Tumor repolarization by an advanced liposomal drug delivery system provides a potent new approach for chemo-immunotherapy.

Immunosuppressive cells in the tumor microenvironment allow cancer cells to escape immune recognition and support cancer progression and dissemination. To improve therapeutic efficacy, we designed a liposomal oxaliplatin formulation (PCL8-U75) that elicits cytotoxic effects toward both cancer and immunosuppressive cells via protease-mediated, intratumoral liposome activation. The PCL8-U75 liposomes displayed superior therapeutic efficacy across all syngeneic cancer models in comparison to free-drug and liposomal controls. The PCL8-U75 depleted myeloid-derived suppressor cells and tumor-associated macrophages in the tumor microenvironment. The combination of improved cancer cell cytotoxicity and depletion of immunosuppressive populations of immune cells is attractive for combination with immune-activating therapy. Combining the PCL8-U75 liposomes with a TLR7 agonist induced immunological rejection of established tumors. This combination therapy increased intratumoral numbers of cancer antigen-specific cytotoxic T cells and Foxp3- T helper cells. These results are encouraging toward advancing liposomal drug delivery systems with anticancer and immune-modulating properties into clinical cancer therapy.

Production and dosimetric aspects of the potent Auger emitter 58mCo for targeted radionuclide therapy of small tumors.

PURPOSE: Based on theoretical calculations, the Auger emitter 58mCo has been identified as a potent nuclide for targeted radionuclide therapy of small tumors. During the production of this isotope, the coproduction of the long-lived ground state 58gCo is unfortunately unavoidable, as is ingrowth of the ground state following the isomeric decay of 58mCo. The impact of 58Co as a beta(+)- and gamma-emitting impurity should be included in the dosimetric analysis. The purpose of this study was to investigate this critical part of dosimetry based on experimentally determined production yields of 58mCo and 58gCo using a low-energy cyclotron. Also, the cellular S-values for 58mCo have been calculated and are presented here for the first time. METHODS: 58mCo was produced via the 58Fe(p,n)58mCo nuclear reaction on highly enriched 58Fe metal. In addition, radiochemical separations of produced radio-cobalt from natFe target material were performed. The theoretical subcellular dosimetry calculations for 58mCo and 58gCo were performed using the MIRD formalism, and the impact of the increasing ground state impurity on the tumor-to-normal-tissue dose ratios (TND) per disintegration as a function of time after end of bombardment (EOB) was calculated. RESULTS: 192 +/- 8 MBq of 58mCo was produced in the irradiation corresponding to a production yield of 10.7 MBq/microAh. The activity of 58gCo was measured to be 0.85% +/- 0.04% of the produced 58mCo activity at EOB. The radio-cobalt yields in the rapid separations were measured to be > 97% with no detectable iron contaminations in the cobalt fractions. Due to the unavoidable coproduction and ingrowth of the long-lived ground state 58gCo, the TND and the potency of the 58mCo decrease with time after EOB. If a future treatment with a 58mCo labeled compound is not initiated before, e.g., 21 h after EOB, the resulting TND will be approximately 50% of the TND of 'pure' 58mCo as a result of the increased normal tissue dose from the ground state. CONCLUSIONS: The Auger emitter 58mCo is a potent radioisotope for targeted radionuclide therapy, and the production of therapeutic quantities should be achievable using a small biomedical cyclotron. However, the unavoidable coproduction and ingrowth of the long-lived ground state 58gCo requires fast radiochemical processing and use of future 58mCo-labeled radiopharmaceuticals in order to exploit the high achievable TND of 58mCo.

Medium to large scale radioisotope production for targeted radiotherapy using a small PET cyclotron.

In recent years the use of radionuclides in targeted cancer therapy has increased. In this study we have developed a high-current solid target system and demonstrated that by the use of a typical low-energy medical cyclotron, it is possible to produce tens of GBq's of many unconventional radionuclides relevant for cancer therapy such as (64)Cu and (119)Sb locally at the hospitals.