Enhanced antitumor activity of combinations of free and HPMA copolymer-bound drugs

Abstract

The synergism in anticancer effect toward human renal carcinoma A498 cells by binary combinations of free and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound anticancer drugs, SOS thiophene (SOS), doxorubicin (DOX), and mesochlorin e 6 monoethylenediamine (Mce 6 ), was evaluated. The combination index (CI) analysis was used to quantify the synergism, antagonism, and additive effects. Both free drugs and HPMA copolymer conjugates, when used as single agents or in combination, exhibited cytotoxic activities against A498 cells, as determined using a modified MTT assay. As single agents, SOS and P-GFLG-SOS (HPMA copolymer conjugates containing SOS bound via glycylphenylalanylleucylglycine [GFLG] spacer) were significantly more effective than the other agents evaluated. The synergistic effects ranked in the order SOS+DOX>P-GFLG-DOX +P-GFLG-Mce 6 ≈DOX+Mce 6 >P-GFLG-SOS+P-GFLG-DOX≈SOS+Mce 6 >P-GFLG-SOS+P-GFLG-Mce 6 . The combination of SOS+DOX proved to be synergistic over all cell growth inhibition levels. All other combinations exhibited synergism in a wide range of drug effect levels. The SOS +Mce 6 and P-GFLG-SOS+P-GFLG-Mce 6 combinations displayed synergism up to drug affected fraction (f a ) values of about 0.8 and reached slight antagonism and nearly additivity at f a = 0.95, respectively. However, all other combinations were synergistic up to f a < 0.9 and were additive at higher f a values. The observations that most combinations produced synergistic effects will be important for clinical translation.

Combination cytotoxicity of backbone degradable HPMA copolymer gemcitabine and platinum conjugates toward human ovarian carcinoma cells

“…In vivo combination chemotherapy and photodynamic therapy (PDT) studies on two cancer models, Neuro 2A neuroblastoma induced in A/J mice [29] and human ovarian carcinoma heterotransplanted in nude mice [30–32], demonstrated that macromolecular combination therapy produced tumor cures which could not be obtained with either chemotherapy or PDT alone. Other combination systems were quantitatively evaluated by combination index (CI) analysis in A498 renal carcinoma cells [33] and in OVCAR-3 ovarian carcinoma cells [34]. The results demonstrated synergistic effects of HPMA copolymer-drug (SOS thiophene, doxorubicin, and chlorin e 6 ) conjugate combinations in a wide range of concentrations.…”

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…A large variety of passive delivery carriers, including long circulating liposomes, polymeric nanoparticles, polymer-PS conjugates or micelles, have been developed[164][165][166][167]. The advantages of these delivery systems lie in their relatively low cost and simple preparation, excellent dispersity in aqueous media, and large cargo of hydrophobic PSs.…”

Macromolecular therapeutics

“…In vivo combination chemotherapy and photodynamic therapy (PDT) studies on two cancer models, Neuro 2A neuroblastoma induced in A/J mice [165] and human ovarian carcinoma heterotransplanted in nude mice [104,166,167], demonstrated that combination therapy produced tumor cures which could not be obtained with either chemotherapy or PDT alone. Other combination systems were quantitatively evaluated by combination index (CI) analysis in A498 renal carcinoma cells [168] and in OVCAR-3 ovarian carcinoma cells [169]. The results demonstrated synergistic effects of HPMA copolymer-drug (SOS thiophene, DOX, and chlorin e 6 ) conjugate combinations in a wide range of concentrations.…”