POLYMERIC CONJUGATES FOR DIAGNOSIS AND THERAPY

摘要

Reactive polymers can be conjugated, directly or by means of linkers and/or others polymers to chelating agents comprising at least one phosphorous atom in the form of a phosphine or phosphine oxide (or precursors thereof) to form conjugates useful in diagnostic and therapeutic applications. In particular this invention provides conjugates comprising a hydrophilic polymer bound, directly or by means of other moieties, to at least one chelating group able to chelate metal radioisotopes comprising at least one phosphine or one phosphine oxide phosphorous. Such chelating groups can be conjugated to the hydrophilic polymer directly or via one or more linkers and/or one or more additional polymers. The use of additional polymers can provide increased loading of chelating agent. The linkers are preferably selected among alkyl groups or aromatic groups or cleavable peptides or other biodegradable sequences. Additionally, one or more targeting molecules can be linked to the hydrophilic polymer directly or by means of linkers and/or others polymers. Due to their polymeric structure, the conjugates according to the invention have enhanced specificity toward certain tissues, such as tumors, inflamed tissued and the liver. The specificity can be further increased by the additional provision of targeting moieties such as antibodies or sugars. These conjugates can be formulated for remaining in the blood circulation for a period for time suitable for diagnostic and therapeutic applications. Moreover they possess thermodynamic and kinetic stability, keeping the metal chelate intact under physiological conditions. The invention also provides a very simple and efficient method for the labelling of radiopharmaceuticals, which avoids the use of any additional reducing agent. Accordingly, metal ions like technetium or rhenium can be added as pertechnetate or pherrhenate to chelating agents comprising polymer and a phosphine and surprisingly it has been found that such chelating agents can act as reducing agents of the metal and the use of an additional reducing agent is not necessary. This allows the preparation of simple kits comprising a component (a) comprising the polymeric chelating agent and a component (b) comprising the metal ion in its highest oxidation state. These two components can be kept separately and combined together just before use to yield the metal complex without the need of further reducing step and purification.