Combination chemotherapy and photodynamic therapy of targetable N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin/mesochlorin e(6)-OV-TL 16 antibody immunoconjugates.

Abstract

The aim of this study was to evaluate the combination chemotherapy and photodynamic therapy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin (DOX) and mesochlorin e(6) (Mce(6)) targeted with an OV-TL 16 monoclonal antibody (P-DOX-Ab and P-Mce(6)-Ab, respectively) in nude mice bearing human ovarian OVCAR-3 carcinoma xenografts. P-DOX-Ab and P-Mce(6)-Ab were synthesized by first conjugating DOX or Mce(6) to an HPMA copolymer precursor (Mw=21000), then reacting with OV-TL 16 antibody. The immunoconjugates were purified by size exclusion chromatography on Superose 6 column and analyzed. The Mce(6) concentration in tissues was determined by a fluorescence assay. Eighteen hours after administration, the tumors received a light dose of 220 J/cm(2) from a KTP 650-nm dye-laser. P-DOX-Ab and P-Mce(6)-Ab had polymer:drug:protein weight ratios of 32:3:62 and 26:2:72, corresponding to polymer:drug:protein molecular ratios of approximately 4:14:1 and 3:8:1, respectively. The biodistribution results indicated that the percentage of total administered dose of Mce(6) in tumors reached approximately 1% for the nontargeted conjugate at 18 h after administration, while that of P-Mce(6)-Ab was approximately 13 times higher. Nude mice bearing OVCAR-3 xenografts that received one i.v. dose of P-DOX-Ab (2.2 mg/kg DOX equivalent) and P-Mce(6)-Ab (1.5 mg/kg Mce(6) equivalent) with light irradiation achieved a xenograft cure rate of more than 60%. The incorporation of OV-TL 16 antibody dramatically enhanced the accumulation in tumors with a concomitant increase in the therapeutic efficacy of P-DOX-Ab and P-Mce(6)-Ab in combination therapy, which may probably be attributed to both antibody targeting and enhanced permeability and retention (EPR) effects.

• Authors: J G Shiah, Y Sun, P Kopecková, C M Peterson, R C Straight, J Kopecek
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 74 Issue 1-3 Pg. 249-53 (Jul 06 2001) ISSN: 0168-3659 [Print] Netherlands
• PMID: 11489502 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Antibodies, Monoclonal
• Immunoconjugates
• Mesoporphyrins
• Methacrylates
• Porphyrins
• meso-chlorin e(6) monoethylene diamine
• Doxorubicin
• hydroxypropyl methacrylate

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, chemistry, pharmacokinetics)
• Antibodies, Monoclonal (administration & dosage, chemistry, pharmacokinetics)
• Doxorubicin (administration & dosage, chemistry, pharmacokinetics)
• Female
• Half-Life
• Immunoconjugates (administration & dosage, chemistry, pharmacokinetics)
• Mesoporphyrins
• Methacrylates (chemistry)
• Mice
• Mice, Nude
• Photochemotherapy
• Porphyrins (administration & dosage, chemistry, pharmacokinetics)
• Tissue Distribution