Participation of lipids in the tumor response to photodynamic therapy and its exploitation for therapeutic gain.

Hydroperoxides of unsaturated membrane lipids (LOOHs) are the most abundant non-radical intermediates generated by photodynamic therapy (PDT) of soft tissues such as tumors and have far longer average lifetimes than singlet oxygen or oxygen radicals formed during initial photodynamic action. LOOH-initiated post-irradiation damage to remaining membrane lipids (chain peroxidation) or to membrane-associated proteins remains largely unrecognized. Such after-light processes could occur during clinical oncological PDT, but this is not well-perceived by practitioners of this therapy.

Photosensitized Oxidative Damage from a New Perspective: The Influence of Before-Light and After-Light Reaction Conditions.

Photooxidative damage is heavily influenced by the presence of bioactive agents. Conversely, bioactive agents influence the local environment, which in turn is perturbed by photooxidative damage. These sorts of processes give rise to a version of the "chicken-and-egg" quandary.

Upregulation of iNOS/NO in Cancer Cells That Survive a Photodynamic Challenge: Role of No in Accelerated Cell Migration and Invasion.

Anti-tumor photodynamic therapy (PDT) is a unique modality that employs a photosensitizer (PS), PS-exciting light, and O to generate cytotoxic oxidants. For various reasons, not all malignant cells in any given tumor will succumb to a PDT challenge. Previous studies by the authors revealed that nitric oxide (NO) from inducible NO synthase (iNOS/NOS2) plays a key role in tumor cell resistance and also stimulation of migratory/invasive aggressiveness of surviving cells.

Cholesterol Hydroperoxide Co-trafficking in Testosterone-generating Leydig Cells: GPx4 Inhibition of Cytotoxic and Anti-steroidogenic Effects.

Trafficking of intracellular cholesterol (Ch) to and into mitochondria of steroidogenic cells is required for steroid hormone biosynthesis. This trafficking is typically mediated by one or more proteins of the steroidogenic acute regulatory (StAR) family. Our previous studies revealed that 7-OOH, a redox-active cholesterol hydroperoxide, could be co-trafficked with Ch to/into mitochondria of MA-10 Leydig cells, thereby inducing membrane lipid peroxidation (LPO) which impaired progesterone biosynthesis.

Hyper-Aggressiveness of Bystander Cells in an Anti-Tumor Photodynamic Therapy Model: Role of Nitric Oxide Produced by Targeted Cells.

When selected tumor cells in a large in vitro population are exposed to ionizing radiation, they can send pro-survival signals to non-exposed counterparts (bystander cells). If there is no physical contact between irradiated and bystander cells, the latter respond to mediators from targeted cells that diffuse through the medium. One such mediator is known to be nitric oxide (NO).

CD44-targeted nanoparticles for co-delivery of docetaxel and an Akt inhibitor against colorectal cancer.

New strategies to develop drug-loaded nanocarriers with improved therapeutic efficacy are needed for cancer treatment. Herein we report a novel drug-delivery nanosystem comprising encapsulation of the chemotherapeutic drug docetaxel (DTX) and recombinant fusion of a small peptide inhibitor of Akt kinase within an elastin-like recombinamer (ELR) vehicle. This combined approach is also precisely targeted to colorectal cancer cells by means of a chemically conjugated DNA aptamer specific for the CD44 tumor marker.

Pro-Tumor Activity of Endogenous Nitric Oxide in Anti-Tumor Photodynamic Therapy: Recently Recognized Bystander Effects.

Various studies have revealed that several cancer cell types can upregulate inducible nitric oxide synthase (iNOS) and iNOS-derived nitric oxide (NO) after moderate photodynamic treatment (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin-IX. As will be discussed, the NO signaled cell resistance to photokilling as well as greater growth and migratory aggressiveness of surviving cells. On this basis, it was predicted that diffusible NO from PDT-targeted cells in a tumor might enhance the growth, migration, and invasiveness of non- or poorly PDT-targeted bystander cells.

Trafficking of oxidative stress-generated lipid hydroperoxides: pathophysiological implications.

Lipid hydroperoxides (LOOHs) are reactive intermediates that arise during peroxidation of unsaturated phospholipids, glycolipids and cholesterol in biological membranes and lipoproteins. Non-physiological lipid peroxidation (LPO) typically occurs under oxidative stress conditions associated with pathologies such as atherogenesis, neurodegeneration, and carcinogenesis. As key intermediates in the LPO process, LOOHs are susceptible to one-electron versus two-electron reductive turnover, the former exacerbating membrane or lipoprotein damage/dysfunction and the latter diminishing it.

Silk-Elastin-like Polymers for Acute Intraparenchymal Treatment of the Traumatically Injured Spinal Cord: A First Systematic Experimental Approach.

Despite the promising potential of hydrogel-based therapeutic approaches for spinal cord injury (SCI), the need for new biomaterials to design effective strategies for SCI treatment and the outstanding properties of silk-elastin-like polymers (SELP), the potential use of SELPs in SCI is currently unknown. In this context, we assessed the effects elicited by the in vivo acute intraparenchymal injection of an SELP named (EIS)-RGD6 in a clinically relevant model of SCI. After optimization of the injection system, the distribution, structure, biodegradability, and cell infiltration capacity of (EIS)-RGD6 were assessed.

Role of nitric oxide in hyper-aggressiveness of tumor cells that survive various anti-cancer therapies.

Low level nitric oxide (NO) produced by inducible NO synthase (iNOS) in many malignant tumors is known to play a key role in the survival and proliferation of tumor cells. NO can also induce or augment resistance to anti-tumor treatments such as platinum-based chemotherapy (CT), ionizing radiotherapy (RT), and non-ionizing photodynamic therapy (PDT). In each of these treatments, tumor cells that survive the challenge may exhibit a striking increase in NO-dependent proliferative, migratory, and invasive aggressiveness compared with non-challenged controls.

The Negative Impact of Cancer Cell Nitric Oxide on Photodynamic Therapy.

Numerous studies have shown that low-flux nitric oxide (NO) in tumors produced mainly by inducible nitric oxide synthase (iNOS/NOS2) can signal for angiogenesis, inhibition of apoptosis, and promotion of cell growth, migration, and invasion. Studies in the authors' laboratory have revealed that iNOS-derived NO in various cancer cell types elicits resistance to cytotoxic photodynamic therapy (PDT) and moreover endows PDT-surviving cells with more aggressive proliferation and migration/invasion. In this chapter, we describe how cancer cell iNOS/NO in vitro can be monitored in different PDT model systems (e.

Elastin-like Polymers as Nanovaccines: Protein Engineering of Self-Assembled, Epitope-Exposing Nanoparticles.

In this chapter we describe two unconventional strategies for the formulation of new nanovaccines. Both strategies are based on obtaining chimeric genes that code for proteins in which the major antigens of the pathogens are fused to an elastin-like recombinamer (ELR) as carrier. ELRs are a family of synthetic protein biopolymers obtained using DNA recombinant techniques.

Anti-steroidogenic effects of cholesterol hydroperoxide trafficking in MA-10 Leydig cells: Role of mitochondrial lipid peroxidation and inhibition thereof by selenoperoxidase GPx4.

Steroid hormone synthesis in steroidogenic cells requires cholesterol (Ch) delivery to/into mitochondria via StAR family trafficking proteins. In previous work, we discovered that 7-OOH, an oxidative stress-induced cholesterol hydroperoxide, can be co-trafficked with Ch, thereby causing mitochondrial redox damage/dysfunction. We now report that exposing MA-10 Leydig cells to Ch/7-OOH-containing liposomes (SUVs) results in (i) a progressive increase in fluorescence probe-detected lipid peroxidation in mitochondrial membranes, (ii) a reciprocal decrease in immunoassay-detected progesterone generation, and ultimately (iii) loss of cell viability with increasing 7-OOH concentration.

Smart Nanoparticles as Advanced Anti-Akt Kinase Delivery Systems for Pancreatic Cancer Therapy.

Pancreatic cancer is one of the deadliest cancers partly due to late diagnosis, poor drug delivery to the target site, and acquired resistance to therapy. Therefore, more effective therapies are urgently needed to improve the outcome of patients. In this work, we have tested self-assembling genetically engineered polymeric nanoparticles formed by elastin-like recombinamers (ELRs), carrying a small peptide inhibitor of the protein kinase Akt, in both PANC-1 and patient-derived pancreatic cancer cells (PDX models).

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment.

The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects.

Soft Hydrogel Inspired by Elastomeric Proteins.

Elastin polypeptides based on -VPGVG- repeated motifs are widely used in the production of biomaterials because they are stimuli-responsive systems. On the other hand, glycine-rich sequences, mainly present in tropoelastin terminal domains, are responsible for the elastin self-assembly. In a previous study, we have recombinantly expressed a chimeric polypeptide, named resilin, elastin, and collagen (REC), inspired by glycine-rich motifs of elastin and containing resilin and collagen sequences as well.

Intermembrane Translocation of Photodynamically Generated Lipid Hydroperoxides: Broadcasting of Redox Damage.

Lipid hydroperoxides (LOOHs), including cholesterol- and phospholipid-derived species, are reactive intermediates that arise during photosensitized peroxidation of unsaturated lipids in biological membranes. These intermediates may appear in cancer cell membranes during anti-tumor photodynamic therapy (PDT). Photodynamically generated LOOHs have several different fates, including (a) iron-catalyzed one-electron reduction to free radical species which trigger damaging chain peroxidation reactions, (b) selenoperoxidase-catalyzed two-electron reduction to redox-inert alcohols (LOHs), and (c) spontaneous or protein-mediated translocation to other lipid membrane compartments where (a) or (b) may take place.

Pathophysiological potential of lipid hydroperoxide intermembrane translocation: Cholesterol hydroperoxide translocation as a special case.

Peroxidation of unsaturated phospholipids, glycolipids, and cholesterol in biological membranes under oxidative stress conditions can underlie a variety of pathological conditions, including atherogenesis, neurodegeneration, and carcinogenesis. Lipid hydroperoxides (LOOHs) are key intermediates in the peroxidative process. Nascent LOOHs may either undergo one-electron reduction to exacerbate membrane damage/dysfunction or two-electron reduction to attenuate this.

Photodynamic Therapy as an Oxidative Anti-Tumor Modality: Negative Effects of Nitric Oxide on Treatment Efficacy.

Anti-tumor photodynamic therapy (PDT) is a unique oxidative stress-based modality that has proven highly effective on a variety of solid malignancies. PDT is minimally invasive and generates cytotoxic oxidants such as singlet molecular oxygen (O). With high tumor site-specificity and limited off-target negative effects, PDT is increasingly seen as an attractive alternative or follow-up to radiotherapy or chemotherapy.

Advanced nanomedicine and cancer: Challenges and opportunities in clinical translation.

Cancer has reached pandemic dimensions in the whole world. Although current medicine offers multiple treatment options against cancer, novel therapeutic strategies are needed due to the low specificity of chemotherapeutic drugs, undesired side effects and the presence of different incurable types of cancer. Among these new strategies, nanomedicine arises as an encouraging approach towards personalized medicine with high potential for present and future cancer patients.

Negative effects of tumor cell nitric oxide on anti-glioblastoma photodynamic therapy.

Glioblastomas are highly aggressive brain tumors that can persist after exposure to conventional chemotherapy or radiotherapy. Nitric oxide (NO) produced by inducible NO synthase (iNOS/NOS2) in these tumors is known to foster malignant cell proliferation, migration, and invasion as well as resistance to chemo- and radiotherapy. Minimally invasive photodynamic therapy (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) is a highly effective anti-glioblastoma modality, but it is also subject to NO-mediated resistance.

Nitric Oxide-elicited Resistance to Antitumor Photodynamic Therapy via Inhibition of Membrane Free Radical-mediated Lipid Peroxidation.

This review focuses on the ability of nitric oxide (NO) to antagonize antitumor photodynamic therapy (PDT). NO's anti-PDT effects were recognized relatively recently and require a better mechanistic understanding for developing new strategies to improve PDT efficacy. Many PDT sensitizers (PSs) are amphiphilic and tend to localize in membrane compartments of tumor cells.

Optimal chest wall prosthesis: comparative study of mechanical and functional behaviour.

Objectives: Chest wall resections are most commonly performed for tumours, infection, radiation necrosis and trauma. Defects in the anterior chest greater than 5 cm, posterior defects more than 10 cm or resection including more than 3 ribs, independently of the location, require skeletal prosthetic reconstruction. The aim of this paper was to evaluate the strength of prostheses that reproduced the normal human anatomy using different materials subjected to the most dangerous loading conditions.