Targeted Imaging Agent to HSP70 Induced In Vivo.

Heat shock protein expression can be induced by heat shock making it possible to artificially modulate their levels noninvasively in vivo in a spatially and temporally controlled manner. Here, we report the use of the major heat shock protein 70 (HSP70) as an inducible target by using the small molecule deoxyspergualin (DSG) conjugated to the near-infrared fluorophore (Cy5.5).

Tumor ablation using low-intensity ultrasound and sound excitable drug.

The cell membrane is a semi-fluid container that defines the boundary of cells, and provides an enclosed environment for vital biological processes. A sound excitable drug (SED) that is non-cytotoxic to cells is developed to disrupt the plasma membrane under gentle ultrasound insonation, 1MHz, 1W/cm. The frequency and power density of insonation are within the physical therapy and medical imaging windows; thus the applied ultrasound is safe and not harmful to tissues.

Safety and efficacy of quadrapeutics versus chemoradiation in head and neck carcinoma xenograft model.

Chemoradiation is the strongest anti-tumor therapy but in resistant unresectable cancers it often lacks safety and efficacy. We compared our recently developed cell-level combination approach, quadrapeutics, to chemoradiation therapy to establish pre-clinical data for its biodistribution, safety and efficacy in head and neck squamous cell carcinoma (HNSCC), as a clinically challenging aggressive and resistant cancer. In vitro and in vivo models of four carcinomas were treated with standard chemoradiation and quadrapeutics using identical drug and radiation doses.

Intraoperative diagnostics and elimination of residual microtumours with plasmonic nanobubbles.

Failure of cancer surgery to intraoperatively detect and eliminate microscopic residual disease (MRD) causes lethal recurrence and metastases, and the removal of important normal tissues causes excessive morbidity. Here, we show that a plasmonic nanobubble (PNB), a non-stationary laser pulse-activated nanoevent, intraoperatively detects and eliminates MRD in the surgical bed. PNBs were generated in vivo in head and neck cancer cells by systemically targeting tumours with gold colloids and locally applying near-infrared, low-energy short laser pulses, and were simultaneously detected with an acoustic probe.

Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential.

Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors.

Polymeric micelles and nanoemulsions as tumor-targeted drug carriers: Insight through intravital imaging.

Intravital imaging of nanoparticle extravasation and tumor accumulation has revealed, for the first time, detailed features of carrier and drug behavior in circulation and tissue that suggest new directions for optimization of drug nanocarriers. Using intravital fluorescent microscopy, the extent of the extravasation, diffusion in the tissue, internalization by tissue cells, and uptake by the RES system were studied for polymeric micelles, nanoemulsions, and nanoemulsion-encapsulated drug. Discrimination of vascular and tissue compartments in the processes of micelle and nanodroplet extravasation and tissue accumulation was possible.

A naturally occurring single amino acid replacement in multiple gene regulator of group A Streptococcus significantly increases virulence.

Single-nucleotide polymorphisms (SNPs) are the most common source of genetic variation within a species; however, few investigations demonstrate how naturally occurring SNPs may increase strain virulence. We recently used group A Streptococcus as a model pathogen to study bacteria strain genotype-patient disease phenotype relationships. Whole-genome sequencing of approximately 800 serotype M59 group A Streptococcus strains, recovered during an outbreak of severe invasive infections across North America, identified a disproportionate number of SNPs in the gene encoding multiple gene regulator of group A Streptococcus (mga).

HSP70 promoter-driven activation of gene expression for immunotherapy using gold nanorods and near infrared light.

Modulation of the cytokine milieu is one approach for vaccine development. However, therapy with pro-inflammatory cytokines, such as IL-12, is limited in practice due to adverse systemic effects. Spatially-restricted gene expression circumvents this problem by enabling localized amplification.

Specific binding of modified ZD6474 (Vandetanib) monomer and its dimer with VEGF receptor-2.

Tumor angiogenesis is an important component of cancer biology driven in part by the hypothesis that tumor vessel growth is a necessary requirement for tumor growth. Angiogenesis does not only depend on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF).

Multivalency of non-peptide integrin αVβ3 antagonist slows tumor growth.

Multivalency is a powerful strategy for achieving high-affinity molecular binding of compounds to increase their therapeutic potency or imaging potential. In our study, multivalent non-peptide integrin αvβ3 antagonists (IA) were designed for antitumor therapy. Docking and molecular dynamics were employed to explore the binding modes of IA monomer, dimer, and trimer.

Efficient electroporation of liposomes doped with pore stabilizing nisin.

Context: Liposomes have a long history as passive and active drug carriers. Recently, a few methods have been realized to control the release from liposomes, including heating, ultrasound and laser.

Objective: We report on a new approach to drive release from liposomes using electric fields.

MRI-based prediction of pulsed high-intensity focused ultrasound effect on tissue transport in rabbit muscle.

Purpose: To design an algorithm for optimizing pulsed high intensity focused ultrasound (p-HIFU) treatment parameters to maximize tissue transport while minimizing thermal necrosis based on MR image guidance.

Materials And Methods: P-HIFU power, duty cycle, and treatment duration were varied to generate different levels of thermal and mechanical deposition in rabbit muscle. Changes in T2-weighted and T1 contrast-enhanced (CE) signal were assessed immediately following treatment and at 24 h.

Estimation of thermal dose from MR thermometry during application of nonablative pulsed high intensity focused ultrasound.

Purpose: To evaluate whether MR thermometry is sufficiently fast, accurate, and spatially resolved for monitoring the thermal safety of nonablative pulsed high intensity ultrasound (pHIFU) treatments.

Materials And Methods: A combination of real MR thermometry data and modeling was used to analyze the effects of temporal and spatial averaging as well as noise on the peak temperatures and thermal doses that would be measured by MR thermometry.

Results: MR thermometry systematically underestimates the temperature and thermal doses during pHIFU treatment.

Phase-shift, stimuli-responsive drug carriers for targeted delivery.

The intersection of particles and directed energy is a rich source of novel and useful technology that is only recently being realized for medicine. One of the most promising applications is directed drug delivery. This review focuses on phase-shift nanoparticles (that is, particles of submicron size) as well as micron-scale particles whose action depends on an external-energy triggered, first-order phase shift from a liquid to gas state of either the particle itself or of the surrounding medium.

Partially polymerized liposomes: stable against leakage yet capable of instantaneous release for remote controlled drug delivery.

A critical issue for current liposomal carriers in clinical applications is their leakage of the encapsulated drugs that are cytotoxic to non-target tissues. We have developed partially polymerized liposomes composed of polydiacetylene lipids and saturated lipids. Cross-linking of the diacetylene lipids prevents the drug leakage even at 40 °C for days.

Pulsed high intensity focused ultrasound mediated nanoparticle delivery: mechanisms and efficacy in murine muscle.

High intensity focused ultrasound (HIFU) is generally thought to interact with biological tissues in two ways: hyperthermia (heat) and acoustic cavitation. Pulsed mode HIFU has recently been demonstrated to increase the efficacy of a variety of drug therapies. Generally, it is presumed that the treatment acts to temporarily increase the permeability of the tissue to the therapeutic agent, however, the precise mechanism remains in dispute.

Augmentation of targeted delivery with pulsed high intensity focused ultrasound.

This paper reviews the enhanced delivery of genes, drugs and therapeutics using ultrasound. It begins with a general overview of the field and the various techniques associated with it, including sonophoresis, hyperthermia (with ultrasound), sonoporation, and microbubble assisted transvascular and targeted delivery. Particular attention is then paid to pulsed high intensity focused ultrasound drug delivery without the use of ultrasound contrast agents.

Application of a nonlinear boundary condition model to adhesion interphase damage and failure.

In an earlier paper [J. Sadler, B. O'Neill, and R.