DPPG₂-based thermosensitive liposomes as drug delivery system for effective muscle-invasive bladder cancer treatment in vivo

Abstract

Purpose

Recommended treatments for muscle-invasive bladder cancer (MIBC) come with considerable morbidity. Hyperthermia (HT) triggered drug release from phosphatidylglycerol-based thermosensitive liposomes (DPPG₂-TSL) might prevent surgical bladder removal and toxicity from systemic chemotherapy. We aimed to assess the efficacy of DPPG₂-TSL with HT in a syngeneic orthotopic rat urothelial carcinoma model.

Methods

A total of 191 female Fischer F344 rats were used. Bladder tumors were initiated by inoculation of AY-27 cells and tumor-bearing rats were selected with cystoscopy and semi-randomized over treatment groups. On days 5 and 8, animals were treated with DOX in different treatment modalities: intravenous (iv) DPPG₂-TSL-DOX with HT, iv free DOX without HT, intravesical DOX without HT, intravesical DOX with HT or no treatment (control group), respectively. Animals were euthanized on day 14 and complete tumor response was assessed by histopathological evaluation.

Results

Iv DPPG₂-TSL-DOX + HT resulted in a favorable rate of animals with complete tumor response (70%), compared to iv free DOX (18%, p = .02), no treatment (0%, p = .001), and intravesical DOX with (43%, p = .35) or without HT (50%, p = .41). All rats receiving intravesical DOX with HT and 24% of rats treated with DPPG₂-TSL-DOX containing the same DOX dose with HT had to be euthanized before day 14 because of substantial bodyweight loss, which was associated with dilated ureters urine retention in a few rats.

Conclusion

Treatment with DPPG₂-TSL-DOX combined with intravesical HT outperformed systemic and intravesical DOX in vivo. There might be a role for DPPG_2-TSL encapsulating chemotherapeutics in the treatment of MIBC in the future.

Keywords:

• Muscle invasive bladder cancer
• treatment
• drug delivery system
• liposomes
• phosphatidylglycerol
• chemotherapeutic

Acknowledgments

We would like to thank Bianca Lemmers-van de Weem, Kitty Lemmens-Hermans, Karin Haas-Cremers and Irith Bergsma for their support during the experiment implementation, and Mirjam de Weijert and Kees Jansen for the biotechnical support. We would also like to thank Gerard van Ooijen for technical support with the thermocouples, Steven Teerenstra for the statistical support, and Pascal Schweizer for the warm contact with Thermosome GmbH.

Ethics approval

The authors state that they have obtained approval of the study design and animal procedures by the national Central Animal Experiments Committee (CCD) and the local Animal Welfare Body (IvD) under the number 2019-0007. Animal procedures were in compliance with the European Union Directive 2010/63/EU and the Declaration of Helsinki.

Disclosure statement

LHL and MH hold shares in Thermosome GmbH. The other authors have no relevant financial or non-financial interests to disclose.

Author contributions

ISGB: Conceptualization, Methodology, Formal analysis, Investigation, Writing Original Draft. MS: Methodology, Investigation, Writing – Review & Editing. LHL: Conceptualization, Writing – Review & Editing. SK: Conceptualization, Methodology, Investigation, Writing – Review & Editing. SdJ: Methodology, Investigation, Writing – Review & Editing. MH: Conceptualization, Writing – Review & Editing. JAW: Supervision, Conceptualization, Methodology, Writing – Review & Editing. EO: Supervision, Conceptualization, Methodology, Writing – Review & Editing.

Data availability statement

Protocols and data are available at the request of the authors.

Additional information

Funding

Partial financial support was received from Thermosome.