Polymeric nanoparticles-based therapeutics show great promise in the treatment of a wide range of diseases, due to the flexibility in which their structures can be modified, with intricate definition over their compositions, structures and properties. Advances in polymerization chemistries and the application of reactive, efficient and orthogonal chemical modification reactions have enabled the engineering of multifunctional polymeric nanoparticles with precise control over the architectures of the individual polymer components, to direct their assembly and subsequent transformations into nanoparticles of selective overall shapes, sizes, internal morphologies, external surface charges and functionalizations. In addition, incorporation of certain functionalities can modulate the responsiveness of these nanostructures to specific stimuli through the use of remote activation. Furthermore, they can be equipped with smart components to allow their delivery beyond certain biological barriers, such as skin, mucus, blood, extracellular matrix, cellular and subcellular organelles. This tutorial review highlights the importance of well-defined chemistries, with detailed ties to specific biological hurdles and opportunities, in the design of nanostructures for various biomedical delivery applications.

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Design of polymeric nanoparticles for biomedical delivery applications

Chemistries that Facilitate Nanotechnology Kim E. Sapsford,† W. Russ Algar, Lorenzo Berti, Kelly Boeneman Gemmill,‡ Brendan J. Casey,† Eunkeu Oh, Michael H. Stewart, and Igor L. Medintz*,‡ †Division of Biology, Department of Chemistry and Materials Science, Office of Science and Engineering Laboratories, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, United States ‡Center for Bio/Molecular Science and Engineering Code 6900 and Division of Optical Sciences Code 5611, U.S. Naval Research Laboratory, Washington, D.C. 20375, United States College of Science, George Mason University, 4400 University Drive, Fairfax, Virginia 22030, United States Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, California 95817, United States Sotera Defense Solutions, Crofton, Maryland 21114, United States

Functionalizing nanoparticles with biological molecules: developing chemistries that facilitate nanotechnology.

The functional groups and site interactions on the surfaces of two-dimensional (2D) layered titanium carbide can be tailored to attain some extraordinary physical properties. Herein a 2D alk-MXene (Ti3C2(OH/ONa)xF2–x) material, prepared by chemical exfoliation followed by alkalization intercalation, exhibits preferential Pb(II) sorption behavior when competing cations (Ca(II)/Mg(II)) coexisted at high levels. Kinetic tests show that the sorption equilibrium is achieved in as short a time as 120 s. Attractively, the alk-MXene presents efficient Pb(II) uptake performance with the applied sorption capacities of 4500 kg water per alk-MXene, and the effluent Pb(II) contents are below the drinking water standard recommended by the World Health Organization (10 μg/L). Experimental and computational studies suggest that the sorption behavior is related to the hydroxyl groups in activated Ti sites, where Pb(II) ion exchange is facilitated by the formation of a hexagonal potential trap.

Unique Lead Adsorption Behavior of Activated Hydroxyl Group in Two-Dimensional Titanium Carbide

The development of nanoparticle-based drug formulations has yielded the opportunities to address and treat challenging diseases. Nanoparticles vary in size but are generally ranging from 100 to 500 nm. Through the manipulation of size, surface characteristics and material used, the nanoparticles can be developed into smart systems, encasing therapeutic and imaging agents as well as bearing stealth property. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. This targeted and sustained drug delivery decreases the drug related toxicity and increase patient’s compliance with less frequent dosing. Nanotechnology has proven beneficial in the treatment of cancer, AIDS and many other disease, also providing advancement in diagnostic testing.

Applications of nanoparticle systems in drug delivery technology

Nanoparticle-based combination therapy toward overcoming drug resistance in cancer

In the past decade, nanomedicine with its promise of improved therapy and diagnostics has revolutionized conventional health care and medical technology. Dendrimers and dendrimer-based therapeutics are outstanding candidates in this exciting field as more and more biological systems have benefited from these starburst molecules. Anticancer agents can be either encapsulated in or conjugated to dendrimer and be delivered to the tumour via enhanced permeability and retention (EPR) effect of the nanoparticle and/or with the help of a targeting moiety such as antibody, peptides, vitamins, and hormones. Imaging agents including MRI contrast agents, radionuclide probes, computed tomography contrast agents, and fluorescent dyes are combined with the multifunctional nanomedicine for targeted therapy with simultaneous cancer diagnosis. However, an important question reported with dendrimer-based therapeutics as well as other nanomedicines to date is the long-term viability and biocompatibility of the nanotherapeutics. This critical review focuses on the design of biocompatible dendrimers for cancer diagnosis and therapy. The biocompatibility aspects of dendrimers such as nanotoxicity, long-term circulation, and degradation are discussed. The construction of novel dendrimers with biocompatible components, and the surface modification of commercially available dendrimers by PEGylation, acetylation, glycosylation, and amino acid functionalization have been proposed as available strategies to solve the safety problem of dendrimer-based nanotherapeutics. Also, exciting opportunities and challenges on the development of dendrimer-based nanoplatforms for targeted cancer diagnosis and therapy are reviewed (404 references).

Design of biocompatible dendrimers for cancer diagnosis and therapy: current status and future perspectives

Polyamidoamine (PAMAM) dendronized hollow fiber membranes (HFMs) were synthesized and used in the recovery of heavy metal ions. The dendronized HFMs showed strong binding ability with Cu2+, Pb2+, and Cd2+ ions. Generation 3 (G3) PAMAM dendronized HFM (G3-HFM) retained 72% of its Cu2+ binding capacity after five cycles of use and recovery. Interestingly, Cu2(OH)3Cl, Pb3(CO3)2(OH)2, and CdCO3 crystals were grown on G3-HFM surface when G3-HFMs were immersed in CuCl2, Pb(NO3)2, and CdCl2 solutions, respectively, while no crystal was observed with nonmodified HFMs. The results provide new insights into the applications of membrane-supported dendrimers in the recovery of heavy metal ions.

Polyamidoamine dendronized hollow fiber membranes in the recovery of heavy metal ions.

The host−guest chemistry of dendrimer−drug complexes is investigated by NMR techniques, including 1H NMR and 2D-NOESY studies. The effects of molecular properties of drug molecules (protonation ability and spatial steric hindrance of charged groups) and surface functionalities of dendrimers (positively charged amine groups and negatively charged carboxylate groups) on the host−guest interactions are discussed. Different interaction mechanisms between dendrimers and drug molecules are proposed on the basis of NMR results. Primary amine- and secondary amine-containing drugs preferentially bind to negatively charged dendrimers by strong electrostatic interactions, whereas tertiary amine and quaternary ammonium-containing drugs have weak binding ability with dendrimers due to relatively low protonation ability of the tertiary amine group and serious steric hindrance of the quaternary ammonium group. Positively charged drugs locate only on the surface of negatively charged dendrimers, whereas negatively charge...

Host-guest chemistry of dendrimer-drug complexes. 2. Effects of molecular properties of guests and surface functionalities of dendrimers.

The host−guest chemistry of dendrimer−drug complexes is of great significance to the design and optimization of dendrimer-based drug delivery systems. The competitive binding of multiple drugs by a single dendrimer in aqueous solutions was investigated by 1H NMR and 2D-NOESY studies. These rapid, noninvasive, and accurate NMR techniques allow us to monitor the signals of various drugs as well as carriers in a complicated host−guest system. Ethanol was used as an internal standard to simultaneously quantify dendrimers and drugs and to estimate the binding ability of dendrimers toward different drug molecules. The results suggested that supramolecular structure of dendrimer−multiple drug complexes is formed based on electrostatic interactions and hydrophobic/hydrogen-bond interactions. Factors including hydrophobic properties, sizes, pKa values, charged groups, and spatial hindrance effects of the drugs influenced the localization of drug molecules on the surface and in the interior pockets. In a ternary ho...

Host−Guest Chemistry of Dendrimer−Drug Complexes. 3. Competitive Binding of Multiple Drugs by a Single Dendrimer for Combination Therapy

A convenient approach for the high-throughput screening of dendrimer-binding drugs by NMR techniques including saturation transfer difference (STD) NMR and Hadamard-encoded nuclear Overhauser effect measurements is presented. The screening results for insoluble drugs show that phenylbutazone and sulfamethoxazole prefer to localize in the interior pockets of dendrimer, while mycophenolic acid mostly binds on the dendrimer surface, and noncharged insoluble drugs like trimethoprim and primidone do not interact with dendrimers. In another path for soluble drugs, n-butanoic acid and dimethylformamide are screened as dendrimer-binding compounds from a screening pool containing eight soluble compounds by STD NMR. The screening of dendrimer-binding insoluble or soluble compounds can be finished within an hour.

Libo Zhao

Papers

Design of biocompatible dendrimers for cancer diagnosis and therapy: current status and future perspectives

Polyamidoamine dendronized hollow fiber membranes in the recovery of heavy metal ions.

Host-guest chemistry of dendrimer-drug complexes. 2. Effects of molecular properties of guests and surface functionalities of dendrimers.

Host−Guest Chemistry of Dendrimer−Drug Complexes. 3. Competitive Binding of Multiple Drugs by a Single Dendrimer for Combination Therapy

High-Throughput Screening of Dendrimer-Binding Drugs