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

The aim of this study was to evaluate the combination chemotherapy and phot odynamic therapy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-boun d 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)-A b were synthesized by first conjugating DOX or Mce(6) to an HPMA copolymer precursor (Mw = 21 000), then reacting with OV-TL 16 antibody. The immunoco njugates were purified by size exclusion chromatography on Superose 6 colum n and analyzed. The Mce(6) concentration in tissues was determined by a flu orescence 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, corres ponding to polymer: drug: protein molecular ratios of approximately 4:14:1 and 3:8: 1, respectively. The biodistribution results indicated that the pe rcentage of total administered dose of Mce(6) in tumors reached approximate ly 1% for the nontargeted conjugate at 18 h after administration, while tha t 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 equiva lent) 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 concom itant increase in the therapeutic efficacy of P-DOX-Ab and P-Mce(6)-Ab in c ombination therapy, which may probably be attributed to both antibody targe ting and enhanced permeability and retention (EPR) effects. (C) 2001 Elsevi er Science B.V. All rights reserved.