This study demonstrates the selective
tumor targeting and the antitumor efficacy of the
N-(2-hydroxypropyl)methacrylamide (
HPMA) copolymer-bound
mesochlorin e6 monoethylenediamine (Mce6) and
HPMA copolymer-bound
Adriamycin (ADR) in combination
photodynamic therapy (
PDT) and
chemotherapy against human ovarian OVCAR-3
carcinoma xenografted in female athynmic mice. The concentrations of Mce6 and ADR in blood and tissues, in free or
HPMA copolymer-bound form, were determined by fluorescence and high-performance liquid chromatography fluorescence assays, respectively. Xenograft responses to single and combination
therapies were recorded. The peak concentration of
HPMA copolymer-Mce6 conjugate in
tumor was achieved 18 h after administration. For
HPMA copolymer-bound drugs, the concentration ratios of liver and spleen versus muscle were significantly higher than those of free drugs. The
HPMA copolymer-bound drugs demonstrated selective targeting and accumulation in the
tumor, probably attributed to the enhanced permeability and retention effect. In vivo studies revealed that all
tumors in the treatment groups showed significant responses after receiving any of the various types of
therapy as compared with controls (P < 0.001).
PDT with
HPMA copolymer-Mce6 conjugate (PDTMC) at a dose of 13.4 mg/kg (1.5 mg/kg of Mce6 equivalent) and light doses of 110 J/cm2 at 12 and 18 h, respectively, resulted in significant suppression of the growth of OVCAR-3
tumors. Three courses of
chemotherapy using 35 mg/kg (2.2 mg/kg of ADR equivalent) of
HPMA copolymer-ADR conjugate (CHEMO) were effective in suppressing the growth of
tumors. Single PDTMC plus multiple CHEMO exhibited significantly greater therapeutic efficacy than multiple CHEMO. In the group of mice receiving multiple PDTMC,
tumor recurrence became obvious after day 20. However, 10 of 12
tumors exhibited complete responses in the group of mice receiving multiple PDTMC plus multiple CHEMO. The least to most effective treatments were ranked as follows: multiple CHEMO < single PDTMC plus multiple CHEMO < multiple PDTMC < multiple PDTMC plus multiple CHEMO. The results clearly demonstrate that: (a)
HPMA copolymer-bound drugs exhibited selective
tumor accumulation contrary to free drugs; (b)
PDT using
HPMA copolymer-Mce6 conjugate with multiple light irradiations was a better
therapy than that with single light irradiation; and (c)
combination chemotherapy and
photodynamic therapy with
HPMA copolymer-ADR and
HPMA copolymer-Mce6 conjugates was the most effective regimen.