Nanoparticle-based Drug Delivery Systems Research Articles

To reduce premature drug release while ensuring burst intracellular drug release of solid lipid nanoparticle-based drug delivery system with clathrin modification

Nanoscale drug delivery system (NDDS) with slow premature drug release (PDR) while ensuring burst intracellular drug release (BIDR) is becoming a hot point in NDDS-based nanomedicine. Here we used clathrin to modify a solid lipid nanoparticle (SLN)-based NDDS of salinomycin (SLN-SAL) to prepare NDDS with reduced PDR while ensuring BIDR. Drug-release-kinetic experiments revealed that clathrin modified SLN-SAL (CMSLN-SAL) reduced PDR while ensured BIDR of its prototype NDDS, SLN-SAL. Mechanism experiments revealed that clathrin modification reduced PDR of SLN-SAL through increasing the mechanical strength of SLN-SAL and ensured BIDR of SLN-SAL through lipid membrane fusion after its clathrin shell was de-polymerized by a cytoplasm enzyme, HSC70. In addition, CMSLN-SAL had significantly higher intracellular uptake and stronger inhibitive effects on cancer cells than that of SLN-SAL. These results demonstrated that clathrin modification is an effective way to reduce PDR while ensuring BIDR and increasing the anticancer effects of SLN-based NDDS.

Nanoparticle-Based Oral Drug Delivery Systems Targeting the Colon for Treatment of Ulcerative Colitis.

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic relapsing inflammation of the gastrointestinal tract. Delivery of orally administered drugs to the colon is highly desirable for the treatment of UC, as it improves their efficacy while reducing systemic toxicity. However, the targeting of oral drugs to the colon, which is located at the distal end of the gastrointestinal tract, is difficult due to physiological challenges, biochemical barriers, and environmental barriers, including those associated with mucus and epithelium. Recent preclinical studies have indicated that nanoparticle-based drug delivery systems (DDS) may be promising tools for targeted delivery to the colon, with potentially effective outcomes in the treatment of UC. This review highlights general considerations and limitations for oral drug delivery to the colon. Further, this review provides a systematic evaluation of synthetic nanoparticle-based DDS, and emerging naturally derived nanoparticles (eg, extracellular vesicles and plant-derived nanoparticles). These novel nanoparticle-based treatment strategies for UC may offer the opportunity for the practical translation of nanoparticle formulas into the clinic.

Dual-pH-sensitive mesoporous silica nanoparticle-based drug delivery system for tumor-triggered intracellular drug release

Reducing the side effects and improving the drug utilization are important work in anti-cancer drug delivery. In this paper, a novel dual-pH-sensitive drug delivery system was reported. Mesoporous silica nanoparticle (MSN) was applied to load anti-cancer drug doxorubicin hydrochloride (DOX) and was covered by mono-6-deoxy-6-EDA-β-cyclodextrine (β-CD-NH2) to block the pores through pH-sensitive boronate ester bond. And the carriers were then coated with methoxy poly(ethylene glycol) (mPEG) through another pH-sensitive benzoic imine bond. mPEG leaving studies, in vitro cellular uptake studies and the flow cytometry analysis, proved that carriers was “stealthy” at pH 7.4, but could be “activated” for cytophagy by cancer cells in weakly acidic tumor tissues (pH 6.5) due to the departure of mPEG. β-CD-NH2 leaving studies, the in vitro drug release studies and the in vitro cytotoxicity studies proved that boronate ester bond linking MSN and β-CD-NH2 was stable at both pH 7.4 and 6.5, but could be hydrolyzed intracellular to release DOX for cellular apoptosis due to the lower pH (5.0). In summary, the novel dual-pH-sensitive drug delivery system fabricated with a dynamic protection strategy should have great application potential in anti-cancer drug delivery fields.

New Avenues for Nanoparticle-Related Therapies

Development of nanoparticle-based drug delivery systems has been attempted for the treatment of cancer over the past decade. The enhanced permeability and retention (EPR) effect is the major mechanism to passively deliver nanodrugs to tumor tissue. However, a recent systematic review demonstrated limited success of these studies, with the clearance of nanoparticles by the mononuclear phagocytic system (MPS) being a major hurdle. Herein, we propose that nanotechnologists should reconsider their research focuses, aiming for therapeutic targets other than cancer. Treatments for diseases that do not (or less) rely on EPR should be considered, such as active targeting or MPS evasion systems. For example, systemic delivery of drugs through intravenous injection can be used to treat sepsis, multi-organ failure, metabolic disorders, blood diseases, immune and autoimmune diseases, etc. Local delivery of nanodrugs to organs such as the lung, rectum, or bladder may enhance the local drug concentration with less clearance via MPS. In transplant settings, ex vivo organ perfusion provides a new route to repair injury of isolated organs in the absence of MPS. Based on a similar concept, chemotherapy with in vivo lung perfusion techniques and other isolated organ perfusion provides opportunities for cancer therapy.

Blood-Vessel-on-a-Chip Platforms for Evaluating Nanoparticle Drug Delivery Systems.

Nanoparticle-based drug delivery systems hold great promise for the treatment of major diseases. However, their slow translation from bench to the clinic posts a concern. It is mainly attributed to the lack of suitable in vitro platforms for rapid and accurate screening of nanomedicine. Recent developments in microfluidic technologies have provided the possibility to reproduce the biomimetic blood vessel microenvironments outside the body, thus offering a convenient means to characterize the in vivo dynamics and biological responses of nanoparticles during circulation. In this review, we discuss the challenges facing the field of nanoparticle drug delivery and highlight the urgent need for construction of blood-vessel-on-a-chip platforms for testing nanomedicine. We subsequently illustrate advances in fabricating various well-controlled blood-vessel-on-a-chip platforms, covering a few examples that have used such models for evaluating nanoparticle behaviors. We then summarize with conclusions and perspectives. We anticipate that, further development of these blood-vessel-on-a-chip platforms with improved biomimetic parameters, tissue specificity, and personalization, will enable their wide applications in drug screening including nanomedicine.

Titania and silica nanoparticles coupled to Chlorin e6 for anti-cancer photodynamic therapy.

In this study, light-sensitive photosensitizers (Chlorin e6, Ce6) were linked to TiO2 and SiO2 nanoparticles (NPs) in order to develop new kinds of NP-based drug delivery systems for cancer treatment by PDT. TiO2 or SiO2 NPs were modified either by the growth of a polysiloxane layer constituted of two silane reagents ((3-aminopropyl)triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS)) around the core (PEGylated NPs: TiO2@4Si-Ce6-PEG, SiO2@4Si-Ce6-PEG) or simply modified by APTES alone (APTES-modified NPs: TiO2-APTES-Ce6, SiO2-APTES-Ce6). Ce6 was covalently attached onto the modified TiO2 and SiO2 NPs via an amide bond. The absorption profile of the hybridized NPs was extended to the visible region of the light. The physicochemical properties of these NPs were explored by TEM, HR-TEM, XRD, FTIR and zeta potential. The photophysical characteristics including the light absorption, the fluorescence properties and the production reactive oxygen species (1O2 and HO) were also addressed. In vitro experiments on glioblastoma U87 cells were performed to evaluate the photodynamic efficiency of the new hybridized NPs. The cells were exposed to different concentrations of NPs and illuminated (λexc = 652 nm, fluence rate 10 J/cm2). In contrast to the PEGylated NPs, the APTES-modified nanosystems were found to be more efficient for PDT. An interesting photodynamic effect was observed in the case of TiO2-APTES-Ce6 NPs. After illumination, the viability of U87 was decreased by 89% when they were exposed to 200 μg/mL of TiO2-APTES-Ce6 NPs, which corresponds to 0.22 μM of Ce6. The same effect can be obtained with free photosensitizer but using a higher concentration of 10 μM of Ce6.

Manipulating the Ordered Nanostructure of Self-Assembled Monoolein and Phytantriol Nanoparticles with Unsaturated Fatty Acids.

Mesophase structures of self-assembled lyotropic liquid crystalline nanoparticles are important factors that directly influence their ability to encapsulate and release drugs and their biological activities. However, it is difficult to predict and precisely control the mesophase behavior of these materials, especially in complex systems with several components. In this study, we report the controlled manipulation of mesophase structures of monoolein (MO) and phytantriol (PHYT) nanoparticles by adding unsaturated fatty acids (FAs). By using high throughput formulation and small-angle X-ray scattering characterization methods, the effects of FAs chain length, cis-trans isomerism, double bond location, and level of chain unsaturation on self-assembled systems are determined. Additionally, the influence of temperature on the phase behavior of these nanoparticles is analyzed. We found that in general, the addition of unsaturated FAs to MO and PHYT induces the formation of mesophases with higher Gaussian surface curvatures. As a result, a rich variety of lipid polymorphs are found to correspond with the increasing amounts of FAs. These phases include inverse bicontinuous cubic, inverse hexagonal, and discrete micellar cubic phases and microemulsion. However, there are substantial differences between the phase behavior of nanoparticles with trans FA, cis FAs with one double bond, and cis FAs with multiple double bonds. Therefore, the material library produced in this study will assist the selection and development of nanoparticle-based drug delivery systems with desired mesophase.

Synchrotron-based X-ray fluorescence study of gold nanorods and skin elements distribution into excised human skin layers.

Understanding the distribution of nanoparticles in skin layers is fundamentally important and essential for developing nanoparticle-based dermal drug delivery systems. In the present study, we provide insights into the distribution of gold nanorods (GNRs) functionalized with hydrophobic or hydrophilic ligands in human skin layers using synchrotron X-ray fluorescence (SR-XRF) spectroscopy, confocal microscopy, and transmission electron microscopy. The results confirmed the important role that the surface chemistry of GNRs plays in their penetration into the skin; the GNRs coated with polyethylene glycol were distributed into the skin layers to a greater extent than the GNRs coated with hydrophobic polystyrene thiol. In addition, SR-XRF analysis revealed that the spatial distribution of endogenous elements (phosphorus and sulfur) in skin layers demonstrated a significant "anti-correlation" relationship with that of GNRs. These results suggest possible association (via adsorption) between the GNRs and these two elements localized in skin, which can be valuable for understanding the penetration mechanism of gold nanoparticles into the skin.

Co-loading of photothermal agents and anticancer drugs into porous silicon nanoparticles with enhanced chemo-photothermal therapeutic efficacy to kill multidrug-resistant cancer cells.

The development of nanoparticles-based drug delivery systems with a high therapeutic efficacy is necessary to treat multidrug-resistant (MDR) cancer cells. Herein, photothermal agents (IR820 dyes) and anticacner drugs (doxorubicin, DOX) were successively incorporated into amino-terminated porous silicon nanoparticles (NH2-PSiNPs) via electrostatic attractions, to prepare DOX/IR820/NH2-PSiNPs nanocomposites with a high loading amount of DOX (13.3%, w/w) and IR820 (18.6%, w/w), respectively. Meanwhile, DOX molecules were also directly loaded into NH2-PSiNPs to form DOX/NH2-PSiNPs nanocomposites (DOX, 18.7%, w/w). Compared with low release percentage (20.3%) of DOX molecules from DOX/NH2-PSiNPs in acidic environments under NIR laser irradiation, DOX/IR820/NH2-PSiNPs had dual pH/NIR light-triggered release and their release percentage could reach 88.1% under the same conditions. Furthermore, cellular interactions tests demonstrated that DOX/IR820/NH2-PSiNPs could delivery more DOX molecules into the nuclei of MDR cancer cells, with efficient intracellular release triggered by NIR light, in contrast to DOX/NH2-PSiNPs. Finally, DOX/IR820/NH2-PSiNPs exhibited an enhanced chemo-photothermal therapeutic efficacy (cell viability, 38.4%) of killing MDR cancer cells in vitro, compared with 85.4% of free DOX and 75.9% of DOX/NH2-PSiNPs. Therefore, based on PSiNPs-based nanocarriers conjugated with photothermal agents and anticancer drugs, NIR light-triggered drug delivery system with higher efficacy of combined chemo-photothermal therapy would have important potential on MDR cancer treatments in future.

Synthesis and Evaluation of Doxorubicin-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

Doxorubicin is an effective and widely used cancer chemotherapeutic agent, but its application is greatly compromised by its cumulative dose-dependent side effect of cardiotoxicity. A gold nanoparticle-based drug delivery system has been designed to overcome this limitation. Five novel thiolated doxorubicin analogs were synthesized and their biological activities evaluated. Two of these analogs and PEG stabilizing ligands were then conjugated to gold nanoparticles, and the resulting Au-Dox constructs were evaluated. The results show that release of native drug can be achieved by the action of reducing agents such as glutathione or under acidic conditions, but reductive drug release gave the cleanest drug release. Gold nanoparticles (Au-Dox) were prepared with different loadings of PEG and doxorubicin, and one formulation was evaluated for mammalian stability and toxicity. Plasma levels of doxorubicin in mice treated with Au-Dox were significantly lower than in mice treated with the same amount of doxorubicin, indicating that the construct is stable under physiological conditions. Treatment of mice with Au-Dox gave no histopathologically observable differences from mice treated with saline, while mice treated with an equivalent dose of doxorubicin showed significant histopathologically observable lesions.

The uptake, retention and clearance of drug-loaded dendrimer nanoparticles in astrocytes - electrophysiological quantification.

Nanoparticle-based drug delivery systems may impose risks to patients due to potential toxicity associated with a lack of clearance from cells or prolonged carrier-cell retention. This work evaluates vesicular cell uptake, retention and the possible transfer of endocytosed methylprednisolone-loaded carboxymethylchitosan/poly(amidoamine) dendrimer nanoparticles (NPs) into secretory vesicles of rat cultured astrocytes. The cells were incubated with NPs and unitary vesicle fusions/fissions with the plasma membrane were monitored employing high-resolution membrane capacitance measurements. In the NP-treated cells the frequency of unitary exocytotic events was significantly increased. The presence of NPs also induces an increase in the size of exocytotic vesicles interacting with the plasma membrane, which exhibit transient fusion with prolonged fusion pore dwell-time. Live-cell confocal imaging revealed that once NPs internalize into endocytotic compartments they remain in the cell for 7 days, although a significant proportion of these merge with secretory vesicles destined for exocytosis. Co-localization studies show the route of clearance of NPs from cells via the exocytotic pathway. These findings bring new insight into the understanding of the intracellular trafficking and biological interactions of drug-loaded dendrimer NPs targeting astrocytes.

Mesoporous silica nanoparticle-based intelligent drug delivery system for bienzyme-responsive tumour targeting and controlled release.

This paper proposes a novel type of multifunctional envelope-type mesoporous silica nanoparticle (MSN) to achieve cancer cell targeting and drug-controlled release. In this system, MSNs were first modified by active targeting moiety hyaluronic acid (HA) for breast cancer cell targeting and hyaluronidases (Hyal)-induced intracellular drug release. Then gelatin, a proteinaceous biopolymer, was grafted onto the MSNs to form a capping layer via glutaraldehyde-mediated cross-linking. To shield against unspecific uptake of cells and prolong circulation time, the nanoparticles were further decorated with poly(ethylene glycol) polymers (PEG) to obtain MSN@HA-gelatin-PEG (MHGP). Doxorubicin (DOX), as a model drug, was loaded into PEMSN to assess the breast cancer cell targeting and drug release behaviours. In vitro study revealed that PEG chains protect the targeting ligand and shield against normal cells. After reaching the breast cancer cells, MMP-2 overpressed by cells hydrolyses gelatin layer to deshield PEG and switch on the function of HA. As a result, DOX-loaded MHGP was selectively trapped by cancer cells through HA receptor-mediated endocytosis and subsequently release DOX due to Hyal-catalysed degradation of HA. This system presents successful bienzyme-responsive targeting drug delivery in an optimal fashion and provides potential applications for targeted cancer therapy.

Tunable Collagen Microfluidic Platform to Study Nanoparticle Transport in theTumor Microenvironment.

This chapter describes the motivation and protocol for creating a perfused 3D microfluidic in vitro platform representative of the tumor microenvironment to study nanoparticle transport. The cylindrical vascularized tumor platform described consists of a central endothelialized microchannel surrounded by a collagen hydrogel matrix containing cancer cells. This system can be employed to investigate key nanoparticle transport events in the tumor such as extravasation, diffusion within the extracellular matrix, and nanoparticle uptake. This easily manufactured tumor platform can be used for novel nanoparticle refinement focused on optimizing nanoparticle features such as size, shape, and functionalization method. This can yield ideal nanoparticles with properties that facilitate increased transport within the tumor microenvironment, leading to more effective nanoparticle-based treatments for cancer including nanoparticle-based drug delivery systems.

Nanoparticles for Targeted Drug Delivery to Cancer Stem Cells and Tumor.

Due to the drug resistance of cancer stem cells (CSCs), CSC-targeted delivery of multiple drugs in nanoparticle-based drug delivery system holds great potential for the destruction of the CSCs and Tumor. In this chapter, we describe the preparation of multi-layered pH-responsive polymeric nanoparticles (NPs) by multiple emulsifications to encapsulate multiple hydrophilic and hydrophobic theranostic agents for controlled and sequenced release. Hyaluronic acid (HA) is used for not only actively targeting the CSCs to reduce their drug resistance due to dormancy (i.e., slow metabolism), but also replacing the commonly used poly (vinyl alcohol) (PVA) as a stabilizing agent to synthesize the nanoparticles.

Utilizing the Lung as aModel to Study Nanoparticle-Based Drug Delivery Systems.

Intranasal administration is a highly effective route for drug delivery and biodistribution studies. Indeed, this route of delivery has become the method of choice to distribute diverse pharmacological agents both locally and systemically. In the majority of preclinical animal models and in human patients, intranasal administration is the preferred method to deliver therapeutic agents to the airways and lungs. However, issues with drug stability and controlled release in the respiratory tract are common problems with many therapeutic agents. Nanoparticle delivery via intranasal administration has tremendous potential to circumvent these common issues. Over the past 30years nanoparticles have gained increased interest as therapeutic delivery vehicles and as tools for improved bioimaging. Integral to the success of nanoparticles in drug delivery and biodistribution is the utilization of mouse models to characterize therapeutic strategies under physiologically relevant in situ conditions. Here, we describe a model of nanoparticle administration to the lungs utilizing intranasal administration and discuss a variety of highly useful techniques to evaluate nanoparticle up-take, biodistribution, and immune response. While these protocols have been optimized for intranasal administration of common fluorescently labeled nanoparticles, they can be applied to any nanoparticle or drug delivery system of interest targeting the lungs and airways.

Lipid bilayer nanoparticle-based drug delivery systems in the treatment of rheumatoid arthritis: a glance at liposomes and exosomes

Lipid bilayer nanoparticle-based drug delivery systems in the treatment of rheumatoid arthritis: a glance at liposomes and exosomes

Antibody-pHPMA functionalised fluorescent silica nanoparticles for colorectal carcinoma targeting.

The systemic application of highly potent drugs such as cytostatics poses the risks of side effects, which could be reduced by using a carrier system able to specifically deliver the encapsulated drug to the target tissue. Essential components of a nanoparticle-based drug delivery system include the drug carrier itself, a targeting moiety, and a surface coating that minimizes recognition by the immune system. The present work reports on the preparation, in vitro characterization and in vivo testing of a new delivery system consisting of fluorescent silica nanoparticles functionalised with a non-immunogenic stealth polymer poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA) and a monoclonal antibody IgG M75 that specifically binds to Carbonic Anhydrase IX (CA IX). CA IX is a promising therapeutic target, as it is a hallmark of several hypoxic tumours including colorectal carcinoma. Uniquely in this work, the monoclonal antibody was covalently coupled to the surface of fluorescently labelled silica nanoparticles via a multivalent amino-reactive co-polymer rather than a traditional bivalent linker. The pHPMA-M75 functionalised SiO2 nanoparticles exhibited excellent colloidal stability in physiological media. Their in vitro characterisation by flow cytometry proved a highly specific interaction with colorectal carcinoma cells HT-29. In vivo study on athymic NU/NU nude mice revealed that the SiO2–pHPMA-M75 nanoparticles are capable of circulating in the blood after intravenous administration and accumulate in the tumour at tenfold higher concentration than nanoparticles without specific targeting, with a considerably longer retention time. Additionally, it was found that by reducing the dose administered in vivo, the selectivity of the nanoparticle biodistribution could be further enhanced in favour of the tumour.

PH-responsive gold nanoclusters-based nanoprobes for lung cancer targeted near-infrared fluorescence imaging and chemo-photodynamic therapy

Nanoparticle-based drug delivery systems have drawn a great deal of attention for their opportunities to improve cancer treatments over intrinsic limits of conventional cancer therapies. Herein, we developed the polypeptide-modified gold nanoclusters (GNCs)-based nanoprobes for tumor-targeted near-infrared fluorescence imaging and chemo-photodynamic therapy. The nanoprobes comprise of tetra-functional components: i) polyethylene glycol (PEG) shell for long blood circulation and better biocompatibility; ii) MMP2 polypeptide (CPLGVRGRGDS) for tumor targeting; iii) cis-aconitic anhydride-modified doxorubicin (CAD) for pH-sensitive drug release; iv) photosensitizer chlorin e6 (Ce6) for photodynamic therapy and fluorescence imaging. The in vitro results demonstrated that the as-synthesized nanoprobes could be efficiently internalized into A549 cells and then significantly enhance the mortality of cancer cells compared with free Ce6 and doxorubicin. For in vivo tests, the nanoprobes showed excellent tumor targeting ability, long blood circulation time, and could remarkably inhibit the growth of tumor. Our results will help to advance the design of combination strategies to enhance the efficacy of imaging-guided cancer therapy. Statement of SignificanceThe as-prepared CDGM NPs could accumulate into the tumor tissue with the enhanced permeability and retention (EPR) effect as well as the active tumor targeting ability from the MMP2 polypeptides.With the acid-sensitive linker, the doxorubicin (DOX) would be released from the synthesized nanoparticles after exposing to the acid tumor microenvironment.The CDGM NPs exhibit excellent tumor targeting ability and could remarkably suppress the growth of tumor compared with free Ce6 and DOX.

Receptor-Mediated Endocytosis of Nanoparticles: Roles of Shapes, Orientations, and Rotations of Nanoparticles.

A complete understanding of the interactions between nanoparticles (NPs) and the cell membrane is essential for the potential biomedical applications of NPs. The rotation of the NP during the cellular wrapping process is of great biological significance and has been widely observed in experiments and simulations. However, the underlying mechanisms of the rotation and their potential influences on the wrapping behavior are far from being fully understood. Here, by coupling the rotation of the NP with the diffusion of the receptors, we set up a model to theoretically investigate the wrapping pathway and the internalization rate of the rotatable NP in the receptor-mediated endocytosis. Based on this model, it is found that the endocytosis proceeds through the symmetric-asymmetric or asymmetric-symmetric-asymmetric wrapping pathway due to the bending and membrane tension competition induced rotation of NP. In addition, we show that the wrapping rate in the direction that the wrapping proceeds can be largely accelerated by the rotation. Moreover, the time to fully wrap the NP depends not only on the size and shape of the NP but also on its rotation and initial orientation. These results reveal the roles of the shape, rotation, and initial orientation of the NP on the receptor-mediated endocytosis and may provide guidelines for the design of NP-based drug delivery systems.

Nanoparticle structure transformation of mPEG grafted chitosan with rigid backbone induced by α-cyclodextrin

This paper presented an interesting nanoparticle-based drug delivery system with morphology transition behavior depending on the content of exposed PEG chain on the particle surface, which is adjustable by addition of different amount of cyclodextrin (α-CD). The effect of α-CD inclusion to the self-assembly behavior of methoxy polyethylene glycol (mPEG) grafted chitosan (CS) was studied. The results showed that the mPEG grafted chitosan (mPEG-g-CS) forms self-assembled nanoparticles with either micelle or hollow sphere morphology depending on the ratio of α-CD to mPEG, as characterized by atomic force microscopy (AFM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). Their sizes and zeta potential increased from 257.6 nmto 768.2nm and from +4.5mV to +11.6mV, respectively, with the increasing amount of α-CD. The correlation between zeta potential and particle size of α-CD/mPEG-g-CS nanoparticles indicated varied PEG density on surface of nanoparticles. Based on the above experimental observations, a likely mechanism for the morphological transition of the rod-coil graft copolymer mPEG-g-CS was proposed.