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Vaccinia virus (VV) is a powerful tool for cancer treatment with the potential for tumor tropism, efficient cell-to-cell spread, rapid replication in cancer cells, and stimulation of anti-tumor immunity. It has a well-defined safety profile and is being assessed in late-stage clinical trials. However, VV clinical utility is limited by rapid bloodstream neutralization and poor penetration into tumors. These factors have often restricted its route of delivery to intratumoral or intrahepatic artery injection and may impede repeat dosing. Chemical stealthing improves the pharmacokinetics of non-enveloped viruses, but it has not yet been applied to enveloped viruses such as VV. In the present study, amphiphilic polymer was used to coat VV, leading to reduced binding of a neutralizing anti-VV antibody (81.8% of polymer-coated VV [PCVV] staining positive versus 97.1% of VV [p = 0.0038]). Attachment of anti-mucin-1 (aMUC1) targeting antibody, to give aMUC1-PCVV, enabled binding of the construct to MUC1. In high MUC1 expressing CAPAN-2 cells, infection with PCVV was reduced compared to VV, while infection was restored with aMUC1-PCVV. Pharmacokinetics of aMUC1-PCVV, PCVV, and VV were evaluated. After intravenous (i.v.) injection of 1 × 108 viral genomes (VG) or 5 × 108 VG, circulation time for PCVV and aMUC1-PCVV was increased, with ~5-fold higher circulating dose at 5 min versus VV., Graphical abstract, Oncolytic viruses, such as vaccinia virus, could be even more effective at attacking solid tumors in patients if they could be administered via the bloodstream without being neutralized by blood components. These studies show that adding a protective coat to vaccinia virus improves its stability in blood.

Aims: Testing ultrasound-mediated cavitation for enhanced delivery of the therapeutic antibody cetuximab to tumors in a mouse model. Methods: Tumors with strong EGF receptor expression were grown bilaterally. Cetuximab was coadministered intravenously with cavitation nuclei, consisting of either the ultrasound contrast agent Sonovue or gas-stabilizing nanoscale SonoTran Particles. One of the two tumors was exposed to focused ultrasound. Passive acoustic mapping localized and monitored cavitation activity. Both tumors were then excised and cetuximab concentration was quantified. Results: Cavitation increased tumoral cetuximab concentration. When nucleated by Sonovue, a 2.1-fold increase (95% CI 1.3- to 3.4-fold) was measured, whereas SonoTran Particles gave a 3.6-fold increase (95% CI 2.3- to 5.8-fold). Conclusions: Ultrasound-mediated cavitation, especially when nucleated by nanoscale gas-entrapping particles, can noninvasively increase site-specific delivery of therapeutic antibodies to solid tumors.

Introduction: The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities. Areas covered: This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by ‘passively’ and ‘actively’ targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of ‘biologics’, antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated. Expert opinion: Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.

The treatment of cancer using nanomedicines is limited by the poor penetration of these potentially powerful agents into and throughout solid tumors. Externally controlled mechanical stimuli, such as the generation of cavitation-induced microstreaming using ultrasound (US), can provide a means of improving nanomedicine delivery. Notably, it has been demonstrated that by focusing, monitoring and controlling the US exposure, delivery can be achieved without damage to surrounding tissue or vasculature. However, there is a risk that such stimuli may disrupt the structure and thereby diminish the activity of the delivered drugs, especially complex antibody and viral-based nanomedicines. In this study, we characterize the impact of cavitation on four different agents, doxorubicin (Dox), cetuximab, adenovirus (Ad) and vaccinia virus (VV), representing a scale of sophistication from a simple small-molecule drug to complex biological agents. To achieve tight regulation of the level and duration of cavitation exposure, a “cavitation test rig” was designed and built. The activity of each agent was assessed with and without exposure to a defined cavitation regime which has previously been shown to provide effective and safe delivery of agents to tumors in preclinical studies. The fluorescence profile of Dox remained unchanged after exposure to cavitation, and the efficacy of this drug in killing a cancer cell line remained the same. Similarly, the ability of cetuximab to bind its epidermal growth factor receptor target was not diminished following exposure to cavitation. The encoding of the reporter gene luciferase within the Ad and VV constructs tested here allowed the infectivity of these viruses to be easily quantified. Exposure to cavitation did not impact on the activity of either virus. These data provide compelling evidence that the US parameters used to safely and successfully delivery nanomedicines to tumors in preclinical models do not detrimentally impact on the structure or activity of these nanomedicines.

New strategies are required to enhance the penetration and tumor-wide distribution of cancer therapeutics, including viruses, antibodies, and oligonucleotides. We have shown previously that increasing the density of a nanoparticle can enhance its ultrasound-mediated transport, particularly when exposed to microstreaming. The current study investigates how the physical characteristics and dynamics of different cavitation nucleation agents affect the cavitation-mediated transport of therapeutics not directly bound to the gas nuclei. SonoVue (Bracco, Milan, Italy) microbubble contrast agent (with 3 μm mean initial bubble diameter) and polymeric gas-entrapping nanoparticles (with 260 nm mean initial bubble diameter) were first compared in terms of inertial cavitation threshold and cavitation persistence. Under the same ultrasound exposure conditions (centre frequencies of either 0.5 MHz or 1.6 MHz, and peak negative pressures from 0.2 MPa to 3.5 MPa) their respective cavitation emissions were found to differ ...

Sub-micron cavitation nuclei with the ability to passively extravasate through the leaky tumor vasculature have been shown to enhance both extravasation and penetration of pharmaceuticals in tumors. The aim of the present work is to optimize the acoustic parameters and maximize drug delivery mediated by cavitational microstreaming. Either lipid-shell microbubbles, or gas-stabilizing polymeric submicron cups of mean diameter 480 nm are co-administered with a model drug through a flow channel formed in agarose gel. The effect of ultrasound frequency, pressure amplitude, pulse duration, duty cycle, and pulse repetition frequency on the delivery of the drug is first evaluated, using both a single-layer and a dual-layer flow phantom that better represents the leaky tumor vasculature and dense extracellular matrix. The optimal parameters at 0.5 MHz and 1.6 MHz are then selected and used to deliver an oncolytic virus, genetically modified to express the RFP reporter gene, thus allowing the quantification of the ...

For effective cancer therapy, therapeutic agents must extravasate from the blood stream into the tumour mass, then overcome the elevated intratumoural pressure and dense extracellular matrix to reach each and every cancer cell. Several recent studies have suggested that inertial cavitation in the absence or presence of artificial cavitation nuclei can significantly enhance the delivery, penetration, and distribution of small-molecule or nanoparticulate therapeutic agents into tumors. We first present a comparison of the reported enhancements in delivery achieved for a range of frequencies and therapeutic sizes without or with pre-seeding of cavitation, with particular emphasis on the potential role of cavitation persistence and spatial distribution. With microstreaming hypothesized to be the dominant transport mechanism for drug delivery, the likely benefit of using sub-micron cavitation nucleation agents capable of extravasating alongside the therapeutic, rather than microbubbles confined to the blood po...