Drug delivery as a means of enhancing the activity of platinum compounds

Platinum based chemotherapy is used in the treatment of a number of tumour types but clinical activity is limited by systemic toxicity and tumour drug resistance. We aim to improve the therapeutic efficacy of platinum compounds through targeted delivery and as a first step have identified a novel delivery system. Encapsulation of drugs can improve their efficacy either through enhanced permeability and retention or by protection from degradation and inactivation. Cucurbit[7]uril (CB[7]) is a rigid macrocycle made from the acid condensation of glycoluril and formaldehyde. We have investigated whether encapsulation of cisplatin within cucurbit[7]uril (CB[7]cp) affects cisplatin sensitivity in vitro and in vivo. CB[7]cp retained activity in vitro in the human ovarian cancer cell line A2780 (IC50 \#956;M CP 0.11±0.01; CB[7]cp 0.09±0.01) and two mismatch repair deficient cisplatin resistant derivatives A2780/cp70 (CP 3.01±0.09; CB[7]cp 2.73±0.21) and MCP1 (CP 0.34±0.01; CB[7]cp 0.35±0.08). The tumour doubling time of xenografts of A2780 grown in athymic nude mice is increased from 3.1±0.1 to 4.9±0.2 days (P< 0.001) by treatment with the maximum tolerated dose (MTD) of cisplatin (6mg/kg). CB[7]cp was tolerated by the mice and a dose of 34mg/kg (equivalent to 6mg/kg cisplatin) increased the doubling time to 6.3±0.5 days but this was not significantly greater than that for cisplatin (P>0.05). However, xenografts of A2780/cp are resistant to the MTD of cisplatin but when treated with CB[7]cp (34mg/kg) the tumour doubling time was increased from 3.2±0.3 to 5.3±0.2 days (P<0.001). CB[7] alone was well tolerated and a dose of 250mg/kg had no effect on tumour growth rates. Encapsulation of cisplatin did not alter the cisplatin sensitivity or the fold resistance of the two A2780 derivatives which suggests that the activity of CB[7]cp seen in the cisplatin resistant tumours is not due to circumvention of resistance at the cellular level. It is more likely that the encapsulation has allowed increased delivery of cisplatin to the tumours without an increase in toxicity. We are now examining the pharmacokinetics of the encapsulated cisplatin. Our current aim is to incorporate other platinum compounds and to further improve their delivery by addition of a targeting component to the complex.