Lurtotecan

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13 g (IC₅₀ = 0.514 μM) and 13o (IC₅₀ = 0.275 μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC₅₀ = 0.511 μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.

Liposomal formulations entrapping a vast number of molecules have improved cancer therapies overcoming certain pharmacokinetic (PK) and pharmacodynamic limitations, many of which are associated with tumor characteristics. In this context, immunoliposomes represent a new strategy that has been widely investigated in preclinical cancer models with promising results, although few have reached the stage of clinical trials. This contrasts with the emerging clinical application of monoclonal antibodies (mAbs). This formulation allows the conjugation of different mAbs or antibody derivatives, such as monovalent variable fragments Fab', to the polymers covering the surface of liposomes. The combination of this targeting strategy together with drug encapsulation in a single formulation may contribute to enhance the efficacy of these associated agents, reducing their toxicities. In this paper we will consider how factors such as particle size, lipid composition and charge, lipid-polymer conjugation, method of production and type of ligand for liposome coupling influence the efficacy of these formulations. Furthermore, the high inter-individual variability in the tumor microenvironment, as well as the poor experimental designs for the PK characterization of liposomes, make the establishment of the relationship between plasma or tumor concentrations and efficacy difficult. Thus, adequate dosing regimens and patient stratification regarding the target expression may contribute to enhance the possibility of incorporating these immunoliposomes into the therapeutic arsenal for cancer treatments. All these issues will be briefly dealt with here, together with a section showing the state of the art of those targeted liposomes that are coming up for testing in clinical trials. Finally, some insights into future developments such as the combination of specificity and controlled release, based on the application of different stimuli, for the manipulation of stability and cargo release, will be offered. This has been included in order to highlight the new opportunities for targeted liposomes, including immunoliposomes.