Stability in plasmas of various species of HPMA copolymer-PGE1 conjugates

Huaizhong Pan, Pavla Kopečková, Jihua Liu, Dong Wang, Scott C. Miller, Jindřich Kopeček

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Purpose. To determine the stability of HPMA copolymer-prostaglandin E 1 (PGE1) conjugates in plasmas of different species and to identify the enzymes responsible for the cleavage of the ester bond. Methods. The conjugates were incubated in human, rat, and mouse plasma at 37°C in the presence and absence of specific esterase inhibitors. The released PGE 1 was analyzed using an HPLC assay. To evaluate the effect of the conformation of the conjugate on the rate of PGE1 release, its structure was modified by the attachment of hydrophobic side chains. Results. The rate of PGE1 release was strongly species dependent. Whereas the conjugate was stable in human plasma, the PGE1 release in rat or mouse plasma was substantial. In rat plasma, the ester bond cleavage was mainly catalyzed by butyrylcholinesterase; in mouse plasma, in addition to butyrylcholinesterase, carboxylesterase also contributed to the cleavage. The formation of compact polymer coils stabilized the ester bond. Conclusions. HPMA copolymer-PGE1 conjugates are strong candidates as novel therapeutics for the treatment of osteoporosis. The observed species differences in plasma stability of ester bonds are of importance, because the ovariectomized rat model is recommended by the FDA for pre-clinical evaluation.

Original languageEnglish (US)
Pages (from-to)2270-2280
Number of pages11
JournalPharmaceutical Research
Volume24
Issue number12
DOIs
StatePublished - Dec 1 2007

Fingerprint

hydroxypropyl methacrylate
Prostaglandins E
Copolymers
Plasmas
Rats
Esters
Butyrylcholinesterase
Plasma (human)
Carboxylesterase
Plasma stability
Esterases
Conformations
Assays
Polymers
Osteoporosis

Keywords

  • Ester bond
  • Esterase
  • HPMA copolymer conjugates
  • Osteoporosis
  • Plasma

ASJC Scopus subject areas

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

Cite this

Stability in plasmas of various species of HPMA copolymer-PGE1 conjugates. / Pan, Huaizhong; Kopečková, Pavla; Liu, Jihua; Wang, Dong; Miller, Scott C.; Kopeček, Jindřich.

In: Pharmaceutical Research, Vol. 24, No. 12, 01.12.2007, p. 2270-2280.

Research output: Contribution to journalArticle

Pan, H, Kopečková, P, Liu, J, Wang, D, Miller, SC & Kopeček, J 2007, 'Stability in plasmas of various species of HPMA copolymer-PGE1 conjugates', Pharmaceutical Research, vol. 24, no. 12, pp. 2270-2280. https://doi.org/10.1007/s11095-007-9449-3
Pan, Huaizhong ; Kopečková, Pavla ; Liu, Jihua ; Wang, Dong ; Miller, Scott C. ; Kopeček, Jindřich. / Stability in plasmas of various species of HPMA copolymer-PGE1 conjugates. In: Pharmaceutical Research. 2007 ; Vol. 24, No. 12. pp. 2270-2280.
@article{b7716a13a8024fd7ab4620b79b9f9984,
title = "Stability in plasmas of various species of HPMA copolymer-PGE1 conjugates",
abstract = "Purpose. To determine the stability of HPMA copolymer-prostaglandin E 1 (PGE1) conjugates in plasmas of different species and to identify the enzymes responsible for the cleavage of the ester bond. Methods. The conjugates were incubated in human, rat, and mouse plasma at 37°C in the presence and absence of specific esterase inhibitors. The released PGE 1 was analyzed using an HPLC assay. To evaluate the effect of the conformation of the conjugate on the rate of PGE1 release, its structure was modified by the attachment of hydrophobic side chains. Results. The rate of PGE1 release was strongly species dependent. Whereas the conjugate was stable in human plasma, the PGE1 release in rat or mouse plasma was substantial. In rat plasma, the ester bond cleavage was mainly catalyzed by butyrylcholinesterase; in mouse plasma, in addition to butyrylcholinesterase, carboxylesterase also contributed to the cleavage. The formation of compact polymer coils stabilized the ester bond. Conclusions. HPMA copolymer-PGE1 conjugates are strong candidates as novel therapeutics for the treatment of osteoporosis. The observed species differences in plasma stability of ester bonds are of importance, because the ovariectomized rat model is recommended by the FDA for pre-clinical evaluation.",
keywords = "Ester bond, Esterase, HPMA copolymer conjugates, Osteoporosis, Plasma",
author = "Huaizhong Pan and Pavla Kopečkov{\'a} and Jihua Liu and Dong Wang and Miller, {Scott C.} and Jindřich Kopeček",
year = "2007",
month = "12",
day = "1",
doi = "10.1007/s11095-007-9449-3",
language = "English (US)",
volume = "24",
pages = "2270--2280",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York",
number = "12",

}

TY - JOUR

T1 - Stability in plasmas of various species of HPMA copolymer-PGE1 conjugates

AU - Pan, Huaizhong

AU - Kopečková, Pavla

AU - Liu, Jihua

AU - Wang, Dong

AU - Miller, Scott C.

AU - Kopeček, Jindřich

PY - 2007/12/1

Y1 - 2007/12/1

N2 - Purpose. To determine the stability of HPMA copolymer-prostaglandin E 1 (PGE1) conjugates in plasmas of different species and to identify the enzymes responsible for the cleavage of the ester bond. Methods. The conjugates were incubated in human, rat, and mouse plasma at 37°C in the presence and absence of specific esterase inhibitors. The released PGE 1 was analyzed using an HPLC assay. To evaluate the effect of the conformation of the conjugate on the rate of PGE1 release, its structure was modified by the attachment of hydrophobic side chains. Results. The rate of PGE1 release was strongly species dependent. Whereas the conjugate was stable in human plasma, the PGE1 release in rat or mouse plasma was substantial. In rat plasma, the ester bond cleavage was mainly catalyzed by butyrylcholinesterase; in mouse plasma, in addition to butyrylcholinesterase, carboxylesterase also contributed to the cleavage. The formation of compact polymer coils stabilized the ester bond. Conclusions. HPMA copolymer-PGE1 conjugates are strong candidates as novel therapeutics for the treatment of osteoporosis. The observed species differences in plasma stability of ester bonds are of importance, because the ovariectomized rat model is recommended by the FDA for pre-clinical evaluation.

AB - Purpose. To determine the stability of HPMA copolymer-prostaglandin E 1 (PGE1) conjugates in plasmas of different species and to identify the enzymes responsible for the cleavage of the ester bond. Methods. The conjugates were incubated in human, rat, and mouse plasma at 37°C in the presence and absence of specific esterase inhibitors. The released PGE 1 was analyzed using an HPLC assay. To evaluate the effect of the conformation of the conjugate on the rate of PGE1 release, its structure was modified by the attachment of hydrophobic side chains. Results. The rate of PGE1 release was strongly species dependent. Whereas the conjugate was stable in human plasma, the PGE1 release in rat or mouse plasma was substantial. In rat plasma, the ester bond cleavage was mainly catalyzed by butyrylcholinesterase; in mouse plasma, in addition to butyrylcholinesterase, carboxylesterase also contributed to the cleavage. The formation of compact polymer coils stabilized the ester bond. Conclusions. HPMA copolymer-PGE1 conjugates are strong candidates as novel therapeutics for the treatment of osteoporosis. The observed species differences in plasma stability of ester bonds are of importance, because the ovariectomized rat model is recommended by the FDA for pre-clinical evaluation.

KW - Ester bond

KW - Esterase

KW - HPMA copolymer conjugates

KW - Osteoporosis

KW - Plasma

UR - http://www.scopus.com/inward/record.url?scp=35848929708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35848929708&partnerID=8YFLogxK

U2 - 10.1007/s11095-007-9449-3

DO - 10.1007/s11095-007-9449-3

M3 - Article

VL - 24

SP - 2270

EP - 2280

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 12

ER -