Hydrophilic polymers are the center of research emphasis in nanotechnology because of their perceived “intelligence”. They can be used as thin films, scaffolds, or nanoparticles in a wide range of biomedical and biological applications. Here we highlight recent developments in engineering uncrosslinked and crosslinked hydrophilic polymers for these applications. Natural, biohybrid, and synthetic hydrophilic polymers and hydrogels are analyzed and their thermodynamic responses are discussed. In addition, examples of the use of hydrogels for various therapeutic applications are given. We show how such systems’ intelligent behavior can be used in sensors, microarrays, and imaging. Finally, we outline challenges for the future in integrating hydrogels into biomedical applications.

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Hydrogels in Biology and Medicine: From Molecular Principles to Bionanotechnology†

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar,Mohali, Punjab-160 062, India, Institute of Biochemistry, Faculty of Medicine, Polytechnic University, Via Ranieri 67, IT-60100 Ancona, Italy,Green Biotechnology Research Group, The Special Division for Human Life Technology, National Institute of Advanced Industrial Science andTechnology, 1-8-31 Midorigaoka, Ikeda, Osaka-563-8577, Japan, and Department of Medicinal Chemistry & Natural Products,The Hebrew University of Jerusalem, School of Pharmacy-Faculty of Medicine, Jerusalem 91120, IsraelReceived March 2, 2004

Chitosan chemistry and pharmaceutical perspectives.

The interaction of nanomaterials with cells and lipid bilayers is critical in many applications such as phototherapy, imaging, and drug/gene delivery. These applications require a firm control over nanoparticle-cell interactions, which are mainly dictated by surface properties of nanoparticles. This critical Review presents an understanding of how synthetic and natural chemical moieties on the nanoparticle surface (in addition to nanoparticle shape and size) impact their interaction with lipid bilayers and cells. Challenges for undertaking a systematic study to elucidate nanoparticle-cell interactions are also discussed.

Effect of Surface Properties on Nanoparticle–Cell Interactions

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

Thermosensitive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules

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

Therapeutic benefit in glial tumors is often limited due to low permeability of delivery systems across the blood−brain barrier (BBB), drug resistance, and poor penetration into the tumor tissue. In an attempt to overcome these hurdles, polyether-copolyester (PEPE) dendrimers were evaluated as drug carriers for the treatment of gliomas. Dendrimers were conjugated to d-glucosamine as the ligand for enhancing BBB permeability and tumor targeting. The efficacy of methotrexate (MTX)-loaded dendrimers was established against U87 MG and U 343 MGa cells. Permeability of rhodamine-labeled dendrimers and MTX-loaded dendrimers across the in vitro BBB model and their distribution into avascular human glioma tumor spheroids was also studied. Glucosylated dendrimers were found to be endocytosed in significantly higher amounts than nonglucosylated dendrimers by both the cell lines. IC50 of MTX after loading in dendrimers was lower than that of the free MTX, suggesting that loading MTX in PEPE dendrimers increased its p...

Methotrexate Loaded Polyether-Copolyester Dendrimers for the Treatment of Gliomas: Enhanced Efficacy and Intratumoral Transport Capability

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.

Patrice Hildgen

Papers

Thermosensitive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules

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

Methotrexate Loaded Polyether-Copolyester Dendrimers for the Treatment of Gliomas: Enhanced Efficacy and Intratumoral Transport Capability

Effect of mechanical properties of hydrogel nanoparticles on macrophage cell uptake

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