Difference-Frequency Ultrasound Imaging With Non-Linear Contrast.

Conventional ultrasound imaging is based on the scattering of sound from inhomogeneities in the density and the speed of sound and is often used in medicine to resolve pathologic compared to normal tissue. Here we demonstrate a difference-frequency ultrasound (dfUS) imaging method that is based on the interaction of two sound pulses that propagate non-collinearly and intersect in space and time. The dfUS signal arises primarily from the second-order non-linear coefficient, a contrast mechanism that differs from linear and harmonic US imaging.

Molecular Weight-Dependent Activity of Aminated Poly(α)glutamates as siRNA Nanocarriers.

RNA interference (RNAi) can contribute immensely to the area of personalized medicine by its ability to target any gene of interest. Nevertheless, its clinical use is limited by lack of efficient delivery systems. Polymer therapeutics can address many of the challenges encountered by the systemic delivery of RNAi, but suffer from inherent drawbacks such as polydispersity and batch to batch heterogeneity.

Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors.

RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target "undruggable" oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(α)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides.

Structure-Function Correlation of Aminated Poly(α)glutamate as siRNA Nanocarriers.

It has been two decades since cationic polymers were introduced to the world of oligonucleotides delivery. However, the optimal physicochemical properties to make them a successful delivery vehicle are yet unknown. An ideal system became particularly interesting and necessary with the introduction of RNA interference as a promising therapeutic approach.

Systemic delivery of siRNA by aminated poly(α)glutamate for the treatment of solid tumors.

Small interfering RNA (siRNA) can silence the expression of a targeted gene in a process known as RNA interference (RNAi). As a consequence, RNAi has immense potential as a novel therapeutic approach in cancer targeted therapy. However, successful application of siRNA for therapeutic purposes is challenging due to its rapid renal clearance, degradation by RNases in the bloodstream, poor cellular penetration, immunogenicity and aggregation in the blood.

Inhibition of Gene Expression and Cancer Cell Migration by CD44v3/6-Targeted Polyion Complexes.

In recent years, siRNA technology has emerged as a promising strategy for gene silencing in cancer therapy. We have designed novel CD44-targeted polyion complexes (PICs) composed of poly(ethylene glycol)-block-polyethylenimine (PEG-b-PEI) and laminin-derived peptides (mA5G27D or mA5G27F) for in vivo siRNA delivery and gene silencing in tumors. The full-length A5G27 peptide (RLVSYNGIIFFLK), from which mA5G27D and mA5G27F are derived, binds to CD44v3 and CD44v6 and inhibits tumor cell migration, invasion, and angiogenesis.

Achieving successful delivery of oligonucleotides--From physico-chemical characterization to in vivo evaluation.

RNA interference is one of the most promising fields in modern medicine to treat several diseases, ranging from cancer to cardiac diseases, passing through viral infections and metabolic pathologies. Since the discovery of the potential therapeutic properties of non-self oligonucleotides, it was clear that it is important to develop delivery systems that are able to increase plasma stability and bestow membrane-crossing abilities to the oligonucleotides in order to reach their cytoplasmic targets. Polymer therapeutics, among other systems, are widely investigated as delivery systems for therapeutic agents, such as oligonucleotides.

Nano-sized polymers and liposomes designed to deliver combination therapy for cancer.

The standard of care for cancer patients comprises more than one therapeutic agent. Treatment is complex since several drugs, administered by different routes, need to be coordinated, taking into consideration their side effects and mechanisms of resistance. Drug delivery systems (DDS), such as polymers and liposomes, are designed to improve the pharmacokinetics and efficacy of bioactive agents (drugs, proteins or oligonucleotides), while reducing systemic toxicity.

Poly(ethylene glycol)-paclitaxel-alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases.

Paclitaxel (PTX) and alendronate (ALN) are effective drugs used for the treatment of breast cancer bone metastases. Growing evidence suggests that low-dose taxanes and bisphosphonates possess anti-angiogenic properties. However, PTX is water-insoluble and toxic, even if administered at anti-angiogenic dosing schedule.

Administration, distribution, metabolism and elimination of polymer therapeutics.

Polymer conjugation is an efficient approach to improve the delivery of drugs and biological agents, both by protecting the body from the drug (by improving biodistribution and reducing toxicity) and by protecting the drug from the body (by preventing degradation and enhancing cellular uptake). This review discusses the journey that polymer therapeutics make through the body, following the ADME (absorption, distribution, metabolism, excretion) concept. The biological factors and delivery system parameters that influence each stage of the process will be described, with examples illustrating the different solutions to the challenges of drug delivery systems in vivo.

Antiangiogenic antitumor activity of HPMA copolymer-paclitaxel-alendronate conjugate on breast cancer bone metastasis mouse model.

Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer.