Size-Dependent In Vivo Transport of Nanoparticles: Implications for Delivery, Targeting, and Clearance.

Understanding the in vivo transport of nanoparticles provides guidelines for designing nanomedicines with higher efficacy and fewer side effects. Among many factors, the size of nanoparticles plays a key role in controlling their in vivo transport behaviors due to the existence of various physiological size thresholds within the body and size-dependent nano-bio interactions. Encouraged by the evolving discoveries of nanoparticle-size-dependent biological effects, we believe that it is necessary to systematically summarize the size-scaling laws of nanoparticle transport in vivo. In this review, we summarized the size effect of nanoparticles on their in vivo transport along their journey in the body: begin with the administration of nanoparticles via different delivery routes, followed by the targeting of nanoparticles to intended tissues including tumors and other organs, and eventually clearance of nanoparticles through the liver or kidneys. We outlined the tools for investigating the in vivo transport of nanoparticles as well. Finally, we discussed how we may leverage the size-dependent transport to tackle some of the key challenges in nanomedicine translation and also raised important size-related questions that remain to be answered in the future.

Tuning the Endocytosis of Hybrid Micelles through Spatial Regulation of Cationic Groups.

The ability of nanocarriers to enter tumor cells can be enhanced by positive surface charge. Nonetheless, the relationship between the spatial distributions of cationic groups and the endocytosis and tumor penetration of nanocarriers remains largely elusive. Here, using quaternary ammonium salt (QAS) as a model cationic group, a series of hybrid micelles (HMs) bearing QAS with different spatial distributions were prepared from star-shaped polymers with well-defined molecular architectures. The structural characteristics of HM, such as spatial location of QAS and local poly(ethylene glycol) (PEG) density near QAS, were investigated by both experimental techniques and dissipative particle dynamics (DPD) simulation. We show that the drug carriers with QAS extending to the micellar outer space allows QAS to facilitate cell surface binding with minimized hindrance, resulting in greatly enhanced endocytosis compared with nanocarriers with QAS attached onto the micellar surface or shielded by a PEG corona. This study offers cues for future development of tumor-penetrating drug delivery systems.

Electromyogram-Based Lip-Reading via Unobtrusive Dry Electrodes and Machine Learning Methods.

Lip-reading provides an effective speech communication interface for people with voice disorders and for intuitive human-machine interactions. Existing systems are generally challenged by bulkiness, obtrusiveness, and poor robustness against environmental interferences. The lack of a truly natural and unobtrusive system for converting lip movements to speech precludes the continuous use and wide-scale deployment of such devices. Here, the design of a hardware-software architecture to capture, analyze, and interpret lip movements associated with either normal or silent speech is presented. The system can recognize different and similar visemes. It is robust in a noisy or dark environment. Self-adhesive, skin-conformable, and semi-transparent dry electrodes are developed to track high-fidelity speech-relevant electromyogram signals without impeding daily activities. The resulting skin-like sensors can form seamless contact with the curvilinear and dynamic surfaces of the skin, which is crucial for a high signal-to-noise ratio and minimal interference. Machine learning algorithms are employed to decode electromyogram signals and convert them to spoken words. Finally, the applications of the developed lip-reading system in augmented reality and medical service are demonstrated, which illustrate the great potential in immersive interaction and healthcare applications.

Precisely synthesized segmented polyurethanes toward block sequence-controlled drug delivery.

The construction of polyurethanes (PUs) with sequence-controlled block structures remains a serious challenge. Here, we report the precise synthesis of PUs with desirable molecular weight, narrow molecular weight distribution, and controlled block sequences from commercially available monomers. The synthetic procedure is derived from a liquid-phase synthetic methodology, which involves diisocyanate-based iterative protocols in combination with a convergent strategy. Furthermore, a pair of multifunctional PUs with different sequence orders of cationic and anion segments were prepared. We show that the sequence order of functional segments presents an impact on the self-assembly behavior and results in unexpected surface charges of assembled micelles, thereby affecting the protein absorption, cell internalization, biodistribution and antitumor effect of the nanocarriers in vitro and in vivo. This work provides a versatile platform for the development of precise multiblock PUs with structural complexity and functional diversity, and will greatly facilitate the clinical translation of PUs in biomedicine.

Anti-P0 Antibody-Conjugated Nanoscale Contrast Agent Targeting the Myelin Sheath for Intraoperative Visible Delineation of Cranial Nerves.

The preservation of cranial nerves is a major problem that surgeons encounter when resecting a tumor in the posterior cranial fossa. Most cranial nerve injuries occur because the tight adhesion between the tumor capsule and cranial nerves renders the nerves indistinguishable. In this study, a nerve-specific nanoscale contrast agent was developed for visually distinguishing cranial nerves from the tumor surface in real time. To enable the contrast agent to specifically bind peripheral nerves, a previously reported biodegradable multiblock polyurethane nanoparticle (BMPU NP) was conjugated with an antibody against myelin protein zero (MPZ, P0), which is expressed on myelin sheaths in peripheral nerve fibers. Coomassie brilliant blue G (CB) was encapsulated into the BMPU NP for visual contrast. The CB-BMPU NP specifically stained mouse peripheral nerve fibers blue when directly applied to the nerve surface ex vivo and in vivo. The CB-BMPU NP also achieved satisfactory visual contrast of the trigeminal nerve in a mouse nerve-tissue adhesion model. This study offers new insights for the development of intraoperatively applied nerve-specific contrast agents for delineating cranial nerves adhered to tumors.

Understanding the effect of alkyl chains of gemini cations on the physicochemical and cellular properties of polyurethane micelles.

Cationic gemini quaternary ammonium (GQA) has been used as a cell internalization promoter to improve the permeability of the cell membrane and enhance the cellular uptake. However, the effect of the alkyl chain length on the cellular properties of nanocarriers has not been elucidated yet. In this study, we developed a series of polyurethane micelles containing GQAs with various alkyl chain lengths. The alteration of the gemini alkyl chain length was found to change the distribution of GQA surfactants in the micellar structure and affect the surface charge exposure, stability, and the protein absorption properties of nanocarriers. Moreover, we also clarified the role of the alkyl chain length in tumor cell internalization and macrophage uptake of polyurethane micelles. This work provides a new understanding on the effect of the GQA alkyl chain length on the physicochemical and biological properties of nanomedicines, and offers guidance on the rational design of effective drug delivery systems where the issue of functional group exposure at the micellar surface should be considered.

Surface Distribution and Biophysicochemical Properties of Polymeric Micelles Bearing Gemini Cationic and Hydrophilic Groups.

Polymeric micelles containing cationic gemini quaternary ammonium (GQA) groups have shown enhanced cellular uptake and efficient drug delivery, while the incorporation of poly(ethylene glycol) (PEG) corona can potentially reduce the absorption of cationic carriers by opsonic proteins and subsequent uptake by mononuclear phagocytic system (MPS). To understand the interactions of GQA and PEG groups and their effects on the biophysicochemical characteristics of nanocarriers, a series of polyurethane micelles containing GQA and different molecular weights of PEG were prepared and carefully characterized. It was found that the GQA and PEG groups are unevenly distributed on the micellar surface to form two kinds of hydrophilic domains. As a result, the particle surface with some defects cannot be completely shielded by the PEG corona. Despite this, the longer PEG chains with a brush conformation provide superior stabilization and steric repulsion against the absorption of proteins and, thus, can reduce the cytotoxicity, protein absorption, and MPS uptake of micelles to some extent. This study provides a new understanding on the interactions between PEG chains and cationic groups and a guideline for the design and fabrication of safe and effective drug delivery systems.

Multifunctional Mixed Micelles Cross-Assembled from Various Polyurethanes for Tumor Therapy.

A challenge in the development of multifunctional drug delivery systems is to establish a reasonable and effective synthetic route for multifunctional polymer preparation. Herein, we propose a unique protocol to prepare multifunctional micelles by a cross-assembly process using three different functional polyurethanes incorporating acidic sensitive hydrazone, folic acid for active targeting, and gemini quaternary ammonium (GQA) as efficient cell uptake ligands, respectively. These multifunctional mixed micelles (GFHPMs) have been endowed tunable particle sizes and zeta potential and a unique three-order-layer cross-assemble structure. Their drug-loading contents have been significantly improved, and drug release profiles displayed controlled release of their payloads under acid condition. The folate and GQA ligands showed a synergistic effect to enhance the cell uptake. Biodistribution and antitumor effect of these micelles were systematically investigated in vivo, the mixed micelles could penetrate into the depths of tumors, and drug concentrations in tumors reached the maximum of 6.5% ID/g at 24 h, resulting in an excellent therapeutic effect that the volumes of tumors treated with GFHPM are five times smaller than those treated with blank micelles. Our present work provides an effective approach to the design of multifunctional nanocarriers for tumor-targeted and programmed intracellular drug delivery.

The preliminary study of immune superparamagnetic iron oxide nanoparticles for the detection of lung cancer in magnetic resonance imaging.

To improve the sensitive and specific detection of metastasis of lung cancer, this study fabricated immune superparamagnetic iron oxide nanoparticles (SPIONs) used in magnetic resonance (MR) immumoimaging. These SPIONs were coated with oleic acid and carboxymethyl dextran, and then conjugated to mouse anti-CD44v6 monoclonal antibody. The physicochemical properties of magnetic nanoparticles without monoclonal antibody were characterized by X-ray powder diffraction (XRD), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). The sizes of the nanoparticles were determined by dynamic light scattering measurements (DLS) and transmission electron microscope (TEM). Coated nanoparticles could well disperse in water with low dosage of CMD as the Fe/CMD ratio is 1/1 and 2/1 (w/w). Importantly, these SPIONs have relatively high saturation magnetization, as measured by vibrating sample magnetometer (VSM). They could efficiently become the transversal relaxation times (T2) contrast agent to improve detection limit through measured in vitro magnetic resonance imaging (MRI) and actively target human lung adenocarcinoma (A549) cells in vitro cell culture. Thus, these immune SPIONs are potentially useful for lung tumor-targeting diagnosis.