Polysialic acid as a drug carrier: evaluation of a new polysialic acid–epirubicin conjugate and its comparison against established drug carriers

Abstract

This paper explores the potential of polysialic acid (PSA) as a carrier for low molecular weight anticancer drugs. A PSA–epirubicin (Epi) conjugate was synthesized and compared against Epi conjugates containing established carriers, namely: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers, poly(ethylene glycol) (PEG) and polyglutamic acid (PGA). Biological assessments in the breast cancer cell line MCF-7 and in the anthracycline resistant MCF-7/DX showed that the PSA–Epi conjugate had the highest activity (40% and 30% cell death in the two cell lines at 1 mM Epi equiv., respectively). FACS studies confirmed internalization of all conjugates by cholesterol-dependent endocytosis. PSA–Epi showed release of Epi (40% at 5 h) when incubated with lysosome extracts. In vivo evaluation showed that all conjugates had a significantly longer half-life compared to free Epi. This study also allowed an investigation on the effect of the polymeric carrier on the biological activity of a conjugate, with the biodegradability of the carrier emerging as an important feature

FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy

“…EPI therefore has been nanosized to various formulations such as micelles [36], liposomes [37], nanoparticles [38,39], and, most interesting for us, water-soluble conjugates to improve its therapeutic index. In general, polymer-EPI conjugates were produced via polymeranalogous reaction in which EPI is attached to polymer through active ester [27] or in the presence of coupling agents [25,28]. Here we report a different way to synthesize the conjugates - RAFT copolymerization.…”

“…However, the polymer conjugation can affect the fluorescence emission [28]. Consequently, the data only from drug fluorescence may be misinterpreted.…”

“…Recently, EPI has been bound to various polymer carriers to improve its properties and delivery. For example, dextran [23], polyethylene glycol (PEG) [24], dendritic PEG [25], human monoclonal antibodies [26], polyHPMA [27,28] and polysialic acid [28] were used as (targetable) carriers.…”

Drug and protein delivery by polymer conjugation

“…In those cases, (for example, when polyglutamic and polysialic acids are used) the polymer is not a simple inert carrier but actively contributes to the site-specific drug activation (i.e. release) [10].…”

“…The polymer has traditionally been regarded as simply a 'platform' that can confer enough size to reduce kidney clearance, shield the protein, and eventually produce passive tumour accumulation. But an increasing number of reports indicate that the polymeric carrier itself plays a key role in biological activity [10]. Initial studies examined libraries of a single polymer to determine the impact of different polymer features on biological activity (see, for example, for HPMA copolymers [11] for PVP [12], for dextran [13] and for PEG [14,15]).…”