Ultrasound contrast agent microbubbles with ultrahigh loading capacity of camptothecin and floxuridine for enhancing tumor accumulation and combined chemotherapeutic efficacy

Abstract

In addition to the well-known use of microbubbles (MBs) as powerful contrast agents for general tissue delineation and perfusion in ultrasound (US) imaging, US-targeted MB destruction (UTMD) has been demonstrated to be an emerging technique for noninvasive drug delivery to tumor sites. However, the very limited drug-loading capacity of conventional MBs remains a great obstacle to their application as an efficacious cancer therapy. In this study, an amphiphilic Janus camptothecin-floxuridine (CF) conjugate was synthesized to engineer CF MBs with ultrahigh drugloading contents (up to 56.7 ± 2.3%). CF MBs were proven to be an excellent contrast agent to enhance US imaging for identifying the location and size of tumors. Upon local US exposure to burst CF MBs under the guidance of contrast-enhanced US imaging, successful conversion of CF MBs into CF NPs in situ resulted in~14 times higher drug accumulation of the CF conjugate via the sonoporation effect than that of CF NPs and CF MBs without US. After CF was internalized by tumor cells and its ester bond was hydrolyzed, camptothecin (CPT) and floxuridine (FUDR) were released at an exact 1:1 ratio to achieve coordinated pharmacokinetics, leading to significantly higher tumor growth inhibition in murine tumor models of CF MBs combined with US (~72.4%) than CF NPs (~54.1%) and liposomes loaded with CPT and FUDR (~21.6%). Overall, these results demonstrate that the combination of CF MBs with US is a powerful strategy for remarkably enhancing the combined chemotherapeutic efficacy and greatly reducing the undesirable side effects.

Nanoplatforms for Targeted Stimuli-Responsive Drug Delivery: A Review of Platform Materials and Stimuli-Responsive Release and Targeting Mechanisms

“…The PFC gas enabled the deep penetration of nanocarrier fragments and PTX release. PFC and extraneous stimuli-induced size change was also used in Liang et al [ 788 ]. They conjugated the hydrophobic drug camptothecin and hydrophilic floxuridine and fabricated a micelle from the resulting amphiphile.…”

Ultrasound‐mediated therapies for the treatment of biofilms in chronic wounds: a review of present knowledge

“…The use of electrostatic force to bond drugs to the MB surface (Rychak and Klibanov, 2014), insertion into the MB shell (Lentacker et al, 2009), loading the drug into the gaseous void and placing a layer of oil at the interface between the gaseous core and MB shell (Tinkov et al, 2009) are all considered low-capacity methods of drug loading (Sirsi and Borden, 2009). To yield a greater MB drug loading capacity, it is common for nanoparticles or liposomes to be conjugated to MBs covalently or with the use of biotin-avidin bridges (Lentacker et al, 2010;Liang et al, 2018). However, methods of achieving a greater drug loading capacity also directly impact upon the stability and acoustic properties of the MB, due to their altered shell thickness and composition (Tzu-Yin et al, 2013;Kooiman et al, 2014).…”

Lytic Release of Cellular ATP: Physiological Relevance and Therapeutic Applications

“…However, the systemic administration of these powerful inhibitors can lead to harsh side effects [ 51 ], which could be alleviated by a local potentiation of these active compounds. Interestingly, ultrasound (US)-targeted microbubble (MB) cavitation (UTMC) offers an externally triggered, spatially controlled and image-guided approach that is promising for local drug release [ 52 , 53 ] and for improving antibody extravasation and efficacy [ 54 , 55 , 56 , 57 ]. However, these exciting results overshadow the fact that the biological effects and signalling pathways stimulated by MB–cell interactions are still poorly understood.…”