Current Organic Chemistry - Volume 20, Issue 17, 2016

Bioorthogonal reactions have been widely used on live-cell labeling, animal tissue imaging, drug delivery, and biomaterials in the recent ten years. Tetrazine bioorthogonal chemistry is not only orthogonal with biological system, other click chemistry and traditional polymer chemistry, but also has superb kinetics, generates biocompatibility products, and proceeds under mild reaction condition. All these features enable tetrazine bioorthogonal chemistry to be widely applied to polymer and biomaterial science. Recently there are many exciting accomplishments. This chemistry can act as an ideal method for polymer and nanoparticle modification, a desired vehicle for nanoparticles in vivo delivery, new polymerization strategy, and novel hydrogel formation platform. In this review, we introduce recent advancements in biomaterials based on tetrazine bioorthogonal chemistry.

The recent progress on controlled-release drug delivery systems with cyclodextrins as functional groups and their applications in nanomedicine are reviewed. As one of the most famous supramolecular host candidates, cyclodextrins with small guest molecules are extensively employed in controlled-release drug delivery systems in nanomedicine fields. The host-guest interactions between cyclodextrins and the guest molecules can be triggered by various stimulations, including temperature, light, pH, etc. In this review, we will focus on the cyclodextrinbased controlled-release systems mainly triggered by light. The comparison between photoresponsive and other controlled-release drug delivery systems is also discussed.

In the past few decades, there has been great interest in the monofunctionalization of inorganic nanoparticles using organic chemistry tool. However, the uncontrollability in the degree of nanoparticle functionalization and the number of functional groups on the nanoparticles restrict their applications. It is now realized that precisely controlling the composition of the nanoparticles (NPs) will be of great importance for many biomedical applications. In this review, we will focus on using organic chemistry tools for monofunctionalization of inorganic nanoparticles, biomedical applications of monofunctionalized NPs, and then also discuss recent advances and future prospects in this emerging field.

Collagen, the most abundant structural protein in mammals, has drawn attention of the scientists in biomedical science to a large extent. Although collagen and collagenous materials are famous for the excellent biological properties (good bioactivity, biodegradability, biocompatibility and lower immunogenicity), they still always suffer from the limitation by the relatively weak mechanical property, chemical stability and resistance to enzymatic degradation. This paper focuses to review the various physical and chemical methods that have been reported to enhance the physicochemical property of collagen and collagenous materials in biomedical applications. The effect of modification on collagen largely depends on the reaction sites and the types of chemical bonds. Modification methods divided into physical and chemical types are discussed in detail in the present review, focusing on both the physicochemical property and the biological property.

With the development of nanotechnology, nano-biomaterials have shown good development prospects in gene therapy. Cationic lipids include a group of amphiphiles that exhibit positive charge which interacts with negatively charged DNA/RNA leading to the formation of complexes containing condensed gene materials. Cationic liposomes complexed with gene materials are promising non-viral carriers for gene therapy. As an environmentally ionized cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) shows positive charge at low pH with moderate pKa value due to the headgroup of tertiary amine. It makes 1,2-dioleyloxy-N,N-dimethyl-3- aminopropane (DODMA) very effective in encapsulating nucleic acids during synthesis by temporarily reducing pH. Thus, lipid nanoparticles with DODMA can have neutral or low zeta potential at physiological pH. These remarkable structure-dependent properties have far reaching application potential in gene therapy. This review summarizes the synthesis methods and structure characteristics of DODMA and derivatives, and illustrates their applications in gene delivery.

Due to core-shell nanostructures, highly branched and star-shaped macromolecules with three dimensional structural symmetry, dendrimers have been widely used as non-viral vectors in gene delivery. However, the performance of dendrimer-based gene vectors is far from ideal, mainly because of the low transfection efficiency and serious cytotoxicity. Therefore, many researchers focused on how to improve the transfection efficiency and reduce the cytotoxicity in the past decade. In this review, we mainly reported the most recent advances of dendrimer-based gene delivery systems. Several typical types of dendrimers for gene delivery were reviewed in detail, such as poly (amido amine) (PAMAM), poly (propylene imine) (PPI), poly(ether imine), poly-Llysine dendrimers. Recent advances about other types of dendrimer were also briefly mentioned. These advances provide a promising route to improve the transfection efficiency and reduce the toxicity, which also illustrates the direction of the future development of dendrimers in gene delivery.

The potential of metabolites to contribute to drug-drug interactions (DDIs) has not been well defined so far. However, metabolites of parent drug compounds can contribute to both side effects and DDIs. To address this unmet challenge, we introduce recent advances as well as our perspectives of the metabolites in DDIs in this review. Firstly, we review several typical examples of organic small molecule drug metabolites as major contributors to DDIs in clinic. Since some of the metabolites are so important in the contributions to DDIs, we then further review how to identify active metabolites in vivo and when such metabolites should trigger DDI assessment. Lastly, we review in vivo animal models, especially humanized/chimeric mice, in improving the quality of preclinical DDI assessments.

In recent years, nanoparticles have held great promise for successful drug targeting and controlled drug release. Many nanoparticle applications have been used to maximize the enhanced effective accumulation and intracellular entry. Because of the physicochemical properties of particles determine their therapeutic efficiency, it is vital to understand the effects of key drug carrier properties such as size, shape and surface chemistry on their internalization performance at the cellular level. Furthermore, these drug carrier properties will also influence their fate in biological systems in vivo. In this review, we introduce distinct internalization routes including phagocytosis and pinocytosis, and discuss the effect of particle size, shape, material composition and charge on the utilization of a selected pathway. We then briefly describe how these parameters affect nanoparticle behavior in vivo. We also focus on the effects of the cell type and the extracellular environment on the internalization processing of nanoparticles. Furthermore, we introduce some strategies and prevalent ligands which are functionalized onto nanoparticles that have been investigated for their ability to efficiently concentrate in desired cell populations and even sub-cellular compartments.