Colloids and Surfaces B: Biointerfaces 16 (1999) 113 – 134 Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials Valery Alakhov a, *, Evgueni Klinski a , Shengmin Li a , Grzegorz Pietrzynski a , Annie Venne a , Elena Batrakova b , Tatiana Bronitch b , Alexander Kabanov b a Supratek Pharma Inc., Building 18, 531 Bld. des Prairies, Laal, Quebec, H7B 1B7, Canada b Department of Pharmaceutical Sciences, College of Pharmacy, Uniersity of Nebraska Medical Centre, 600 South 42nd Street, Omaha, NB, 68198 -6025, USA Abstract A new doxorubicin formulation (SP1049C) has been developed using a combination of two polyethylene oxide polypropylene oxide block copolymers, in particular Pluronic L61 and Pluronic F127. The analysis of cytotoxic activity of this product on the cell screen panel has shown that SP1049C is highly effective against multidrug resistant cells that are normally not susceptible to doxorubicin and most other cytotoxic drugs. Further mechanistic studies have revealed that SP1049C has higher activity than doxorubicin due to: (i) increase in the drug uptake; (ii) inhibition of the energy-dependent drug efflux; and (iii) changes in intracellular drug trafficking. The experiments on in vivo tumour models have confirmed high efficacy of SP1049C against drug-resistant tumours, as well as suggested that this product has considerably broader efficacy than doxorubicin. The analysis of pharmacokinetics and biodistribution of SP1049C has shown that it accumulates in tumour tissue more effectively than doxorubicin, while distribution of the formulation in normal tissues is similar to that of doxorubicin. The toxicity studies of the copolymer composition used in SP1049C and of the product itself have demonstrated that the carrier has high safety margin, while toxicity of SP1049C is similar to that of doxorubicin suggesting that no additional adverse effects should be expected in clinical trials of SP1049C. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Doxorubicin; Block copolymers; Pluronic; Multidrug resistant tumours www.elsevier.nl/locate/colsurfb 1. Introduction Anthracyclines are amongst the most widely used anticancer agents in man, but are limited by toxicity considerations, as well as by inherent or induced drug resistance (for review see [1,2]). Sev- eral approaches were explored to improve the therapeutic index of anthracyclines and to extend their utility by using various drug delivery sys- tems, for example, liposomes [3,4], polymer and antibody based conjugates [5,6]. The use of these systems significantly enhanced the pharmacologi- cal properties of anticancer drugs. In particular, liposomal formulations of doxorubicin [3] and daunorubicin [7] demonstrated lowered toxicity and increased accumulation in tumours. Some of * Corresponding author. 0927-7765/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII:S0927-7765(99)00064-8