DPPG(2)-Based Thermosensitive Liposomes with Encapsulated Doxorubicin Combined with Hyperthermia Lead to Higher Doxorubicin Concentrations in the Bladder Compared to Conventional Application in Pigs: A Rationale for the Treatment of Muscle-Invasive Bladder Cancer

F Johannes P van Valenberg,1,* Iris SG Brummelhuis,1,* Lars H Lindner,2 Felix Kuhnle,2 Barbara Wedmann,2 Pascal Schweizer,3 Martin Hossann,3 J Alfred Witjes,1 Egbert Oosterwijk1 1Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands; 2Department of Medicine III, University Hospital LMU Munich, Munich, Germany; 3Thermosome GmbH, Munich, Germany*These authors contributed equally to this workCorrespondence: Iris SG BrummelhuisDepartment of Urology, Radboud University Medical Center, Geert Grooteplein Zuid 10 (610), PO Box 9101, Nijmegen 6500 HB, the NetherlandsTel +31 24 3619515Fax +31 24 3635121Email iris.brummelhuis@radboudumc.nlPurpose: Current treatment options for muscle-invasive bladder cancer (MIBC) are associated with substantial morbidity. Local release of doxorubicin (DOX) from phosphatidyldiglycerol-based thermosensitive liposomes (DPPG2-TSL-DOX) potentiated by hyperthermia (HT) in the bladder wall may result in bladder sparing without toxicity of systemic chemotherapy. We investigated whether this approach, compared to conventional DOX application, increases DOX concentrations in the bladder wall while limiting DOX in essential organs.Materials and Methods: Twenty-one pigs were anaesthetized, and a urinary catheter equipped with a radiofrequency-emitting antenna for HT (60 minutes) was placed. Experimental groups consisted of iv low or full dose (20 or 60 mg/m2) DPPG2-TSL-DOX with/without HT, iv low dose (20 mg/m2) free DOX with HT, and full dose (50 mg/50 mL) intravesical DOX with/without HT. After the procedure, animals were immediately sacrificed. HPLC was used to measure DOX levels in the bladder, essential organs and serum, and fluorescence microscopy to evaluate DOX distribution in the bladder wall.Results: Iv DPPG2-TSL-DOX with HT resulted in a significantly higher bladder wall DOX concentration which was more homogeneous distributed, than iv and intravesical free DOX administration with HT. Specifically in the detrusor, DPPG2-TSL-DOX with HT led to a > 7- and 44-fold higher DOX concentration, compared to iv free DOX with HT and intravesical DOX, respectively. Organ DOX concentrations were significantly lower in heart and kidneys, and similar in liver, spleen and lungs, following iv DPPG2-TSL-DOX with HT, compared to iv free DOX. Intravesical DOX led to the lowest organ DOX concentrations.Conclusion: Iv DPPG2-TSL-DOX combined with HT achieved higher DOX concentrations in the bladder wall including the detrusor, compared to conventional iv and intravesical DOX application. In combination with lower DOX accumulation in heart and kidneys, compared to iv free chemotherapy, DPPG2-TSL-DOX with HT has great potential to attain a role as a bladder-sparing treatment for MIBC.Keywords: MIBC, drug delivery system, therapy, chemotherapeutic, local release, porcine model