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

Iris S G Brummelhuis,Michiel Simons,Lars H Lindner,Simone Kort,Sytse De Jong,Martin Hossann,J Alfred Witjes,Egbert Oosterwijk

doi:10.1080/02656736.2021.1983038

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 DPPG2-TSL encapsulating chemotherapeutics in the treatment of MIBC in the future.

Highlights

Bladder cancer is the fifth most commonly diagnosed cancer in the United States and Europe and represents substantial health, economic and social burden [1]
Experimental heating protocol Sixty minutes of hyperthermia was achieved by conductive heat exchange, by circulating water for injection or DOX solution from a warm water bath in the bladder
We show that treatment with DPPG2-Thermosensitive liposomes (TSL)-DOX with HT resulted in the highest number of animals with complete tumor response (70%), which was significantly better than iv free DOX (18%, p 1⁄4 .02) and no treatment (0%, p 1⁄4 .001), and moderately better than intravesical DOX with or without HT (43% vs. 50%, respectively, not significant)

Summary

Introduction

Bladder cancer is the fifth most commonly diagnosed cancer in the United States and Europe and represents substantial health, economic and social burden [1]. Patients with advanced age (representing the majority of the MIBC population) are frequently medically unfit or unwilling to undergo RC, causing a risk of undertreatment [7]. This key issue in MIBC management highlights the need for bladder-sparing treatments. ‘Multimodality treatment’ (MMT) involves a transurethral resection of the bladder tumor and subsequent intravenous (iv) chemotherapy with radiotherapy but is associated with grade 3 and 4 adverse events in 36% of patients [8]. To improve bladder-sparing treatment of MIBC, prevention of systemic toxicity is imperative. Liposome-based chemotherapeutic drug delivery systems which are currently in clinical use have shown a favorable toxicity profile compared to conventional chemotherapy (with unencapsulated drug), but a similar therapeutic effect.

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Conclusion