Nanotechnology-augmented sonodynamic therapy and associated immune-mediated effects for the treatment of pancreatic ductal adenocarcinoma.

Purpose: Sonodynamic therapy (SDT) is emerging as a cancer treatment alternative with significant advantages over conventional therapies, including its minimally invasive and site-specific nature, its radical antitumour efficacy with minimal side effects, and its capacity to raise an antitumour immune response. The study explores the efficacy of SDT in combination with nanotechnology against pancreatic ductal adenocarcinoma.

Methods: A nanoparticulate formulation (HPNP) based on a cathepsin B-degradable glutamate-tyrosine co-polymer that carries hematoporphyrin was used in this study for the SDT-based treatment of PDAC.

Exploiting a Rose Bengal-bearing, oxygen-producing nanoparticle for SDT and associated immune-mediated therapeutic effects in the treatment of pancreatic cancer.

Sonodynamic therapy (SDT) is an emerging stimulus-responsive approach for the targeted treatment of solid tumours. However, its ability to generate stimulus-responsive cytotoxic reactive oxygen species (ROS), is compromised by tumour hypoxia. Here we describe a robust means of preparing a pH-sensitive polymethacrylate-coated CaO nanoparticle that is capable of transiently alleviating tumour hypoxia.

Investigating the performance of a novel pH and cathepsin B sensitive, stimulus-responsive nanoparticle for optimised sonodynamic therapy in prostate cancer.

Nano-formulations that are responsive to tumour-related and externally-applied stimuli can offer improved, site-specific antitumor effects, and can improve the efficacy of conventional therapeutic agents. Here, we describe the performance of a novel stimulus-responsive nanoparticulate platform for the targeted treatment of prostate cancer using sonodynamic therapy (SDT). The nanoparticles were prepared by self-assembly of poly(L-glutamic acid-L-tyrosine) co-polymer with hematoporphyrin.

Targeted chemo-sonodynamic therapy treatment of breast tumours using ultrasound responsive microbubbles loaded with paclitaxel, doxorubicin and Rose Bengal.

Mastectomy is a common surgical treatment used in the management of breast cancer but has associated physical and psychological consequences for the patient. Breast conservation surgery (BCS) is an alternative to mastectomy but is only possible when the tumour is of an appropriate size. Neo-adjuvant chemotherapy has been successfully used to downstage tumours and increase the number of patients eligible for BCS.

Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer.

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.

Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target-specific cancer therapy.

Stimuli-responsive anticancer formulations can promote drug release and activation within the target tumour, facilitate cellular uptake, as well as improve the therapeutic efficacy of drugs and reduce off-target effects. In the present work, indocyanine green (ICG)-containing polyglutamate (PGA) nanoparticles were developed and characterized. Digestion of nanoparticles with cathepsin B, a matrix metalloproteinase overexpressed in the microenvironment of advanced tumours, decreased particle size and increased ICG cellular uptake.

Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle.

In this manuscript we describe the preparation of an oxygen-loaded microbubble (O2MB) platform for the targeted treatment of pancreatic cancer using both sonodynamic therapy (SDT) and antimetabolite therapy. O2MB were prepared with either the sensitiser Rose Bengal (O2MB-RB) or the antimetabolite 5-fluorouracil (O2MB-5FU) attached to the microbubble (MB) surface. The MB were characterised with respect to size, physical stability and oxygen retention.

Sonodynamic Therapy: Concept, Mechanism and Application to Cancer Treatment.

Sonodynamic therapy (SDT) represents an emerging approach that offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. It involves the sensitization of target tissues with a non-toxic sensitizing chemical agent and subsequent exposure of the sensitized tissues to relatively low-intensity ultrasound. Essentially, both aspects (the sensitization and ultrasound exposure) are harmless, and cytotoxic events occur when both are combined.

Oxygen carrying microbubbles for enhanced sonodynamic therapy of hypoxic tumours.

Tumour hypoxia represents a major challenge in the effective treatment of solid cancerous tumours using conventional approaches. As oxygen is a key substrate for Photo-/Sono-dynamic Therapy (PDT/SDT), hypoxia is also problematic for the treatment of solid tumours using these techniques. The ability to deliver oxygen to the vicinity of the tumour increases its local partial pressure improving the possibility of ROS generation in PDT/SDT.

Treating cancer with sonodynamic therapy: a review.

Sonodynamic therapy (SDT) has emerged as a promising option for the minimally invasive treatment of solid cancerous tumours. SDT requires the combination of three distinct components: a sensitising drug, ultrasound, and molecular oxygen. Individually, these components are non-toxic but when combined together generate cytotoxic reactive oxygen species (ROS).

Polymeric microbubbles as delivery vehicles for sensitizers in sonodynamic therapy.

Microbubbles (MBs) have recently emerged as promising delivery vehicles for sensitizer drugs in sonodynamic therapy (SDT). The ability to selectively destroy the MB and activate the sensitizer using an external ultrasound trigger could provide a minimally invasive and highly targeted therapy. While lipid MBs have been approved for use as contrast agents in diagnostic ultrasound, the attachment of sensitizer drugs to their surface results in a significant reduction in particle stability.

Sonoporation increases therapeutic efficacy of inducible and constitutive BMP2/7 in vivo gene delivery.

An ideal novel treatment for bone defects should provide regeneration without autologous or allogenous grafting, exogenous cells, growth factors, or biomaterials while ensuring spatial and temporal control as well as safety. Therefore, a novel osteoinductive nonviral in vivo gene therapy approach using sonoporation was investigated in ectopic and orthotopic models. Constitutive or regulated, doxycycline-inducible, bone morphogenetic protein 2 and 7 coexpression plasmids were repeatedly applied for 5 days.

Extending the tissue penetration capability of conventional photosensitisers: a carbon quantum dot-protoporphyrin IX conjugate for use in two-photon excited photodynamic therapy.

A carbon quantum dot (CQD)-protoporphyrin (IX) sensitisier conjugate was designed to exploit the large two-photon absorption cross section of CQDs and enable the indirect excitation of the sensitiser with 800 nm irradiation via FRET.

Ultrasound-mediated gene transfer (sonoporation) in fibrin-based matrices: potential for use in tissue regeneration.

It has been suggested that gene transfer into donor cells is an efficient and practical means of locally supplying requisite growth factors for applications in tissue regeneration. Here we describe, for the first time, an ultrasound-mediated system that can non-invasively facilitate gene transfer into cells entrapped within fibrin-based matrices. Since ultrasound-mediated gene transfer is enhanced using microbubbles, we compared the efficacy of neutral and cationic forms of these reagents on the ultrasound-stimulated gene transfer process in gel matrices.

The effects of microencapsulated Lactobacillus casei on tumour cell growth: In vitro and in vivo studies.

It has been known for some time that the micro-milieu of solid tumours provides an ideal environment for growth of facultative and strictly anaerobic bacteria, and it has been shown that certain species including Lactobacillus and Clostridium can colonise those environments leading to regression of tumour growth. Such observations have given rise to the concept of bacteriolytic therapy where live microorganisms might be employed to colonise the tumour and exert a tumorolytic effect. In choosing such an approach, it would be advantageous to exploit a relatively non-pathogenic strain and provide some form of containment that would enable site-specific injection and minimise dispersion of the microorganism throughout the host.

Microbubble-sonosensitiser conjugates as therapeutics in sonodynamic therapy.

A Rose Bengal sonosensitiser has been covalently attached to a lipid microbubble and the resulting conjugate shown to produce higher levels of singlet oxygen, enhanced cytotoxicity in a cancer cell line and a greater reduction in tumour growth than the sonosensitiser alone.

The effects of ultrasound and light on indocyanine-green-treated tumour cells and tissues.

Photodynamic therapy (PDT) is emerging as a treatment modality for the management of neoplastic disease. Despite considerable clinical success, its application for the treatment of deep-seated lesions is constrained by the inability of visible light to penetrate deeply into tissues. An emerging alternative approach exploits the fact that many photosensitisers respond to ultrasound, eliciting cytotoxic effects on target cells and tissues; this has become known as sonodynamic therapy (SDT).

Microbubble-enhanced ultrasound-mediated gene transfer--towards the development of targeted gene therapy for cancer.

Ultrasound-mediated gene transfer is emerging as a possible alternative to viral gene transfer, and pre-clinical data suggest that it may play a significant role in gene therapy-based approaches to the treatment of disease. As an extracorporeal stimulus, ultrasound can non-invasively and transiently compromise cell membrane permeability (sonoporation), thereby offering the promise of delivering either genes or oligonucleotide-based therapeutics to cells and tissues in a site-specific manner. The membrane-permeabilising effects of ultrasound can be greatly enhanced using microbubble preparations, many of which have, in the past, found application as ultrasound contrast agents.

Studies on neutral, cationic and biotinylated cationic microbubbles in enhancing ultrasound-mediated gene delivery in vitro and in vivo.

Ultrasound-mediated gene transfer is emerging as a practical means of facilitating targeted gene expression and is significantly enhanced in the presence of exogenously added microbubbles. This study explores the influence of microbubble surface modifications on their interaction with plasmid DNA and target cells, and the functional consequences of those interactions in terms of ultrasound-mediated gene transfer. Polyethylene glycol-stabilized, lipid-shelled microbubbles with neutral (SDM201), cationic (SDM202) and biotinylated cationic (SDM302) surfaces were compared in terms of their abilities to interact with a luciferase-encoding reporter plasmid DNA and with target cells in vitro.

Enhanced ROS production and cell death through combined photo- and sono-activation of conventional photosensitising drugs.

A combination of light and ultrasound activation of two conventional photosensitising drugs, methylene blue and rose bengal, was shown to generate higher levels of reactive oxygen species (ROS) and lower LD50 values than either light or ultrasound activation alone.

Exploiting ultrasound-mediated effects in delivering targeted, site-specific cancer therapy.

Although the concept of employing ultrasound for the treatment of cancer is not a new one, virtually all existing ultrasound-based clinical cancer treatments are based on hyperthermic ablation. This review seeks to highlight the potential offered by more subtle ultrasound-triggered phenomena such as sonoporation in delivering novel targeted cancer treatment modalities.

Ultrasound-enhanced drug dispersion through solid tumours and its possible role in aiding ultrasound-targeted cancer chemotherapy.

It has been demonstrated that inadequate dispersion of cancer chemotherapeutic drugs throughout the tissues of larger, relatively poorly vascularised tumours compromises the therapeutic effectiveness of such drugs. Recently we demonstrated that electric fields could be exploited to achieve dispersion of a cancer chemotherapeutic drug through relatively impermeable tissues of a poorly vascularised solid tumour model. Using a modified Sonidel SP100 sonoporator we demonstrate that ultrasound may enhance the toxicity of a cancer chemotherapeutic drug by dispersing the drug through relatively impermeable tissues of a non-vascularised tumour model in vivo.

Electrokinetic dispersion of a cancer chemotherapeutic drug for the treatment of solid tumours.

Compromised tumour vascularisation presents a significant challenge to chemotherapeutic-based treatment of solid tumours. In this study we use subtle electric field characteristics to facilitate electrokinetic movement of a cancer chemotherapeutic agent in an ionically complex environment. We demonstrate that such an approach can be exploited to facilitate the electrokinetic movement of camptothecin from a peritumoural site through otherwise relatively impermeable tumour tissues.