Abstract
Delivery of drugs and nanomedicines to tumors is often heterogeneous and insufficient and, thus, of limited efficacy. Microbubbles in combination with ultrasound have been found to improve delivery to tumors, enhancing accumulation and penetration. We used a subcutaneous prostate cancer xenograft model in mice to investigate the effect of free and nanoparticle-encapsulated cabazitaxel in combination with ultrasound and microbubbles with a lipid shell or a shell of nanoparticles. Sonopermeation reduced tumor growth and prolonged survival (26%–100%), whether the free drug was co-injected with lipid-shelled microbubbles or the nanoformulation was co-injected with lipid-shelled or nanoparticle-shelled microbubbles. Coherently with the improved therapeutic response, we found enhanced uptake of nanoparticles directly after ultrasound treatment that lasted several weeks (2.3 × –15.8 × increase). Neither cavitation dose nor total accumulation of nanoparticles could explain the variation within treatment groups, emphasizing the need for a better understanding of the tumor biology and mechanisms involved in ultrasound-mediated treatment.
Highlights
Chemotherapy, alone or in combination with other treatment modalities, is one of the most common treatments for cancer patients (Chabner and Roberts 2005; Miller et al 2019), but a lack of specificity combined with unfavorable pharmacokinetic properties limits the therapeutic benefit of the drugs
We have previously reported an in-house-made treatment platform consisting of protein MBs stabilized by polymeric NPs (NPMBs) containing the cytotoxic drug cabazitaxel and fluorescent dyes for imaging, coated with poly(ethylene glycol) (PEG) (Mørch et al 2015)
The size distributions of the NPMBs and SonoVue are illustrated in Figure 3, along with a scanning electron microscopy (SEM) image of the NPMBs and microscopy images of NPMBs and SonoVue
Summary
Chemotherapy, alone or in combination with other treatment modalities, is one of the most common treatments for cancer patients (Chabner and Roberts 2005; Miller et al 2019), but a lack of specificity combined with unfavorable pharmacokinetic properties limits the therapeutic benefit of the drugs. The local oscillation of MBs caused by ultrasound can result in several bio-effects that enhance the permeability of the target tissue, allowing enhanced accumulation and improved penetration of the therapeutic agent. These effects have been explored in multiple preclinical studies (Lentacker et al 2014; Liu et al 2014; Lammertink et al 2015; Boissenot et al 2016; Van Wamel et al.2016a, 2016b; Aslund et al 2017a; Snipstad et al 2017b; Lamsam et al 2018; Meng et al 2019) and in several published and ongoing clinical trials (ClinicalTrials.gov identifiers NCT04146441, NCT03458975, NCT03477019, NCT04021420, NCT03385200 and NCT04021277) (Kotopoulis et al 2013; Carpentier et al 2016; Dimcevski et al 2016; Wang et al 2018; Idbaih et al 2019; Mainprize et al 2019). Inclusion of NPs on the MB shell has been reported to make delivery of NPs more effective both in vivo (Burke et al 2011, 2014) and in vitro (De Cock et al 2016)
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