Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.

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Principles of nanoparticle design for overcoming biological barriers to drug delivery

Polydopamine and Its Derivative Materials: Synthesis and Promising Applications in Energy, Environmental, and Biomedical Fields

■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

A review of stimuli-responsive nanocarriers for drug and gene delivery

The development of microgels/nanogels for drug delivery applications

Catechol-functionalized chitosan/pluronic hydrogels for tissue adhesives and hemostatic materials.

Layer-by-layer (LbL) assembly has attracted much attention because of its ability to create multifunctional films on surfaces while maintaining bulk properties.[1] The method relies on sequential adsorption of polymers onto bulk surfaces from solution, giving rise to complex multilayered films. LbL assembly is simple to implement and offers extensive control over film properties and composition during stepwise adsorption of components. Although the vast majority of LbL films are built from polyelectrolytes via electrostatic interaction between layers, more recently LbL films have been made with hydrogen-bonding of polymers,[2] and other building blocks such as inorganic nanoparticles have been used, giving access to even greater control of chemical and physical properties of LbL films.

Substrate-Independent Layer-by-Layer Assembly by Using Mussel-Adhesive-Inspired Polymers†

Cancer-cell-targeted gene silencing was observed with a magnetic-nanoparticle platform (MEIO, magnetism-engineered iron oxide) on which a fluorescent dye, siRNA, and a RGD-peptide targeting moiety were attached (see picture). The different functionalities enable the macroscopic (magnetic resonance) and microscopic (fluorescence) imaging of target cells. This system may be suitable for concurrent diagnostic and therapeutic applications.

All-in-one target-cell-specific magnetic nanoparticles for simultaneous molecular imaging and siRNA delivery.

Hyaluronic acid (HA) hydrogels are widely pursued as tissue regenerative and drug delivery materials due to their excellent biocompatibility and biodegradability. Inspired by mussel adhesion, we report here a novel class of thermo-sensitive and injectable HA/Pluronic F127 composite tissue-adhesive hydrogels applicable for various biomedical applications. HA conjugated with dopamine (HA-DN) was mixed with thiol end-capped Pluronic F127 copolymer (Plu-SH) to produce a lightly cross-linked HA/Pluronic composite gel structure based on Michael-type catechol-thiol addition reaction. The HA/Pluronic hydrogels exhibited temperature-dependent sol–gel phase transition behaviors different from Pluronic hydrogels. Rheological studies showed that the sol–gel transitions were rapid and reversible in response to temperature. The HA/Pluronic hydrogels could be injected in vivo in a sol state at room temperature using a syringe, but immediately became a robust gel state at body temperature. The in situ formed hydrogels exhibited excellent tissue-adhesion properties with superior in vivo gel stability and are potentially useful for drug and cell delivery.

Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction

Inorganic nanocrystals have attracted much attention for therapeutic and diagnostic applications due to their unique optical, magnetic, and fluorescent properties.[1] Among these various nanocrystals, colloidal superparamagnetic iron oxide (e.g., γ-Fe2O3 and Fe3O4) have been extensively highlighted for many biomedical applications such as contrast agents for magnetic-resonance (MR) imaging, therapeutic gene carriers, protein purification, and sensors for nucleic-acid and virus detection.[2] In principle, it is of utmost importance to prepare highly stable magnetic nanocrystals in aqueous solutions to maximize in vivo half-life and tissue-specificity. However, the fabrication of such stable, bioactive magnetic nanocolloids has proven to be nontrivial.

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Yuhan Lee

Papers

Catechol-functionalized chitosan/pluronic hydrogels for tissue adhesives and hemostatic materials.

Substrate-Independent Layer-by-Layer Assembly by Using Mussel-Adhesive-Inspired Polymers†

All-in-one target-cell-specific magnetic nanoparticles for simultaneous molecular imaging and siRNA delivery.

Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction

Bioinspired Surface Immobilization of Hyaluronic Acid on Monodisperse Magnetite Nanocrystals for Targeted Cancer Imaging