Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

Abstract

SP1049C is a novel anticancer agent containing doxorubicin and two nonionic pluronic block copolymers. In preclinical studies, SP1049C demonstrated increased efficacy compared to doxorubicin. The objectives of this first phase I study were to determine the toxicity profile, dose-limiting toxicity, maximum tolerated dose and pharmacokinetic profile of SP1049C, and to document any antitumour activity. The starting dose was 5 mg m À2 (doxorubicin content) as an intravenous infusion once every 3 weeks for up to six cycles. A total of 26 patients received 78 courses at seven dose levels. The dose-limiting toxicity was myelosuppression and DLT was reached at 90 mg m À2 . The maximum tolerated dose was 70 mg m À2 and is recommended for future trials. The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin. Evidence of antitumour activity was seen in some patients with advanced resistant solid tumours. Phase II trials with this agent are now warranted to further define its antitumour activity and safety profile.

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…Histochemical examination of tissue sections from Pluronic ® -treated animals revealed no pathological changes in brain capillaries [310]. Importantly, no cerebral toxicity of any kind was observed in human Phase I and Phase II trials of SP1049C, a Pluronic ® -based formulation of Doxorubicin to treat MDR tumors [145,149,312]. All together, it is likely, that this formulation, already validated in human trials, can be adopted to enhance CNS drug delivery.…”

“…Examples include polymeric micelles [118,[123][124][125][126], DNA/polycation complexes ("polyplexes") [127][128][129][130][131][132][133][134][135], block ionomer complexes [116,[136][137][138][139], nanogels [140][141][142][143][144] and others. Of these materials, polymeric micelles have been evaluated in human trials for the delivery of anti-cancer agents [145][146][147][148][149]. The promising results of these trials suggest that polymeric micelles are likely to find practical use in medicine.…”

“…After reaching target cells drug is released from the micelle via diffusion. Several clinical trials are completed or underway to evaluate polymeric micelles for delivery of anti-cancer drugs [145][146][147][148][149].…”

Novel Nanomaterials for Clinical Neuroscience

“…After reaching target cells, the drug is released from the micelle via diffusion. Several clinical trials are completed or are underway to evaluate polymeric micelles for delivery of anti-cancer drugs (Danson et al 2004;Kim et al 2004;Matsumura et al 2004;Armstrong et al 2006;Matsumura 2006).…”

Multidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir

“…Recently, nanocarrier‐drugs have been proposed as promising candidates against the MDR effect, as being mainly ascribed to their easy cellular uptake, i.e., cellular entry of “disguised” drugs via nanoparticle (NP) endocytosis would lead to enhanced cellular uptake of drugs 8, 9, 10, 11, 12, 13, 14, 15, 16. Although enhanced drug efficacy was indeed observed in some cases, whether there is a MDR reversal effect remained unclear, because of the lack of comparisons of drug efficacy between drug sensitive cells and its corresponding resistant cells.…”