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 (DPPG 2 -TSL) might prevent surgical bladder removal and toxicity from systemic chemotherapy. We aimed to assess the efficacy of DPPG 2 -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) DPPG 2 -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 DPPG 2 -TSL-DOX þ HT resulted in a favorable rate of animals with complete tumor response (70%), compared to iv free DOX (18%, p ¼ .02), no treatment (0%, p ¼ .001), and intravesical DOX with (43%, p ¼ .35) or without HT (50%, p ¼ .41). All rats receiving intravesical DOX with HT and 24% of rats treated with DPPG 2 -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 DPPG 2 -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.

Recent Preclinical and Clinical Progress in Liposomal Doxorubicin

“…On the other hand, lower DOX accumulation was detected in the heart and kidney of (DPPG-TSLDOX + HT)-treated pigs [ 132 ]. Consistent with this finding, rats treated with DPPG-TSLDOX + HT demonstrated higher complete tumor response than free DOX-treated rats (70% vs. 18%) [ 133 ].…”

“…DPPG-TSLDOX was investigated as a treatment for muscle-invasive bladder cancer in rats and pigs [ 132 , 133 ]. Valenberg et al evaluated DOX accumulation in the bladder wall of pigs treated with 20 mg/kg and 60 mg/kg of DPPG-TSLDOX and free DOX.…”

Liposomal Drug Delivery Systems for Cancer Therapy: The Rotterdam Experience

“…A great leap in the application of TSL happened when ultra-fast releasing PEGylated TSL containing lysolipid (LTSL) was invented [ 27 , 111 , 121 , 123 , 124 ] and the concept of intravascular drug release was introduced. Later, the group of Lars Lindner developed another ultrafast-releasing TSL, with a release rate comparable to LTSL at a mild HT of 42 °C, by addition of 1.2-dipalmitoyl-sn-glycero-3- phosphoglyceroglycerol (DPPGOG or DPPG2, T c 39.7 °C), a derivative of the naturally occurring DPPG, into TSL composed of DPPC:DSPC [ 125 , 126 ], and which is now ready for clinical trial investigations under the commercial name of Thermosome ® ( , accessed on 23 October 2010) [ 127 ].…”