Derivatives of dextran : synthesis and applications in oncology

Abstract

Targeted therapy for cancer treatment using cytostatic drugs and radionuclides is becoming an increasingly important tool in clinical oncology. Much research is focused on the development of effective tumour targeting compounds. The present study describes the construction of dextran based tumour targeting conjugates and examples of their applications in oncology. The behaviour of charge-modified dextran was investigated in patients with superficial urinary bladder cancer. Cationic dextran showed a strong tumour selective accumulation indicating possible to use it as a vehicle for therapeutic compounds. Epirubicin was coupled to the cationic dextran resulting in a cytotoxic formulation. The cationic epirubicin-dextran conjugate was tested in vitro and showed a marked inhibitory effect on the growth of three human bladder cancer cell-lines. Interestingly, the cationic moiety of the conjugate enhanced the inhibitory effect. The cytotoxicity of cationic epirubicin-dextran was comparable to free epirubicin. To allow rhenium-188 chelation, cysteine was coupled to dextran resulting in free sulfbydryl side-groups. The cysteine-dextran was labelled with 188Re using 188Re-gluconate as transchelator. The labelling efficiency was 60-70%, and radiochemical purity was > 95%. In the presence of an antioxidant, the 188Re-dextran had a high stability. The 99mTc-tricabonyl method was adapted for tecnetium-99m labelling of a somatostatin-dextran conjugate. The in vitro stability of the labelled conjugate was evaluated by size-exclusion high performance liquid chromatography (HPLC). The labelled conjugate interacted with serum protein (-30% of radioactivity was associated with serum protein after 24 h incubation at 37°C). The biodistribution and blood half-life of somatostatin-dextran70 were investigated in normal mice. The results showed enhanced plasma half-life, ~27 h after subcutaneous administration. The biodistribution showed uptake in liver, spleen and kidneys indicating the route of digestion and excretion. The conjugate showed high somatostatin receptor-binding affinity when tested in vitro on rat brain co1iex membranes. The different dextran conjugates described in this study have a potential of becoming tools in clinical oncology, such as the cationic dextran derivatives for superficial bladder cancer and radioactive/non-radioactive somatostatin-dextran for systemic tumour targeting. The clinical relevance of non-radioactive somatostatin-dextran70 in the treatment of somatostatin receptor positive tumours is currently being investigated in clinical phase I-II studies.