Sonoporation enhances liposome accumulation and penetration in tumors with low EPR

Abstract

The Enhanced Permeability and Retention (EPR) effect is a highly variable phenomenon. To enhance EPR-mediated passive drug targeting to tumors, several different pharmacological and physical strategies have been evaluated over the years, including e.g. TNFα-treatment, vascular normalization, hyperthermia and radiotherapy. Here, we systematically investigated the impact of sonoporation, i.e. the combination of ultrasound (US) and microbubbles (MB), on the tumor accumulation and penetration of liposomes. Two different MB formulations were employed, and their ability to enhance liposome accumulation and penetration was evaluated in two different tumor models, which are both characterized by relatively low levels of EPR (i.e. highly cellular A431 epidermoid xenografts and highly stromal BxPC-3 pancreatic carcinoma xenografts). The liposomes were labeled with two different fluorophores, enabling in vivo computed tomography/fluorescence molecular tomography (CT-FMT) and ex vivo two-photon laser scanning microscopy (TPLSM). In both models, in spite of relatively high inter- and intra-individual variability, a trend towards improved liposome accumulation and penetration was observed. In treated tumors, liposome concentrations were up to twice as high as in untreated tumors, and sonoporation enhanced the ability of liposomes to extravasate out of the blood vessels into the tumor interstitium. These findings indicate that sonoporation may be a useful strategy for improving drug targeting to tumors with low EPR.

Retracted: Ultrasound‐triggered breast tumor sonodynamic therapy through hematoporphyrin monomethyl ether‐loaded liposome

“…As a drug delivery system, liposomes consist of an aqueous center for incorporation of hydrophilic molecules and exhibit some advantages including biocompatibility, capacity for self‐assembly, ability to carry large drug payloads (Sercombe et al, ). Consistent with our findings, liposomes as carrier for antitumor agent show accumulation at tumor site at high levels (Kang et al, ; Theek et al, ). Intriguingly, lungs showed significant uptake for free HMME but did not trap liposomes inside, indicating the low side effects of liposomal HMME for SDT.…”

Sequential HIFU heating and nanobubble encapsulation provide efficient drug penetration from stealth and temperature sensitive liposomes in colon cancer

“…5). Recently, Deese et al reported that sonoporation using MBs enhanced the extravasation and penetration of relatively large liposomal nanocarriers out of the blood vessels into the tumor interstitium by a variety of mechanisms, including perfusion modulation, mechanical disruption, and pore formation in tumor vessels [30]. Whether a similar mechanisms drive drug delivery and uptake in presence in presence of nanobubbles is currently not known.…”

Status and trends in the development of clinical diagnostic agents

“…Sonoporation, the temporary formation of pores in the cell membrane by a combination of MB and US or focused US (FUS), has been shown to enhance drug delivery . MB can be modified for this purpose, e.g., by loading them with drugs or therapeutic DNA, binding targeting ligands onto their surface, or refining their size, shell thickness, and circulation time .…”