Nanoparticle-based Drug Delivery Systems Research Articles

Cell-mediated and cell membrane-coated nanoparticles for drug delivery and cancer therapy

Nanotechnology-based drug delivery platforms have been developed over the last two decades because of their favorable features in terms of improved drug bioavailability and stability. Despite recent advancement in nanotechnology platforms, this approach still falls short to meet the complexity of biological systems and diseases, such as avoiding systemic side effects, manipulating biological interactions and overcoming drug resistance, which hinders the therapeutic outcomes of the NP-based drug delivery systems. To address these issues, various strategies have been developed including the use of engineered cells and/or cell membrane-coated nanocarriers. Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions, targeting, and homing of either engineered cells or cell membrane-coated nanocarriers to the sites of interest. In this context, we comprehensively discuss various cell- and cell membrane-based drug delivery approaches towards cancer therapy, the therapeutic potential of these strategies, and the limitations associated with engineered cells as drug carriers and cell membrane-associated drug nanocarriers. Finally, we review various cell types and cell membrane receptors for their potential in targeting, immunomodulation and overcoming drug resistance in cancer.

The Use of Nanomedicine for Targeted Therapy against Bacterial Infections.

The emergence of drug resistance combined with limited success in the discovery of newer and effective antimicrobial chemotherapeutics poses a significant challenge to human and animal health. Nanoparticles may be an approach for effective drug development and delivery against infections caused by multi-drug resistant bacteria. Here we discuss nanoparticles therapeutics and nano-drug delivery against bacterial infections. The therapeutic efficacy of numerous kinds of nanoparticles including nanoantibiotics conjugates, small molecules capped nanoparticles, polymers stabilized nanoparticles, and biomolecules functionalized nanoparticles has been discussed. Moreover, nanoparticles-based drug delivery systems against bacterial infections have been described. Furthermore, the fundamental limitation of biocompatibility and biosafety of nanoparticles is also conferred. Finally, we propose potential future strategies of nanomaterials as antibacterials.

Theranostic applications of stimulus-responsive systems based on carbon dots

Over recent years, many different nanoparticle-based drug delivery systems (NDDSs) have been developed. Recently the development of stimulus-responsive NDDSs has come into sharper focus. Carbon dots (CDs) possess outstanding features such as useful optical properties, good biocompatibility, and the ability for easy surface modification. Appropriate surface modification can allow these NDDSs to respond to various chemical or physical stimuli that are characteristic of their target cells or tissue (frequently malignant cells or tumors). The present review covers recent developments of CDs in NDDSs with a particular focus on internal stimulus response capability that allows simultaneous imaging and therapeutic delivery (theranostics). Relevant stimuli associated with tumor cells and tumors include pH levels, redox potential, and different enzymatic activities can be used to activate the CDs at the desired sites.

Multivalent Aptamer-modified DNA Origami as Drug Delivery System for Targeted Cancer Therapy

In spite of great development in nanoparticle-based drug delivery systems(DDSs) for improved therapeutic efficacy, it remains challenging for effective delivery of chemotherapeutic drugs to targeted tumor cells. In this work, we report a triangle DNA origami as targeted DDS for cancer therapy. DNA origami shows excellent biocompatibility and stability in cell culture medium for 24 h. In addition, the DNA origami structures conjugated with multivalent aptamers enable for efficient delivery of anticancer drug doxorubicin(Dox) into targeted cancer cell due to their targeting function, reducing side effects associated with nonspecific distribution. Moreover, we also demonstrated that the multivalent aptamer-modified DNA origami loading Dox exhibits prominent therapeutic efficacy in vitro. Accordingly, this work provides a good paradigm for the development of DNA origami nanostructure-based targeted DDS for cancer therapy.

Amino acid–intercalated layered double hydroxide core @ ordered porous silica shell as drug carriers: Design and applications

Abstract

Scanning acoustic microscopy of quantum dot aggregates

Quantum dot (QD) aggregate formation is essential, especially, in nanoparticle-based drug delivery systems. Imaging of these targeted QD aggregates exposes information about the the treatment of many diseases including cancer. Scanning Acoustic Microscopy (SAM) is a non-invasive and rapid imaging modality, which can obtain qualitative and quantitative features simultaneously. In our study, acoustic impedance microscopy of QD aggregates was performed by SAM for evaluating the potential of SAM in the detection of lead-sulphide (PbS), graphene and cadmium-telluride/cadmium sulphide (CdTe/CdS) quantum dot aggregates for the first time. Absorption spectra of QDs, obtained with an ultraviolet-visible spectrometer, and fluorescence spectra of QD aggregates, obtained with an inverted fluorescence microscope, are also demonstrated. The success of imaging quantum dot aggregates by SAM indicated the potential of SAM in monitoring the micro-environment of the disease and also the therapeutic effect of the drug-loaded QD aggregates.

Smart Unimolecular Micelle-Based Polyprodrug with Dual-Redox Stimuli Response for Tumor Microenvironment: Enhanced in Vivo Delivery Efficiency and Tumor Penetration.

Low delivery efficiency and limited tumor penetration of nanoparticle-based drug delivery systems (DDSs), the two most concerned issues in tumor therapy, have been considered as the "Achilles' heel" for tumor treatment. In this study, we have designed a highly sensitive dual-redox-responsive prodrug-based starlike polymer β-CD-b-P(CPTGSH-co-CPTROS-co-OEGMA) (CPGR) for synergistic chemotherapy. The high glutathione (GSH) concentration and high reactive oxygen species (ROS) levels are in a dynamic equilibrium in the tumor microenvironment (TME) and could trigger the disintegration of CPGR micelles, which can promote the release of anticancer drug camptothecin (CPT) completely and intelligently. In order to verify the synergistic antitumor mechanism, two corresponding single-responsive β-CD-b-P(CPTGSH-co-OEGMA) (CPG) and β-CD-b-P(CPTROS-co-OEGMA) (CPR) were altogether prepared as contrast. Both in vitro and in vivo studies confirmed the enhanced anticancer activity of CPGR micelles in comparison of single responsive micelles. This work contributes to the orchestrated design of dual-redox-responsive DDSs for synergetic antitumor chemotherapy, which provides a good approach for the development of dual-redox-responsive nanomedicine.

Targeted Nanoparticle Drug Delivery System for the Enhancement of Cancer Immunotherapy.

Immunotherapy is one of the most potent options for cancer treatment, with numerous breakthroughs in this field, bringing us closer to the realization of cancer eradication. However, the intrinsic limits of immunotherapy, such as its low responsive rate, narrow therapeutic window and systemic toxicity, have hindered its clinical application and thus prompted the development of nanotechnology-assisted modality for more effective and safer cancer immunotherapy. By locally increasing the drug concentration and limiting drug exposure to normal tissues, nanocarriers significantly potentiate the effects of immunotherapy while reducing side effects. Additionally, nanoparticle-based drug delivery systems allow different therapeutic strategies as a complement to conventional immunotherapeutic modalities, providing numerous novel and effective approaches for combinational cancer therapy. In this review, we first briefly introduce the five main classes of immunotherapy, and then we extensively covered some advanced biomaterials and novel strategies of nanotechnology intervention and detailed how these approaches function to enhance immunotherapeutic and combinational combination therapeutic efficacy.

Shedding Light on the Trehalose-Enabled Mucopermeation of Nanoparticles with Label-Free Raman Spectroscopy.

Nanoparticle-based drug delivery systems have attracted significant interest owing to their promise as tunable platforms that offer improved intracellular release of cargo therapeutics. However, significant challenges remain in maintaining the physiological stability of the mucosal matrix due to the nanoparticle-induced reduction in the matrix diffusivity and promotion of mucin aggregation. Such aggregation also adversely impacts the permeability of the nanoparticles, and thus, diminishes the efficacy of nanoparticle-based formulations. Here, an entirely complementary approach is proposed to the existing nanoparticle functionalization methods to address these challenges by using trehalose, a naturally occurring disaccharide that offers exceptional protein stabilization. Plasmon-enhanced Raman spectroscopy and far-red fluorescence emission of the plasmonic silver nanoparticulate clusters are harnessed to create a unique dual-functional, aggregating, and imaging agent that obviates the need of an additional reporter to investigate mucus-nanoparticle interactions. These spectroscopy-based density mapping tools uncover the mechanism of mucus-nanoparticle interactions and establish the protective role of trehalose microenvironment in minimizing the nanoparticle aggregation. Thus, in contrast to the prevailing belief, these results demonstrate that nonfunctionalized nanoparticles may rapidly penetrate through mucus barriers, and by leveraging the bioprotectant attributes of trehalose, an in vivo milieu for efficient mucosal drug delivery can be generated.

Abstract 2178: Targeted delivery of chemotherapeutic agents employing nanovesicles effectively reduced intrahepatic tumors

Abstract Background and Aims: Currently there is no appropriate method for effective and targeted delivery of chemotherapeutic agents to tumor sites. The conventional chemotherapy is afflicted with lack of effective drug delivery to the tumor site, unwanted injury to actively dividing healthy cells, and numerous side effects due to toxicity. The present study was aimed to develop a biologically derived nanoparticle based drug delivery system for the effective treatment of primary hepatic tumors. Methods: Intrahepatic tumors were induced in immunosuppressed mice using PLC/PRF/5 hepatocellular carcinoma (HCC) cells stably transfected with a mammalian expression vector carrying luciferase gene for in-vivo imaging. Nanovesicles ranging from 80-150 nm were isolated from bovine skim milk using ultracentrifugation and characterized using nanoparticle tracking analysis (NTA) and electron microscopy. Purified nanovesicles were loaded with chemotherapeutic agents and antisense oligonucleotides for grossly deregulated microRNAs specific to HCC. Animals with uniform intrahepatic tumors were injected with nanovesicle loaded anticancer agents through tail vein. Tumor regression was monitored weekly using in-vivo imaging system and the animals were maintained up to 8 weeks. Results: Bioluminescence based in-vivo imaging demonstrated significant reduction of tumor size in treated animals compared to untreated controls. There was increased survival rate and complete absence of metastasis in all treated animals. Untreated mice developed large intrahepatic tumors, which also metastasized to other organs. There were no side effects or immunological reactions in animals injected with plain nanovesicles without loading of any anticancer agents. Conclusions: The present study demonstrated that milk derived nanovesicles can be effectively used for successful delivery of anticancer agents into intrahepatic tumors. Nanovesicle based targeted drug delivery system could be an effecient method for the treatment of primary hepatic tumors.* Presenting author E-mail: georgej@kanazawa-med.ac.jp Note: This abstract was not presented at the meeting. Citation Format: Joseph George, Nobuhiko Hayashi, Takashi Saito, Mikihiro Tsutsumi, Mutsumi Tsuchishima. Targeted delivery of chemotherapeutic agents employing nanovesicles effectively reduced intrahepatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2178.

The Application of Microfluidics in Preparing Nano Drug Delivery Systems

The Application of Microfluidics in Preparing Nano Drug Delivery Systems

Hyaluronidase-Responsive Mesoporous Silica Nanoparticles with Dual-Imaging and Dual-Target Function.

Nanoparticle-based drug delivery systems are among the most popular research topics in recent years. Compared with traditional drug carriers, mesoporous silica nanoparticles (MSN) offer modifiable surfaces, adjustable pore sizes and good biocompatibility. Nanoparticle-based drug delivery systems have become a research direction for many scientists. With the active target factionalized, scientists could deliver drug carriers into cancer cells successfully. However, drugs in cancer cells could elicit drug resistance and induce cell exocytosis. Thus, the drug cannot be delivered to its pharmacological location, such as the nucleus. Therefore, binding the cell membrane and the nuclear target on the nanomaterial so that the anticancer drug can be delivered to its pharmacological action site is our goal. In this study, MSN-EuGd was synthesized by doping Eu3+ and Gd3+ during the synthesis of MSN. The surface of the material was then connected to the TAT peptide as the nucleus target for targeting the cancer nucleus and then loaded with the anticancer drug camptothecin (CPT). Then, the surface of MSN-EuGd was bonded to the hyaluronic acid as an active target and gatekeeper. With this system, it is possible and desirable to achieve dual imaging and dual targeting, as well as to deliver drugs to the cell nucleus under a hyaluronidase-controlled release. The experimental approach is divided into three parts. First, we conferred the material with fluorescent and magnetic dual-imaging property by doping Eu3+ and Gd3+ into the MSN. Second, modification of the cell membrane target molecule and the nucleus target molecule occurred on the surface of the nanoparticle, making the nanoparticle a target drug carrier. Third, the loading of drug molecules into the carrier gave the entire carrier a specific target profile and enabled the ability to treat cancer. In this study, we investigated the basic properties of the drug carrier, including physical properties, chemical properties, and in vitro tests. The result showed that we have successfully designed a drug delivery system that recognizes normal cells and cancer cells and has good anticancer effects.

Formulation of Pioglitazone-Eudragit® RS100 Nanobeads and Nanofibers Using Electrospraying Technique

In the present study, a novel polymeric nanoparticle-based drug delivery system was developed to enhance the dissolution rate of poorly water-soluble drug pioglitazone hydrochloride (PGH) using hydrophilic Eudragit® RS100 (Eudr) as a carrier. The new nanoformulations were prepared in different drug : polymer ratios (1 : 5 and 1 : 10) at total solution concentrations of (5–20% w/v) employing electrospraying as one-step, self-dispersing, and productive method. The physicochemical attributes of the electrosprayed samples (ESs) were evaluated conducting scanning electron microscopy (FE-SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) as well as in vitro dissolution studies. FE-SEM results indicated that the size and morphology of the ESs were influenced by the drug: polymer ratios and solution concentrations, where a rise in the polymer ratio led to the particle size augmentation while the solution concentration enhancement yielded in the fiber establishment. The DSC and XRPD analysis revealed amorphization of the drug where, the FTIR evaluation verified absence of any chemical interactions between the drug-polymer within the electrospraying procedure. In vitro release studies of the ESs exhibited biphasic release pattern with higher release rates compared to the pure drug. Our finding demonstrated that the electrospraying as a cost-benefit technique could be effectively employed to improve the physicochemical features of PGH.

A novel controllable molecularly imprinted drug delivery system based on the photothermal effect of graphene oxide quantum dots

Design and development of nanoparticle-based drug delivery systems (DDS) have always been extremely challenging due to unacceptable leakage of drug or unsatisfactory release in the lesion. Herein, we presented an effective approach for facile preparation of DDS by imprinting doxorubicin (DOX) via miniemulsion polymerization. In order to investigate the release of DOX in this system, the cumulative release of DOX by molecularly imprinted polymers (GMIPs) and non-imprinted polymers (GNIPs) was compared. The results revealed that the DOX’s leakage of GMIPs was more moderate than that of GNIPs. Moreover, after fitting the release curves with several mathematical models, it was found that the release of DOX from the GMIPs can be partially fitted with zero-order model (R2 = 0.929) which implied that molecular imprinting techniques for drug loading could reduce the common ‘burst effect.’ In addition, excellent release of DOX with controllable property was achieved by switching photothermal effect of graphene oxide quantum dots which were doped in GMIPs as the near-infrared light (NIR) window. Thus, it would be anticipated that the novel drug-loaded GMIPs combining with inductive NIR heating would be promising to be applied in the synergy of chemotherapy and thermotherapy for cancer therapy.

Engineered pH‐responsive hydrazone‐carboxylate complexes‐encapsulated 2D matrices for cathepsin‐mediated apoptosis in cancer

Spurred by the current advancements in engineering various intelligent nanoparticle-based drug delivery systems, conjugation of drugs with the stimuli-responsive molecular switches has become one of the most efficient approaches to deliver a drug cargo in spatiotemporal controlled fashions. In this study, we fabricated an innovative pH-triggered hydrazone-carboxylate complex of doxorubicin (Dox), which was subsequently encapsulated in the layered double hydroxide (LDH) nanoparticles for effective cancer therapeutics. These two-dimensional (2D) biodegradable matrices efficiently delivered Dox by pH-triggered release in the acidic lysosomal environment and their subsequent escape to cytosol. Moreover, the delivered Dox molecules and high positively-charged surfaces of LDHs facilitated the cancer cell ablation via enhancing the cathepsins-mediated cell apoptosis assisted by free radical species generation. The critical advancements in the nanoparticle-based designs and substantial ablation of tumor cells through a free radical attack indicate that the designed pH-triggered drug composites can be used for efficient cancer therapeutics. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1184-1194, 2019.

Essentials and Perspectives of Computational Modelling Assistance for CNS-oriented Nanoparticle-based Drug Delivery Systems

The blood-brain barrier (BBB) is a complex system controlling two-way substances traffic between circulatory (cardiovascular) system and central nervous system (CNS). It is almost perfectly crafted to regulate brain homeostasis and to permit selective transport of molecules that are essential for brain function. For potential drug candidates, the CNSoriented neuropharmaceuticals as well as for those of primary targets in the periphery, the extent to which a substance in the circulation gains access to the CNS seems crucial. With the advent of nanopharmacology, the problem of the BBB permeability for drug nano-carriers gains new significance. Compared to some other fields of medicinal chemistry, the computational science of nano-delivery is still premature to offer the black-box type solutions, especially for the BBB-case. However, even its enormous complexity can spell out the physical principles, and as such subjected to computation. The basic understanding of various physicochemical parameters describing the brain uptake is required to take advantage of their usage for the BBB-nano delivery. This mini-review provides a sketchy introduction of essential concepts allowing application of computational simulation to the BBB-nano delivery design.

Importance of Polymer Length in Fructose-Based Polymeric Micelles for an Enhanced Biological Activity

The efficiency of nanoparticle-based drug delivery systems to accumulate in targeted tumor sites is low owing primarily to the various biological mechanisms that promote premature clearance, such as renal filtration or the mononuclear phagocyte system (MPS). Such obstacles to enhanced tumor accumulation of nanomedicines remain formidable challenges to drug carrier design. It is thought that nanoparticles decorated with bioactive groups such as glycopolymers, compared to individual monovalent carbohydrate ligands, can assist in the enhanced delivery of payloads to tumors due to their multivalent effect. While glycopolymers are widely applied, limited attention has been dedicated to understanding how the presentation of glycopolymers on the surface of micelle may affect the biological activity. We utilized biodegradable and biocompatible polylactide–fructose block copolymers to investigate the effect of chain length of the hydrophilic fructose block on the biological activity. Three different fructose chain...

Recent advances and challenges of repurposing nanoparticle-based drug delivery systems to enhance cancer immunotherapy.

Cancer immunotherapy is an attractive treatment option under clinical settings. However, the major challenges of immunotherapy include limited patient response, limited tumor specificity, immune-related adverse events, and immunosuppressive tumor microenvironment. Therefore, nanoparticle (NP)-based drug delivery has been used to not only increase the efficacy of immunotherapeutic agents, but it also significantly reduces the toxicity. In particular, NP-based drug delivery systems alter the pharmacokinetic (PK) profile of encapsulated or conjugated immunotherapeutic agents to targeted cancer cells or immune cells and facilitate the delivery of multiple therapeutic combinations to targeted cells using single NPs. Recently, advanced NP-based drug delivery systems were effectively utilized in cancer immunotherapy to reduce the toxic side effects and immune-related adverse events. Repurposing these NPs as delivery systems of immunotherapeutic agents may overcome the limitations of current cancer immunotherapy. In this review, we focus on recent advances in NP-based immunotherapeutic delivery systems, such as immunogenic cell death (ICD)-inducing drugs, cytokines and adjuvants for promising cancer immunotherapy. Finally, we discuss the challenges facing current NP-based drug delivery systems that need to be addressed for successful clinical application.

Upconversion Nanoparticle-Based Strategy for Crossing the Blood-Brain Barrier to Treat the Central Nervous System Disease.

The blood-brain barrier (BBB) is a major challenge for the treatment of central nervous system (CNS) diseases. The BBB strictly regulates the movement of molecules into and out of the brain, and therefore protects the brain from noxious agents. However, for this reason the BBB also acts as a major obstacle that prevents most therapeutic molecules from getting into the target site of the brain. Therefore, it is essential to develop an efficient and general approach to overcome the BBB and transport the drug to the targeted region. Nanoparticle-based drug delivery systems are emerging as a promising drug delivery platform, due to their distinct advantages of tunable biophysical properties such as surface chemistry, size, and shape leading to various biological actions (like clearance, biodistribution, and biocompatibility) in the body. Therefore, it was hypothesized that the surface and shape of nanoparticles will influence their BBB permeation efficiency. Here, we describe a series of upconversion nanoparticles with different surfaces (oleic acid-free, DNA-modified, Silica coating, and PEG-encapsulated), PEGylated UCNPs with various shapes were generated (including sphere and rod). The cellular uptake ability, biodistribution, and BBB penetration of those UCNPs were assessed in cultured cells (NSC-34 neuron- like cells) and in vivo (zebrafish models).

Oriented attachment of VNAR proteins, via site-selective modification, on PLGA-PEG nanoparticles enhances nanoconjugate performance.

Herein we report the construction of a nanoparticle-based drug delivery system which targets a key regulator in tumour angiogenesis. We exploit a Variable New Antigen Receptor (VNAR) domain, conjugated using site-specific chemistry, to direct poly lactic acid-co-glycolic acid-polyethylene glycol (PLGA-PEG) nanoparticles to delta like canonical Notch ligand 4 (DLL4). The importance of site-specific chemistry is demonstrated.