Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).     

The Peptide Functionalized Inorganic Nanoparticles for Cancer-Related Bioanalytical and Biomedical Applications

In order to improve their bioapplications, inorganic nanoparticles (NPs) are usually functionalized with specific biomolecules. Peptides with short amino acid sequences have attracted great attention in the NP functionalization since they are easy to be synthesized on a large scale by the automatic synthesizer and can integrate various functionalities including specific biorecognition and therapeutic function into one sequence. Conjugation of peptides with NPs can generate novel theranostic/drug delivery nanosystems with active tumor targeting ability and efficient nanosensing platforms for sensitive detection of various analytes, such as heavy metallic ions and biomarkers. Massive studies demonstrate that applications of the peptide–NP bioconjugates can help to achieve the precise diagnosis and therapy of diseases. In particular, the peptide–NP bioconjugates show tremendous potential for development of effective anti-tumor nanomedicines. This review provides an overview of the effects of properties of peptide functionalized NPs on precise diagnostics and therapy of cancers through summarizing the recent publications on the applications of peptide–NP bioconjugates for biomarkers (antigens and enzymes) and carcinogens (e.g., heavy metallic ions) detection, drug delivery, and imaging-guided therapy. The current challenges and future prospects of the subject are also discussed.     

Single-step process to produce surface-functionalized polymeric nanoparticles

Nanoparticles (NPs) are a versatile medium for the localization of therapeutics to tumors and for cellular and tissue imaging. The ability to impart targeting capability or enhance cellular uptake is dependent in part on the presentation of relevant surface functionality, among other design parameters. Currently, the production of functionalized polymeric NPs requires the a priori synthesis of polymers bearing such functionality. Here we describe a process to produce functionalized polymeric NPs derived from nonfunctional polymers in a single step. This was achieved by tailoring the solvation of the polymer using a binary solvent system such that the addition of an aqueous phase rich in water-soluble polymer or polyelectrolytes results in the formation of NPs with the concomitant functionalization of NP surfaces with the polymeric moieties introduced into the aqueous phase. This strategy also allows for easy control over NP size independent of surface functionality. We have demonstrated that poly(lactic-co-glycolic acid) (PLGA) NPs bearing surface functionality as diverse as biological polysaccharides such as heparin, water-soluble ionic polymers, and poly(ethylene glycol) can be prepared under identical conditions in a single step, with surface coverage (mass %) ranging from 3 to >70%. We expect this novel process to enable complex surface engineering of NP chemistry that hitherto was impossible using existing approaches.     

Disruption of supported lipid bilayers by semihydrophobic nanoparticles

Understanding the interaction between functional nanoparticles and cell membranes is critical to use nanomaterials for broad biomedical applications with minimal cytotoxicity. In this work, we have investigated the effect of adsorbed semihydrophobic nanoparticles (NPs) on the dynamics and morphology of model cell membranes. We have systematically varied the degree of surface hydrophobicity of carboxyl end-functionalized polystyrene NPs of varied size in buffer solutions with varied ionic strength. It is observed that semihydrophobic NPs can readily adsorb on neutral SLBs and drag lipids from SLBs to NP surfaces. Above a critical NP concentration, the disruption of SLBs is observed, accompanied with the formation and rapid growth of lipid-poor regions on NP-adsorbed SLBs. In the study of the effect of solution ionic strength on NP surface hydrophobic degree and the growth of lipid-poor regions, we have concluded that the hydrophobic interaction enhanced by screened electrostatic interaction underlies the envelopment of NPs by lipids that are attracted from SLBs to the surface of NPs or their aggregates. Hence, the formation and growth of lipid-poor regions, or vaguely referred as "pores" or "holes" in the literature, can be controlled by NP concentration, size, and surface hydrophobicity, which is critical to design functional nanomaterials for effective nanomedicine while minimizing possible cytotoxicity.     

A C5N2 Nanoparticle Based Direct Nucleus Delivery Platform for Synergistic Cancer Therapy

Intracellular targeting has the same potential as tissue targeting to increase therapy efficacy, especially for drugs that are toxic to DNA. By adjusting intracellular traffic, we developed a novel direct‐nucleus‐delivery platform based on C₅N₂ nanoparticles (NPs). Supramolecular interactions of C₅N₂ NPs with the cell membrane enhanced cell uptake; abundant edge amino groups promoted fast and effective rupture of early endosomes; and the appropriate size of the NPs was also crucial for size‐dependent nuclear entry. As a proof of concept, the platform was not only suitable for the effective delivery of molecular drugs/dyes (doxorubicin, hydroxycamptothecine, and propidium iodide) and MnO₂ nanoparticles to the nucleus, but was also photoresponsive for nucleus‐targeting photothermal therapy (PTT) and photodynamic therapy (PDT) to further greatly increase anticancer efficacy. This strategy might open the door to a new generation of nuclear‐targeted enhanced anticancer therapy.     

Size and surface effects on the magnetic properties of NiO nanoparticles

NiO nanoparticles (NPs) were prepared by a sol-gel process using the citrate route. The sol-gel parameters were tuned to obtain samples with different average particle sizes, ranging from 12 to 70 nm. Magnetic characterization revealed an increase in the blocking temperature with the diameter of the NPs and an increase in the effective magnetic anisotropy (K(eff)) with decreasing particle size. The magnetic moment per particle was calculated for all samples using the susceptibility value at T = 300 K. The number of uncompensated spins per NP was found to be proportional to n (n(S)≡ total number of spins), indicating that they are randomly distributed on the NP surface. For small diameters (<30 nm) the surface anisotropy constant was estimated, using, for NiO NPs, a recent model describing the evolution of K(eff) with particle size. Hysteretic loops performed at low temperatures after field cooling displayed loop shifts (～6.5 kOe in the field axis and ～0.18 emu g(-1) vertically), coercive field enhancement (H(C)≈ 4.8 kOe) and training effects for the smaller NPs. The sample with NPs of larger diameters presented magnetic properties close to those of bulk NiO.     

纳米粒子的精准组装

纳米材料由于其独特的光、电、磁、力学等性质,成为了构建功能材料与器件的理想基元。实现纳米粒子的精确组装,是探究粒子之间的耦合聚集性质和制备宏观功能器件的基础。但是由于纳米粒子的小尺寸以及在溶液中运动的随机性与复杂性,精准控制纳米粒子组装体的形貌以及在空间中的相对位置仍存在巨大挑战。为了将纳米粒子组装成理想的有序结构,许多控制粒子组装的策略与方法得到发展。本文首先概述了纳米粒子自组装的控制方法与典型形貌,着重分析了影响粒子精准排布的因素与控制方法,并对纳米粒子及其组装体的光学性质与器件应用的最新研究进展进行了讨论,最后对目前纳米粒子精准组装所面临的挑战以及未来发展的方向进行了展望。     

Size tuning of luminescent silicon nanoparticles with meso-porous silicon membranes

Size tuning of silicon (Si) nanoparticles (NPs) with the use of meso-porous silicon (meso-PS) free-standing layers is reported for the first time. Accumulation of Si NPs inside the membrane pores during the filtering process (NP transport through the meso-PS) leads to an auto-filtration effect (called Si-by-Si (SBS) filtration) allowing more efficient size selection of the NPs. General complex fractal shape and surface chemistry of the whole porous network, layer thickness as well as a given initial NP size dispersion determine final size of the NPs in the filtered solution. Moreover, quantum of step-like NP size increasing equal to 0.12 nm was found.     

Ultra‐pH‐Responsive and Tumor‐Penetrating Nanoplatform for Targeted siRNA Delivery with Robust Anti‐Cancer Efficacy

RNA interference (RNAi) gene silencing technologies have shown significant potential for treating various diseases, including cancer. However, clinical success in cancer therapy remains elusive, mainly owing to suboptimal in vivo delivery of RNAi therapeutics such as small interference RNA (siRNA) to tumors. Herein, we developed a library of polymers that respond to a narrow pH change (ultra‐pH‐responsive), and demonstrated the utility of these materials in targeted and deep tumor‐penetrating nanoparticle (NP) for in vivo RNAi. The new NP platform is mainly composed of the following key components: i) internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration; ii) polyethylene glycol (PEG) chains to prolong blood circulation; and iii) sharp pH‐responsive hydrophobic polymer to improve endosome escape. Through systematic studies of structure–function relationship, the optimized RNAi NPs (<70 nm) showed efficient gene silencing and significant inhibition of tumor growth with negligible toxicities in vivo.     

Temperature triggered self-assembly of polypeptides into multivalent spherical micelles

We report herein thermally responsive elastin-like polypeptides (ELPs) in a linear AB diblock architecture with an N-terminal peptide ligand that self-assemble into spherical micelles when heated slightly above body temperature. A series of 10 ELP block copolymers (ELP(BC)'s ) with different molecular weights and hydrophilic-to-hydrophobic block ratios were genetically synthesized by recursive directional ligation. The self-assembly of these polymers from unimers into micelles was investigated by light scattering, fluorescence spectroscopy, and cryo-TEM. These ELP(BC)'s undergo two phase transitions as a function of solution temperature: a unimer-to-spherical micelle transition at an intermediate temperature and a micelle-to-bulk aggregate transition at a higher temperature when the hydrophilic-to-hydrophobic block ratio is between 1:2 and 2:1. The critical micelle temperature is controlled by the length of the hydrophobic block, and the size of the micelle is controlled by both the total ELP(BC) length and hydrophilic-to-hydrophobic block ratio. These polypeptide micelles display a critical micelle concentration in the range 4-8 microM demonstrating the high stability of these structures. These studies have also identified a subset of ELP(BC)'s bearing terminal peptide ligands that are capable of forming multivalent spherical micelles that present multiple copies of the ligand on their corona in the clinically relevant temperature range 37-42 degrees C and target cancer cells. These ELP(BC)'s may be useful for drug targeting by thermally triggered multivalency. More broadly, the design rules uncovered by this study should be applicable to the design of other thermally reversible nanoparticles for diverse applications in medicine and biology.     

Imidazolium-based zwitterionic surfactant: a new amphiphilic Pd nanoparticle stabilizing agent

Palladium nanoparticles (NPs) with an average size of 3.4 nm were prepared in water using imidazolium-based surfactant 3-(1-dodecyl-3-imidazolio)propanesulfonate (ImS3-12) as a stabilizer. The Pd NPs are highly dispersible in water and chloroform and were characterized by transmission electron microscopy, energy-dispersive X-ray spectroscopy, powder X-ray diffraction, and dynamic light scattering. The results indicate that in water the NP surface is covered with a double layer of ImS3-12 molecules. The NPs were effective in the aqueous biphasic hydrogenation of cyclohexene, with easy recycling and no loss of catalytic activity after four successive runs.     

Hydrophobic Cysteine Poly(disulfide)‐based Redox‐Hypersensitive Nanoparticle Platform for Cancer Theranostics

Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus‐sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side‐effects. We report the development of a novel L ‐cysteine‐based poly (disulfide amide) (Cys‐PDSA) family for fabricating redox‐triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt % docetaxel) and tunable properties. The polymers are synthesized through one‐step rapid polycondensation of two nontoxic building blocks: L ‐cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydrophobicity, degradation rate, redox response, and secondary self‐assembly after NP reductive dissociation. In vitro and in vivo results demonstrate these NPs’ excellent biocompatibility, high selectivity of redox‐triggered drug release, and significant anticancer performance. This system provides a promising strategy for advanced anticancer theranostic applications.     

Cell-bound nanoparticles for tissue targeting and immunotherapy: Engineering of the particle–membrane interface

Nanoparticles (NPs) have been developed as vehicles for delivering a variety of payloads including small molecules, nucleic acids, and proteins. To overcome the non-specific biodistribution of nanomaterials and target specific sites in vivo, there has been a surge of interest in using autologous cells as NP carriers. To design cell– NP constructs for active targeting, an understanding of the physicochemical interactions that underline NP adhesion, detachment, and uptake is necessary. In this article, we critically analyze the various properties that affect cell–nanomaterial interactions. We describe how physical properties of the cellular plasma membrane such as curvature, membrane tension, and lipid composition affect the attachment of NPs. We discuss the effect of NP properties including size, shape, stiffness, and chemical composition as well as the environmental conditions on the cell–NP interactions. We conclude with an overview of recent applications of cell–NP constructs including cellular hitchhiking, backpacking, and responsive surface attachment for drug delivery.     

Construction of nanoparticle superstructures on the basis of host-guest interaction to achieve performance integration and modulation

Creation of nanoparticle (NP) architectures via a self-assembly strategy is the current means to integrate and/or modulate the functionalities of NPs. In this paper, we demonstrate the capability for constructing NP spherical superstructures through the specific interaction between host and guest molecules, for instance the model system of α-cyclodextrin (α-CD) and oleic acid (OA), which are decorated on two different NPs beforehand. Subsequently, the OA-decorated hydrophobic NPs are dispersed in hexane, whereas the α-CD-decorated NPs are dispersed in water. The blending of these two immiscible solutions produces NP binary superstructures because of the multiple linkages between the α-CD- and OA-decorated NPs. Control experiments indicate that the self-assembly of NPs occurs either at the hexane/water interface to form hybrid films or in the aqueous phase to generate spherical architectures, which strongly depends on the amount and the size of α-CD-decorated NPs. The high ratio and small size of the α-CD-decorated NPs facilitate the formation of spherical architectures. Competitive experiments with the addition of host α-CD and guest sodium oleate clearly confirm that the main driving force for the NP co-assembly is the specific interaction between α-CD and OA. In addition, the flexible decoration of α-CD and OA on the NPs makes the current strategy generally applicable for a variety of NPs, such as the superstructures of Au/Fe(3)O(4), Pt/Fe(3)O(4), and Au/NaYF(4):Yb,Tm, which is expected to promote the further application of NPs in environmental and biological sciences.     

Gold-Speckled SPION@SiO2 Nanoparticles Decorated with Thiocarbohydrates for ASGPR1 Targeting: Towards HCC Dual Mode Imaging Potential Applications

Efforts are made to perform an early and accurate detection of hepatocellular carcinoma (HCC) by simultaneous exploiting multiple clinically non-invasive imaging modalities. Original nanostructures derived from the combination of different inorganic domains can be used as efficient contrast agents in multimodal imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) and Au nanoparticles (NPs) possess well-established contrasting features in magnetic resonance imaging (MRI) and X-ray computed tomography (CT), respectively. HCC can be targeted by using specific carbohydrates able to recognize asialoglycoprotein receptor 1 (ASGPR1) overexpressed in hepatocytes. Here, two different thiocarbohydrate ligands were purposely designed and alternatively conjugated to the surface of Au-speckled silica-coated SPIONs NPs, to achieve two original nanostructures that could be potentially used for dual mode targeted imaging of HCC. The results indicated that the two thiocarbohydrate decorated nanostructures possess convenient plasmonic/superparamagnetic properties, well-controlled size and morphology and good selectivity for targeting ASGPR1 receptor.     

Capping nanoparticles with graphene quantum dots for enhanced thermoelectric performance

Graphene quantum dots (GQDs) are shown to serve as phase transfer agents to transfer various types of nanoparticles (NPs) from non-polar to polar solvents. Thorough characterization of the NPs proves complete native ligand exchange. Pellets of this GQD–NP composite show that the GQDs limit the crystal size during spark plasma sintering, yielding enhanced thermoelectric performance compared with NPs exchanged with inorganic ions. A photoluminescence study of the GQD–NP composite also suggests energy transfer from GQDs to NPs.     

Concentration–polarization effect of poly(sodium styrene sulfonate) on size distribution of colloidal silver nanoparticles during diafiltration experiments

Polyelectrolyte (PEL)-based dual systems and nanoparticles (NPs) are two topics which have generated great interest as a result of their many and novel applications. Here, PEL–NPs system which appears transitorily when a high molecular weight PEL solution is mixed with metal NP colloidal dispersions during diafiltration is studied. The aim of this paper was to analyze the concentration–polarization effect of PEL molecules on size distribution of NPs capable to pass through the ultrafiltration membrane. Poly(sodium styrene sulfonate) (PSSNa) and silver nanoparticles (AgNPs) were used as PEL and metal NP colloidal dispersion, respectively. It was seen that particle size decreased from 42.4?±?37.8 to 10.1?±?0.7 nm in the presence of PSSNa and concentration–polarization. In addition, our results indicate that polarization–concentration phenomenon can be used to modify the size distribution of NP colloidal dispersions, that by changes of polarization–concentration features is possible the modification of NP size in the permeate during diafiltration experiments and that in presence of concentration–polarization, PSSNa was only a modifier factor of medium. In addition, it was observed that exclusion size of ultrafiltration membrane is an important element for establishing of particle size in the permeate.     

Synthesis of copper nanoparticles stabilized by polyoxyethylenesorbitan monooleate

We studied the influence of synthesis parameters and the composition of the reaction mixture on the size and morphology of copper nanoparticles (NPs). Use of a surfactant (polyoxyethylenesorbitan monooleate) is promising for confining NP growth and stabilizing NPs. Concentration ranges of existence were determined for copper NP dispersions stable to aggregation and sedimentation. Scanning electron microscopy and dynamic light scattering were used to show that: the NP size varied from 10 to 65 nm, the average diameter was 25–35 nm, and the shape was spherical. The sizes of copper NP aggregates were determined.     

Polyelectrolyte-templated synthesis of bimetallic nanoparticles

Bimetallic nanoparticles (NPs) are known to exhibit enhanced optical and catalytic properties that can be optimized by tailoring NP composition, size, and morphology. Galvanic deposition of a second metal onto a primary metal NP template is a versatile method for fabricating bimetallic NPs using a scalable, solution-based synthesis. We demonstrate that the galvanic displacement reaction pathway can be controlled through appropriate surface modification of the NP template. To synthesize bimetallic Au-Ag NPs, we used colloidal Ag NPs modified by layer-by-layer (LBL) assembled polyelectrolyte layers to template the reduction of HAuCl(4). NPs terminated with positively and negatively charged polyelectrolytes yield highly contrasting morphologies and Au surface concentrations. We propose that these charged surface layers control galvanic charge transfer by controlling nucleation and diffusion at the deposition front. This surface-directed synthetic strategy can be advantageously used to tailor both overall NP morphology and Au surface concentrations.