Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy.

Despite considerable progress has been achieved in hypoxia-associated anti-tumor therapy, the efficacy of utilizing hypoxia-activated prodrugs alone is not satisfied owing to the inadequate hypoxia within the tumor regions. In this work, a mitochondrial targeted nanoplatform integrating photodynamic therapy, photothermal therapy and hypoxia-activated chemotherapy has been developed to synergistically treat cancer and maximize the therapeutic window. Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study. Chlorin e6 (Ce6) and triphenyl phosphonium (TPP) were conjugated onto the surface of the nanoplatform. Under the action of TPP, the obtained nanoplatform preferentially accumulated in mitochondria to restore the drug activity and avoid drug resistance. Using 660 nm laser to excite Ce6 can generate ROS and simultaneously exacerbate the cellular hypoxia. While under the irradiation of 808 nm laser, the nanoplatform produced local heat which can increase the release of TH302 in tumor cells, ablate cancer cells as well as intensify the tumor hypoxia levels. The aggravated tumor hypoxia then significantly boosted the anti-tumor efficiency of TH302. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.

31P NMR and chloride ion kinetics of alkylating monoester phosphoramidates.

31P NMR spectroscopy was used to study the solvolysis kinetics of a novel series of alkylating monoester phosphoramidates (4a-d) under model physiologic conditions. Halide ion kinetics were used to determine the rate of aziridinium ion formation. The solvolysis rates showed the expected dependence upon substitution at the reactive nitrogen; comparison of 4a with phosphoramide mustard (1a) indicated that replacement of the amino group by alkoxy decreased the solvolysis rate by approximately 10-fold. The rate of conversion of starting compound (4a-d) to solvolysis product was essentially equal to the rate of halide ion release, suggesting that the aziridinium ion is a short-lived intermediate. 1H NMR and 31P NMR kinetics experiments performed in the absence and presence of trapping agent (dimethyldithiocarbamate) confirmed that the aziridinium ion was too short-lived to be observed via NMR. These compounds were also tested for cytotoxicity against L1210 leukemia and B16 melanoma cells in vitro; the monoalkylators 4c and 4d showed no activity, 4a was weakly cytotoxic, and 4b was comparable in activity to phosphoramide mustard.

Basis and new developments in the field of oxazaphosphorines.

All the research results summarized herein were gained in the attempt to improve selectivity in cancer chemotherapy: "Chemotherapeutic agents are not only ends in themselves, they are also beginnings,. . . Selectivity must be our goal and understanding its basis our guide to the future" (138). The development of the OAP cytostatics CP, IFO, TRO, and SUFO derives from the idea of applying the principle of transport form/active form to the highly reactive nitrogen mustard compounds. The desired conversion of the reactive nitrogen mustard into an inactive transport form (latentiation) was performed by chemical synthesis. The requirement for an enzymatic activation of the transport form to give the active form in the target organ cancer cell was met and has been shown to occur in a sequence of various metabolic reactions. The goal of a substantial increase in the therapeutic range of alkylating agents has been achieved with the development of the OAP cytostatics. The higher cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. A further increase in the cancerotoxic selectivity in OAPs was achieved by the development of mesna as a regional uroprotector. Mesna eliminates the danger of therapy-limiting urotoxic side effects of OAPs, allowing administration of higher dosages and more safely optimizing their therapeutic efficacy and partly overcoming resistance phenomena. The stabilization of the primary OAP metabolites (MAFO), opens up new possibilities in clinical therapy and in preclinical tests, for examination in the clonogenic stem cell test, for in vitro purging in ABMT, and for the regional therapy of tumors. A completely new type of therapy is emerging for OAP, specifically for low-dosage MAFO, as an immunomodulator, under certain circumstances, in combination with further substances, from the biological response modifier group.