Innate immune humoral factors, C1q and factor H, with differential pattern recognition properties, alter macrophage response to carbon nanotubes

Interaction between the complement system and carbon nanotubes (CNTs) can modify their intended biomedical applications. Pristine and derivatised CNTs can activate complement primarily via the classical pathway which enhances uptake of CNTs and suppresses pro-inflammatory response by immune cells. Here, we report that the interaction of C1q, the classical pathway recognition molecule, with CNTs involves charge pattern and classical pathway activation that is partly inhibited by factor H, a complement regulator. C1q and its globular modules, but not factor H, enhanced uptake of CNTs by macrophages and modulated the pro-inflammatory immune response. Thus, soluble complement factors can interact differentially with CNTs and alter the immune response even without complement activation. Coating CNTs with recombinant C1q globular heads offers a novel way of controlling classical pathway activation in nanotherapeutics. Surprisingly, the globular heads also enhance clearance by phagocytes and down-regulate inflammation, suggesting unexpected complexity in receptor interaction. From the Clinical Editor: Carbon nanotubes (CNTs) maybe useful in the clinical setting as targeting drug carriers. However, it is also well known that they can interact and activate the complement system, which may have a negative impact on the applicability of CNTs. In this study, the authors functionalized multi-walled CNT (MWNT), and investigated the interaction with the complement pathway. These studies are important so as to gain further understanding of the underlying mechanism in preparation for future use of CNTs in the clinical setting.L.P., A.G.T., L.K., G.S. and U.K. thank Brunel University London for strategic Infrastructure funding. H.A.K. acknowledges the Deanship of Scientific Research at King Saud University for funding via Group No. RGP-009

Pulmonary surfactant protein SP-D opsonises carbon nanotubes and augments their phagocytosis and subsequent pro-inflammatory immune response

Carbon nanotubes (CNTs) are increasingly being developed for use in biomedical applications, including drug delivery. One of the most promising applications under evaluation is in treating pulmonary diseases such as tuberculosis. Once inhaled or administered, the nanoparticles are likely to be recognised by innate immune molecules in the lungs such as hydrophilic pulmonary surfactant proteins. Here, we set out to examine the interaction between surfactant protein D (SP-D), a key lung pattern recognition molecule and CNTs, and possible downstream effects on the immune response via macrophages. We show here that a recombinant form of human SP-D (rhSP-D) bound to oxidised and carboxymethyl cellulose (CMC) coated CNTs via its C-type lectin domain and enhanced phagocytosis by U937 and THP-1 macrophages/monocytic cell lines, together with an increased pro-inflammatory response, suggesting that sequestration of SP-D by CNTs in the lungs can trigger an unwanted and damaging immune response. We also observed that functionalised CNTs, opsonised with rhSP-D, continued to activate complement via the classical pathway, suggesting that C1q, which is the recognition sub-component of the classical pathway, and SP-D have distinct pattern recognition sites on the CNTs. Consistent with our earlier reports, complement deposition on the rhSP-D opsonised CNTs led to dampening of the pro-inflammatory immune response by THP-1 macrophages, as evident from qPCR, cytokine array and NF-κB nuclear translocation analyses. This study highlights the importance of understanding the interplay between innate immune humoral factors including complement in devising nanoparticle based drug delivery strategies

Interactions of the innate immune system with carbon nanotubes

The therapeutic application of nanomaterials requires that they are biocompatible and can reach the desired target. The innate immune system is likely to be the first defence machinery that would recognise the nanomaterials as 'non-self'. A number of studies have addressed the issue of how carbon nanotubes (CNTs) interact with phagocytic cells and their surface receptors that can impact on their intracellular processing and subsequent immune response. In addition, soluble innate immune factors also get involved in the recognition and clearance of CNTs. The interaction of CNTs with the complement system, the most potent and versatile innate immune mechanism, has shed interesting light on how complement activation on the surface of CNTs can modulate their phagocytosis and effector cytokine response. The charge or altered molecular pattern on the surface of CNTs due to functionalization and derivatization can also dictate the level of complement activation and subsequent inflammatory response. It is becoming evident that complement deposition may facilitate phagocytic uptake of CNTs through receptor routes that leads to dampening of pro-inflammatory response by complement-receptor bearing macrophages and B cells. Thus, recombinant complement regulators decorated on the CNT surface can constructively influence the therapeutic strategies involving CNTs and other nanoparticles

MR-Guided Biopsy of the Prostate: An Overview of Techniques and a Systematic Review

Context:\ud Systematic transrectal ultrasound-guided biopsy (TRUSBx) is the gold standard for detecting prostate cancer. This systematic approach is characterized by low sensitivity (39–52%) and high specificity (81–82%). Magnetic resonance (MR)–guided biopsy techniques are becoming more and more available, but there is no current consensus on the optimal technique.\ud \ud Objective:\ud This review presents an overview of MR-guided biopsy techniques for prostate cancer detection.\ud \ud Evidence acquisition:\ud Current literature was reviewed regarding MR-guided biopsy for prostate cancer detection. A literature search was performed using the commercially available MedLine online search engine. Combinations of the following search and Medical Subject Headings terms were applied to retrieve relevant articles: “magnetic resonance,” “prostatic neoplasms,” and “biopsy.” Review articles and studies describing techniques other than MR-guided biopsy were excluded.\ud \ud Evidence synthesis:\ud Biopsy of the prostate is an essential procedure for determining optimal treatment. Systematic TRUSBx is the gold standard, but it fails to detect numerous tumors. Diagnostic MR imaging provides more accurate selection of regions in which tumors are suspected. Using these diagnostic images during an MR-directed biopsy procedure improves quality of the biopsy. In open MR scanners, the prebiopsy images often must be registered to the real-time biopsy images because open MR scanners do not provide optimal tissue contrast; thus, the patient must first be examined in a closed MR scanner and then biopsied in an open scanner. The advantage of open MR over closed MR is that the physician has easy patient access. With special equipment, prostate MR-guided biopsy is also possible in a closed system. Closed MR scanners can be used for the prebiopsy scan as well as for the biopsy procedure.\ud \ud Conclusions:\ud The combination of a diagnostic MR examination and MR-guided biopsy is a promising tool and may be used in patients with previous negative TRUSBx

Magnetic drug delivery with FePd nanowires

Magnetic drug delivery is a promising method to target a drug to a diseased area while reducing negative side effects caused by systemic administration of drugs. In magnetic drug delivery a therapeutic agent is coupled to a magnetic nanoparticle. The particles are injected and at the target location withdrawn from blood flow by a magnetic field. In this study a FePd nanowire is developed with optimised properties for magnetic targeting. The nanowires have a high magnetic moment to reduce the field gradient needed to capture them with a magnet. The dimensions and the materials of the nanowire and coating are such that they are dispersable in aqueous media, non-cytotoxic, easily phagocytosed and not complement activating. This is established in several in-vitro tests with macrophage and endothelial cell lines.Along with the nanowires a magnet is designed, optimised for capture of the nanowires from the blood flow in the hind leg of a rat. The system is used in a pilot scale . in-vivo experiment. No negative side effects from injection of the nanowires were found within the limited time span of the experiment. In this first pilot experiment no nanowires were found to be targeted by the magnet, or in the liver, kidneys or spleen, most likely the particles were removed during the fixation procedure

Complement activation by carbon nanotubes and its influence on the phagocytosis and cytokine response by macrophages.

Carbon nanotubes (CNTs) have promised a range of applications in biomedicine. Although influenced by the dispersants used, CNTs are recognized by the innate immune system, predominantly by the classical pathway of the complement system. Here, we confirm that complement activation by the CNT used here continues up to C3 and C5, indicating that the entire complement system is activated including the formation of membrane-attack complexes. Using recombinant forms of the globular regions of human C1q (gC1q) as inhibitors of CNT-mediated classical pathway activation, we show that C1q, the first recognition subcomponent of the classical pathway, binds CNTs via the gC1q domain. Complement opsonisation of CNTs significantly enhances their uptake by U937 cells, with concomitant downregulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines in both U937 cells and human monocytes. We propose that CNT-mediated complement activation may cause recruitment of cellular infiltration, followed by phagocytosis without inducing a pro-inflammatory immune response. Carbon nanotubes (CNTs) are recognized by the innate immune system, especially by the classical pathway of the complement system. Complement activation is usually associated with a pro-inflammatory response. Here, we show that complement deposition on CMC- and RNA-CNTs can enhance their uptake by phagocytes, which in turn, leads to dampening of pro-inflammatory cytokine production. It appears that CNT-mediated complement activation may cause recruitment of cellular infiltration, followed by enhanced phagocytosis and suppression of cytokine storm