Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice

Abstract

Based on the results of our studies, encapsulation of cisplatin in long-circulating pegylated liposomes has overcome limitations experienced with other liposomal cisplatin formulations. SPI-077 has a prolonged circulation time and increased tumor Pt disposition, and its antitumor effect is significantly improved compared to cisplatin in murine colon and lung cancer models.

In vivo administration of liposomal vincristine sensitizes drug‐resistant human solid tumors

“…2 Moreover, the increased circulation time allows enhanced liposome accumulation in the areas with compromised vasculature, such as sites of inflammation and tumors. [3][4][5][6][7] A number of preclinical studies reported that drug encapsulation in liposomes increases the efficacy of several anticancer agents both in vitro and in vivo. In particular, liposome formulations of doxorubicin and daunorubicin exhibit a higher antitumor activity and reduced toxicity compared to the free form of the drugs in several experimental tumors and are able to overcome drug resistance.…”

A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin

“…Data from tumour-bearing mouse models showed a significantly greater antitumour activity compared to cisplatin and a significantly increased tumour exposure to platinum. This coincided with a decreased platinum exposure to the kidneys, the principal organ of cisplatin toxicity (Newman et al, 1999). On the basis of these preclinical results, in addition to the previous success of STEALTH ® liposomal doxorubicin, phase I studies in both adult and paediatric patients, with advanced cancer not amenable to other cancer treatments, were performed in the UK and Europe.…”

“…The pharmacokinetics of SPI-77 were significantly altered from those associated with cisplatin treatment and implied that the cisplatin was maintained inside the liposome with no detectable free cisplatin measured in plasma at any point following administration. Although preclinical data suggested that low plasma levels of free cisplatin would explain the lack of toxicity seen with SPI-77 in murine tumour models, the complete retention of cisplatin within the liposomes was not predicted as significant antitumour activity was observed (Newman et al, 1999). Both the paediatric and adult phase I studies were stopped at a dose of 320 mg m -2 in order to address the issue of reformulation of liposomally bound cisplatin, i.e.…”

“…These liposomes are thought to accumulate in tumours following extravasation through the tumour vasculature, due to their small size, long circulation time and reduced interaction with components of the blood including lipoproteins, cells, opsonins and other liposomes (Woodle and Lasic, 1992). Preclinical studies in tumour-bearing mice showed SPI-77 to have superior antitumour activity compared to the same cumulative dose of cisplatin with higher cumulative doses of SPI-77 being well tolerated and exhibiting increased antitumour affect (Newman et al, 1999). Significantly, SPI-77-treated animals had a 28-fold higher tumour exposure to platinum, as determined by area-under-the-curve (AUC), than cisplatin-treated animals, but a 4-fold lower exposure of platinum to the kidneys, which represents the primary target organ of toxicity associated with cisplatin treatment.…”

Polybutylcyanoacrylate Nanoparticles and Drugs of the Platinum Family: Last Status

“…This action results in increasement of drug accumulation in tumor due to an increase in entrapment and permeability of blood vessels. For more selective delivery of cisplatinum to tumors, this drug is used as conjugation of drug-dissolved polymer, colloid nanocarriers like pegylated liposomes, poly aspartic acidpoly ethylene glycol micelles, poly caprolactone-poly ethylene glycol micelles, poly caprolactone-poly 2-(N,Ndimethylamino) ethyl methacrylate micelles [3][4][5][6][7][8][9]. No carrier able to deliver cisplatinum to tumors effectively is developed yet.…”