Biodistribution of Free and N-(2-hydroxypropyl)methacrylamide Copolymer-Bound Mesochlorin e(6) and Adriamycin in Nude Mice Bearing Human Ovarian Carcinoma OVCAR-3 Xenografts

J Control Release. 1999 Aug 27;61(1-2):145-57. doi: 10.1016/s0168-3659(99)00113-3.

Abstract

The purpose of this study was to examine the biodistribution of the photosensitizing drug, mesochlorin e(6) monoethylenediamine (Mce(6)), and the antineoplastic agent, adriamycin (ADR), as well as their N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates in female nu/nu athymic mice bearing human ovarian carcinoma OVCAR-3 xenografts. The levels of Mce(6) and HPMA copolymer-bound Mce(6) in tissues were assayed spectrophotometrically, while the levels of ADR and HPMA copolymer-bound ADR were determined using high-performance liquid chromatography. It appeared that the circulation lifetimes of HPMA copolymer-bound Mce(6) and ADR were three times more than those of the drugs in the free form. The concentrations of the HPMA copolymer-conjugated drugs in tumor reached maximum levels 18 h post injection. Intravenous injection routinely gave higher tissue levels of the drugs than intraperitoneal administration at time intervals less than 24 h. The biodistribution of the HPMA copolymer-bound drugs in tumor-bearing mice was significantly different from that of the free drugs, which is important in optimizing the treatment protocols. In particular, the HPMA copolymer-conjugated drugs accumulated at significantly higher levels in tumor tissues. This effect is attributed to the increased vascular permeability and reduced lymphatic drainage characteristic of tumor tissues [enhanced permeability and retention (EPR) effect].

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Doxorubicin / administration & dosage*
  • Doxorubicin / pharmacokinetics
  • Female
  • Humans
  • Methacrylates / administration & dosage*
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Ovarian Neoplasms / metabolism*
  • Photochemotherapy*
  • Photosensitizing Agents / administration & dosage*
  • Photosensitizing Agents / pharmacokinetics
  • Porphyrins / administration & dosage*
  • Porphyrins / pharmacokinetics
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Methacrylates
  • Photosensitizing Agents
  • Porphyrins
  • Doxorubicin
  • hydroxypropyl methacrylate