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 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.
Shiah
J G
JG
Department of Pharmaceutics and Pharmaceutical Chemistry, 30 S., 2000 E., Room 301, University of Utah, Salt Lake City, UT 84112, USA.
Sun
Y
Y
Kopecková
P
P
Peterson
C M
CM
Straight
R C
RC
Kopecek
J
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D008652:Mesoporphyrins; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D010778:Photochemotherapy; D011166:Porphyrins / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D008652:Mesoporphyrins; D008689:Methacrylates; D011166:Porphyrins; C088297:meso-chlorin e(6) monoethylene diamine; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate