https://dash.harvard.edu/bitstream/handle/1/29293165/Cancer%20Nanotechnology.pdf?sequence=1

Cancer Nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

Microplastics are a pollutant of environmental concern Their presence in food destined for human consumption and in air samples has been reported Thus, microplastic exposure via diet or inhalation could occur, the human health effects of which are unknown The current review article draws upon cross-disciplinary scientific literature to discuss and evaluate the potential human health impacts of microplastics and outlines urgent areas for future research Key literature up to September 2016 relating to accumulation, particle toxicity, and chemical and microbial contaminants was critically examined Although microplastics and human health is an emerging field, complementary existing fields indicate potential particle, chemical and microbial hazards If inhaled or ingested, microplastics may accumulate and exert localized particle toxicity by inducing or enhancing an immune response Chemical toxicity could occur due to the localized leaching of component monomers, endogenous additives, and adsorbed enviro

Plastic and Human Health: A Micro Issue?

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).

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Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

Design and functionalization strategies for multifunctional nanocarriers (e.g., nanoparticles, micelles, polymersomes) based on biodegradable/biocompatible polymers intended to be employed for active targeting and drug delivery are reviewed. This review will focus on the nature of the polymers involved in the preparation of targeted nanocarriers, the synthesis methods to achieve the desired macromolecular architecture, the selected coupling strategy, the choice of the homing molecules (vitamins, hormones, peptides, proteins, etc.), as well as the various strategies to display them at the surface of nanocarriers. The resulting morphologies and the main colloidal features will be given as well as an overview of the biological activities, with a special focus on the main in vivo achievements.

Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery

The therapeutic efficacy of systemic drug-delivery vehicles depends on their ability to evade the immune system, cross the biological barriers of the body and localize at target tissues. White blood cells of the immune system--known as leukocytes--possess all of these properties and exert their targeting ability through cellular membrane interactions. Here, we show that nanoporous silicon particles can successfully perform all these actions when they are coated with cellular membranes purified from leukocytes. These hybrid particles, called leukolike vectors, can avoid being cleared by the immune system. Furthermore, they can communicate with endothelial cells through receptor-ligand interactions, and transport and release a payload across an inflamed reconstructed endothelium. Moreover, leukolike vectors retained their functions when injected in vivo, showing enhanced circulation time and improved accumulation in a tumour.

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Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions

Assessment of PEG on polymeric particles surface, a key step in drug carrier translation.

Uptake and intracellular trafficking of hydrogel nanoparticles (NPs) of N,N-diethyl acrylamide and 2-hydroxyethyl methacrylate crosslinked with N,N′-methylene-bis-acrylamide were studied with a RAW 264.7 murine macrophage cell line. Results show that the uptake rate, the mechanism of internalization and the concentration of internalized NPs are correlated to the NP Young modulus. Soft NPs are found to be internalized preferentially via macropinocytosis while the uptake of stiff NPs is mediated by a clathrin-dependent mechanism. NPs with an intermediate Young modulus exhibit multiple uptake mechanisms. The accumulation rate of the NPs into lysosomal compartments of the cell is also dependent on the NP elasticity. Our results suggest that control over the mechanical properties of hydrogel NPs can be used to tailor the cellular uptake mechanism and kinetics of drug delivery.

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Effect of mechanical properties of hydrogel nanoparticles on macrophage cell uptake

Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilization, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers is their ability to either cross biological barriers themselves, or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, nanocarriers may have to cross different physiological barriers in their journey towards their target. In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumor vasculature and blood brain barrier targeting), oral administration (gastrointestinal lining), and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting - size, shape, surface chemistry, surface patterning of nanovectors - will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers, although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature.

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Cell encapsulation in microcapsules allows the in situ delivery of secreted proteins to treat different pathological conditions. Spherical microcapsules offer optimal surface-to-volume ratio for protein and nutrient diffusion, and thus, cell viability. This technology permits cell survival along with protein secretion activity upon appropriate host stimuli without the deleterious effects of immunosuppressant drugs. Microcapsules can be classified in 3 categories: matrix-core/shell microcapsules, liquid-core/shell microcapsules, and cells-core/shell microcapsules (or conformal coating). Many preparation techniques using natural or synthetic polymers as well as inorganic compounds have been reported. Matrix-core/shell microcapsules in which cells are hydrogel-embedded, exemplified by alginates capsule, is by far the most studied method. Numerous refinement of the technique have been proposed over the years such as better material characterization and purification, improvements in microbead generation methods, and new microbeads coating techniques. Other approaches, based on liquid-core capsules showed improved protein production and increased cell survival. But aside those more traditional techniques, new techniques are emerging in response to shortcomings of existing methods. More recently, direct cell aggregate coating have been proposed to minimize membrane thickness and implants size. Microcapsule performances are largely dictated by the physicochemical properties of the materials and the preparation techniques employed. Despite numerous promising pre-clinical results, at the present time each methods proposed need further improvements before reaching the clinical phase.

Jean-Michel Rabanel

Papers

Assessment of PEG on polymeric particles surface, a key step in drug carrier translation.

Effect of mechanical properties of hydrogel nanoparticles on macrophage cell uptake

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Progress Technology in Microencapsulation Methods for Cell Therapy

Characterization of rhodamine loaded PEG-g-PLA nanoparticles (NPs): Effect of poly(ethylene glycol) grafting density