArticle

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title = "Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after IV administration",
abstract = "Purpose: Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors. Methods: Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76{\%} of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo. Results: X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt{\%} and did not aggregate in PBS or 90{\%} (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration. Conclusions: Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors.",
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T1 - Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after IV administration

AU - Wakaskar, Rajesh R.

AU - Bathena, Sai Praneeth R

AU - Tallapaka, Shailendra B.

AU - Ambardekar, Vishakha V.

AU - Gautam, Nagsen

AU - Thakare, Rhishikesh

AU - Simet Chadwick, Samantha M

AU - Curran, Stephen M.

AU - Singh, Rakesh K

AU - Dong, Yuxiang

AU - Vetro, Joseph A

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Purpose: Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors. Methods: Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo. Results: X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration. Conclusions: Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors.

AB - Purpose: Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors. Methods: Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo. Results: X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration. Conclusions: Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors.

KW - drug delivery

KW - peripheral shell cross-linking

KW - pluronic F127

KW - poloxamer 407

KW - polymer nanocarriers

KW - premature drug release

KW - vascular disrupting agents

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