Abstract
Ultrasound (US) in combination with microbubbles (MB) has had promising results in improving delivery of chemotherapeutic agents. However, most studies are done in immunodeficient mice with xenografted tumors. We used two phenotypes of the spontaneous transgenic adenocarcinoma of the mouse prostate (TRAMP) model to evaluate if US + MB could enhance the therapeutic efficacy of cabazitaxel (Cab). Cab was either injected intravenously as free drug or encapsulated into nanoparticles. In both cases, Cab transiently reduced tumor and prostate volume in the TRAMP model. No additional therapeutic efficacy was observed combining Cab with US + MB, except for one tumor. Additionally, histology grading and immunostaining of Ki67 did not reveal differences between treatment groups. Mass spectrometry revealed that nanoparticle encapsulation of Cab increased the circulation time and enhanced the accumulation in liver and spleen compared with free Cab. The therapeutic results in this spontaneous, clinically relevant tumor model differ from the improved therapeutic response observed in xenografts combining US + MB and chemotherapy.
Highlights
Prostate cancer is the third most deadly cancer among men in the European Union, with an estimated 107,300 deaths in 2018 (Ferlay et al 2018)
We investigated if NP encapsulation and US + MB could enhance the therapeutic efficacy of cabazitaxel (Cab) in two phenotypes of the TRAMP model
Eighty-two TRAMP mice were screened for poorly differentiated (PD) tumors, and 16 tumors were detected in the age range 17À25 wk
Summary
Prostate cancer is the third most deadly cancer among men in the European Union, with an estimated 107,300 deaths in 2018 (Ferlay et al 2018). More efficient therapies are needed to improve prostate cancer survival. Nanoparticles (NP) and ultrasound combined with microbubbles (US + MB) are promising methods to increase the delivery and efficacy of chemotherapeutic drugs. Through encapsulation of drugs in NP, the pharmacokinetic properties can be altered to improve efficacy and reduce adverse effects (Peer et al 2007). NP have had promising results in pre-clinical studies (Fusser et al 2019), and the improvement to treatment response has been attributed to the enhanced permeability and retention effect (EPR effect), where NP target tumors because of leaky tumor capillaries and are retained.
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