NIOSOMES CONTAINING N-(2-HYDROXYPROPYL)METHACRYLAMIDE COPOLYMER-DOXORUBICIN (PK1) - EFFECT OF METHOD OF PREPARATION AND CHOICE OF SURFACTANT ON NIOSOME CHARACTERISTICS AND A PRELIMINARY-STUDY OF BODY DISTRIBUTION

PK1 is an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubic in conjugate currently in early clinical development. Niosome encapsul ation is a means to increase PK1 blood residence time, potentially pro mote tumour uptake and produce a slow, sustained release of active dru g. Factors effecting encapsulation efficiency and size of PK1-niosome formulations were studied. Five surfactants were used to prepare PK1-n iosomes; hexadecyl poly-5-oxyethylene ether (C16EO5); octadecyl poly-5 -oxyethylene ether (C18EO5); hexadecyl diglycerol ether (C(16)G(2)); s orbitan monopalmitate (Span 40) and sorbitan monostearate (Span 60). A ll were mixed in equimolar ratio with cholesterol and varying amounts of Solulan C24 (a cholesteryl poly-24-oxyethylene ether) (9-39 mol%). Dicetylphosphate (DCP) was also added (2 mol%). Passive association of PK1 with preformed C(16)G(2) and Span 60 vesicles was low (3-4%) whil e subsequent dehydration (freeze drying) followed by rehydration of th e formulation increased the entrapment to 61% in the C(16)G(2) formula tion. Transmission electron microscopy revealed that these niosomes ha d an electron dense core, evidence of intravesicular concentration of PK1. Increasing Solulan C24 content resulted in decreased PK1 entrapme nt after freeze drying, and the vesicle size was also decreased. Solul an C24 (39 mol%) caused pronounced vesicle aggregation on freeze dryin g, whereas at lower levels (9 mol%), PK1 appeared to act as a cryoptro tectant and the mean size of C(16)G(2) niosomes was 235 nm. A PK1:surf actant/lipid ratio of 0.3 (11.2 mg ml(-1) doxorubicin) was achieved wi th Span 60 niosomes. This formulation, and the C(16)G(2) niosomes, did not induce red blood cell lysis at the proposed dose for in vivo use. Preliminary in vivo biodistribution studies showed PK1-C(16)G(2) nios omes to be mainly taken up by the liver and spleen. After 24 h, 25 and 3% of dose administered was present as free doxorubicin in these orga ns respectively. (C) 1997 Elsevier Science B.V.