Fundamental relationships between the composition of pluronic block copolymers and their hypersensitization effect in MDR cancer cells.
OBJECTIVE
Previous studies have demonstrated that Pluronic block copolymers hypersensitize multiple drug resistant (MDR) cancer cells, drastically increasing the cytotoxic effects of anthracyclines and other anticancer cytotoxics in these cells. This work evaluates the dose dependent effects of these polymers on (i) doxorubicin (Dox) cytotoxicity and (ii) cellular accumulation of P-glycoprotein probe, rhodamine 123 (R123) in MDR cancer cells.


METHODS
Dox cytotoxicity and R123 accumulation studies are performed on monolayers of drug-sensitive (KB, MCF-7, Aux-B1) and MDR (KBv, MCF-7/ADR, CHrC5) cells.


RESULTS
Both tests reveal strong effects of Pluronic copolymers observed at concentrations below the critical micelle concentration (CMC) and suggest that these effects are due to the copolymer single chains ("unimers"). Using block copolymers with various lengths of hydrophobic propylene oxide (PO) and hydrophilic ethylene oxide (EO) segments these studies suggest that the potency of Pluronic unimers in MDR cells increases with elevation of the hydrophobicity of their molecule. Optimization of Pluronic composition in R123 accumulation and Dox cytotoxicity studies reveals that Pluronic copolymers with intermediate lengths of PO chains and relatively short EO segments have the highest net efficacy in MDR cells.


CONCLUSIONS
The relationship between the structure of Pluronic block copolymers and their biological response modifying effects in MDR cells is useful for determining formulations with maximal efficacy with respect to MDR tumors.
Batrakova
E
E
College of Pharmacy, Department of Pharmaceutical Sciences, Nebraska Medical Center, Omaha 68198-6025, USA.
Lee
S
S
Li
S
S
Venne
A
A
Alakhov
V
V
Kabanov
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D002294:Carcinoma, Squamous Cell; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D008970:Molecular Weight; D020442:Poloxamer / Q000737:chemistry / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014867:Water / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005079:Excipients; D005456:Fluorescent Dyes; D014867:Water; D020442:Poloxamer; D020112:Rhodamine 123; D004317:Doxorubicin