Nanoparticle-based Drug Delivery Systems Research Articles

Meta-analysis of material properties influencing nanoparticle plasma pharmacokinetics

Thorough characterization of the plasma pharmacokinetics (PK) is a critical step in clinical development of novel therapeutics and is routinely performed for small molecules and biologics. However, there is a paucity of even basic characterization of PK for nanoparticle-based drug delivery systems. This has led to untested generalizations about how nanoparticle properties govern PK. Here, we present a meta-analysis of 100 nanoparticle formulations following IV administration in mice to identify any correlations between four PK parameters derived by non-compartmental analysis (NCA) and four cardinal properties of nanoparticles: PEGylation, zeta potential, size, and material. There was a statistically significant difference between the PK of particles stratified by nanoparticle properties. However, single linear regression between these properties and PK parameters showed poor predictability (r2 < 0.10 for all analyses), while multivariate regressions showed improved predictability (r2 > 0.38, except for t1/2). This suggests that no single nanoparticle property alone is even moderately predictive of PK, while the combination of multiple nanoparticle features does provide moderate predictive power. Improved reporting of nanoparticle properties will enable more accurate comparison between nanoformulations and will enhance our ability to predict in vivo behavior and design optimal nanoparticles.

Glucose-Responsive Charge-Switchable Lipid Nanoparticles for Insulin Delivery.

Lipid nanoparticle-based drug delivery systems have a profound clinical impact on nuclear acid-based therapy and vaccination. Recombinant human insulin, a negatively-charged biomolecule like mRNA, may also be delivered by rationally-designed positively-charged lipid nanoparticles with glucose-sensing elements and be released in a glucose-responsive manner. Herein, we have designed phenylboronic acid-based quaternary amine-type cationic lipids that can self-assemble into spherical lipid nanoparticles in an aqueous solution. Upon mixing insulin and the lipid nanoparticles, a heterostructured insulin complex is formed immediately arising from the electrostatic attraction. In a hyperglycemia-relevant glucose solution, lipid nanoparticles become less positively charged over time, leading to reduced attraction and subsequent insulin release. Compared with native insulin, this lipid nanoparticle-based glucose-responsive insulin shows prolonged blood glucose regulation ability and blood glucose-triggered insulin release in type 1 diabetic mouse model.

Inhalable Nanoparticle-based Dry Powder Formulations for Respiratory Diseases: Challenges and Strategies for TranslationalResearch.

The emergence of novel respiratory infections (e.g., COVID-19) and expeditious development of nanoparticle-based COVID-19 vaccines have recently reignited considerable interest in designing inhalable nanoparticle-based drug delivery systems as next-generation respiratory therapeutics. Among various available devices in aerosol delivery, dry powder inhalers (DPIs) are preferable for delivery of nanoparticles due to their simplicity of use, high portability, and superior long-term stability. Despite research efforts devoted to developing inhaled nanoparticle-based DPI formulations, no such formulations have been approved to date, implying a research gap between bench and bedside. This review aims to address this gap by highlighting important yet often overlooked issues during pre-clinical development. We start with an overview and update on formulation and particle engineering strategies for fabricating inhalable nanoparticle-based dry powder formulations. An important but neglected aspect in in vitro characterization methodologies for linking the powder performance with their bio-fate is then discussed. Finally, the major challenges and strategies in their clinical translation are highlighted. We anticipate that focused research onto the existing knowledge gaps presented in this review would accelerate clinical applications of inhalable nanoparticle-based dry powders from a far-fetched fantasy to a reality.

Intra-articular nanoparticles based therapies for osteoarthritis and rheumatoid arthritis management.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic and progressive inflammatory joint diseases that affect a large population worldwide. Intra-articular administration of various therapeutics is applied to alleviate pain, prevent further progression, and promote cartilage regeneration and bone remodeling in both OA and RA. However, the effectiveness of intra-articular injection with traditional drugs is uncertain and controversial due to issues such as rapid drug clearance and the barrier afforded by the dense structure of cartilage. Nanoparticles can improve the efficacy of intra-articular injection by facilitating controlled drug release, prolonged retention time, and enhanced penetration into joint tissue. This review systematically summarizes nanoparticle-based therapies for OA and RA management. Firstly, we explore the interaction between nanoparticles and joints, including articular fluids and cells. This is followed by a comprehensive analysis of current nanoparticles designed for OA/RA, divided into two categories based on therapeutic mechanisms: direct therapeutic nanoparticles and nanoparticles-based drug delivery systems. We highlight nanoparticle design for tissue/cell targeting and controlled drug release before discussing challenges of nanoparticle-based therapies for efficient OA and RA treatment and their future clinical translation. We anticipate that rationally designed local injection of nanoparticles will be more effective, convenient, and safer than the current therapeutic approach.

Design and characterizations of pH-responsive drug delivery vehicles using molecular docking

ABSTRACT Performing wet bench experiments to search for lead molecules for drug delivery is a long and tedious process where computational tools have played a crucial role. Molecular docking studies have been carried out for selecting the nanocarrier, and the results of the computational studies have been validated using the model protein Ova albumin and anticancer drug 5-Fluorouracil (5-FU) with mesoporous silica (MSNPs) and chitosan nanoparticles (CSNPs) as the nanocarriers. Formulated nanocarriers were tested for in-vitro release, which showed a sustained release of the drugs. In-vitro studies on the lung cancer cell line A459 revealed excellent biocompatibility and non-toxic nature of the designed drug delivery system. This chitosan nanoparticle-based drug delivery system could have the potential for chemotherapeutic treatment of cancer.

Synthesis, Characterization, and Antibacterial Assessment (Synergism) of Silver Nanoparticles Prepared with Stem Bark Extract of Sterculia diversifolia

Microbial infections present a challenging arena to the modern world. Traditional antibiotics are now familiar to microbes. To counter this microbial familiarity, a novel approach is a nanoparticle-based drug delivery system that exhibits promising results and overcomes these problems. This study was conducted to explore the efficacy of silver nanoparticles (AgNPs) by utilizing stem bark extract of Sterculia diversifolia followed by physicochemical characterization including ultraviolet-visible spectrophotometry (UV-Vis), X-ray diffractometer (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Fourier-transform infrared spectroscopy. The UV-Vis characteristic spectral peak was recorded at 430 nm. XRD confirmed the crystalline structure of AgNPs, while FTIR confirmed phytochemicals in their capping, stabilization, and synthesis of AgNPs. SEM devised the particle size range of 100 nm at 30,000× magnification. TEM showed nanoparticles morphology, which is spherical in nature, while obtained nanoparticles were 100 nm in size. The antibacterial activity of synthesized NPs showed significant action against S. aureus and P. aeruginosa. Similarly, crude extract and n-hexane fraction showed maximum zone of inhibition. Promising results suggest that stem bark extract AgNPs of Sterculia diversifolia can be studied further for microbial mechanisms as well as formulation-based studies.

Insights into the Degradation of Polymer-Drug Conjugates by an Overexpressed Enzyme in Cancer Cells.

Intensive efforts have been made to provide better treatments to cancer patients. Currently, nanoparticle-based drug delivery systems have gained propulsion, as they can overcome the drawbacks of free drugs. However, drug stability inside the nanocapsule must be ensured to prevent burst release. To overcome this, drugs conjugated to amphiphilic copolymers, assembled into nanoparticles, can provide a sustained release if endogenously degraded. Thus, we have designed and assessed the drug release viability of polymer-drug conjugates by the human Carboxylesterase 2, for a targeted drug activation. We performed molecular dynamics simulations applying a quantum mechanics/molecular mechanics potential to study the degradation profiles of 30 designed conjugates, where six were predicted to be hydrolyzed by this enzyme. We further analyzed the enzyme-substrate environment to delve into what structural features may lead to successful hydrolysis. These findings contribute to the development of new medicines ensuring effective cancer treatments with fewer side effects.

Experimental Methods for the Biological Evaluation of Nanoparticle-Based Drug Delivery Risks.

Many novel medical therapies use nanoparticle-based drug delivery systems, including nanomaterials through drug delivery systems, diagnostics, or physiologically active medicinal products. The approval of nanoparticles with advanced therapeutic and diagnostic potentials for applications in medication and immunization depends strongly on their synthesizing procedure, efficiency of functionalization, and biological safety and biocompatibility. Nanoparticle biodistribution, absorption, bioavailability, passage across biological barriers, and biodistribution are frequently assessed using bespoke and biological models. These methods largely rely on in vitro cell-based evaluations that cannot predict the complexity involved in preclinical and clinical studies. Therefore, assessing the nanoparticle risk has to involve pharmacokinetics, organ toxicity, and drug interactions manifested at multiple cellular levels. At the same time, there is a need for novel approaches to examine nanoparticle safety risks due to increased constraints on animal exploitation and the demand for high-throughput testing. We focus here on biological evaluation methodologies that provide access to nanoparticle interactions with the organism (positive or negative via toxicity). This work aimed to provide a perception regarding the risks associated with the utilization of nanoparticle-based formulations with a particular focus on assays applied to assess the cytotoxicity of nanomaterials.

Raman Spectroscopy Characterization of Multi-Functionalized Liposomes as Drug-Delivery Systems for Neurological Disorders.

The characterization of nanoparticle-based drug-delivery systems represents a crucial step in achieving a comprehensive overview of their physical, chemical, and biological features and evaluating their efficacy and safety in biological systems. We propose Raman Spectroscopy (RS) for the characterization of liposomes (LPs) to be tested for the control of neuroinflammation and microglial dysfunctions in Glioblastoma multiforme and Alzheimer's disease. Drug-loaded LPs were functionalized to cross the blood-brain barrier and to guarantee localized and controlled drug release. The Raman spectra of each LP component were used to evaluate their contribution in the LP Raman fingerprint. Raman data analysis made it possible to statistically discriminate LPs with different functionalization patterns, showing that each molecular component has an influence in the Raman spectrum of the final LP formulation. Moreover, CLS analysis on Raman data revealed a good level of synthetic reproducibility of the formulations and confirmed their stability within one month from their synthesis, demonstrating the ability of the technique to evaluate the efficacy of LP synthesis using small amount of sample. RS represents a valuable tool for a fast, sensitive and label free biochemical characterization of LPs that could be used for quality control of nanoparticle-based therapeutics.

The Role of Silver Nanoparticles in the Diagnosis and Treatment of Cancer: Are There Any Perspectives for the Future?

Cancer is a fatal disease with a complex pathophysiology. Lack of specificity and cytotoxicity, as well as the multidrug resistance of traditional cancer chemotherapy, are the most common limitations that often cause treatment failure. Thus, in recent years, significant efforts have concentrated on the development of a modernistic field called nano-oncology, which provides the possibility of using nanoparticles (NPs) with the aim to detect, target, and treat cancer diseases. In comparison with conventional anticancer strategies, NPs provide a targeted approach, preventing undesirable side effects. What is more, nanoparticle-based drug delivery systems have shown good pharmacokinetics and precise targeting, as well as reduced multidrug resistance. It has been documented that, in cancer cells, NPs promote reactive oxygen species (ROS) production, induce cell cycle arrest and apoptosis, activate ER (endoplasmic reticulum) stress, modulate various signaling pathways, etc. Furthermore, their ability to inhibit tumor growth in vivo has also been documented. In this paper, we have reviewed the role of silver NPs (AgNPs) in cancer nanomedicine, discussing numerous mechanisms by which they render anticancer properties under both in vitro and in vivo conditions, as well as their potential in the diagnosis of cancer.

Pre-treatment of oncolytic reovirus improves tumor accumulation and intratumoral distribution of PEG-liposomes.

PEGylated liposomes (PEG-liposomes) are a promising drug delivery vehicle for tumor targeting because of their efficient tumor disposition profiles via the enhanced permeability and retention (EPR) effect. However, tumor targeting of PEG-liposomes, particularly their delivery inside the tumors, is often disturbed by physical barriers in the tumor, including tumor cells themselves, extracellular matrices, and interstitial pressures. In this study, B16 melanoma tumor-bearing mice were injected intravenously with oncolytic reovirus before administration of PEG-liposomes to enhance PEG-liposomes' tumor disposition. Three days after reovirus administration, significant expression of reovirus sigma 3 protein, elevation of apoptosis-related gene expression, and activation of caspase 3 in the tumors were found. Apoptotic cells were found inside the tumors. These data indicated that reovirus efficiently replicated in the tumors and induced apoptosis of tumor cells. The tumor disposition levels of PEG-liposomes were approximately doubled by reovirus pre-administration, compared with a PBS-pretreated group. PEG-liposomes were widely distributed in the tumors of reovirus-pretreated mice, whereas in the PBS-pretreated group, PEG-liposomes were found mainly around or inside the blood vessels in the tumors. Pre-treatment with reovirus also improved the tumor accumulation of PEG-liposomes in human pancreatic BxPC-3 tumors. 3D imaging analysis of whole BxPC-3 tumors demonstrated that pretreatment with reovirus led to the enhancement of PEG-liposome accumulation inside the tumors. Combination treatment with reovirus and paclitaxel-loaded PEG-liposomes (PTX-PEG-liposomes) significantly suppressed B16 tumor growth. These results provide important information for clinical use of combination therapy of reovirus and nanoparticle-based drug delivery system (DDS).

Enhanced oral bioavailability from food protein nanoparticles: A mini review.

The oral route is the most desirable drug administration path. The oral bioavailability is always compromised from the poor physicochemical and/or biopharmaceutical properties of the active pharmaceutical ingredients. Food protein nanoparticles show promise for oral drug delivery, with improved biosafety and cost-effectiveness compared to polymeric nanoparticles. More importantly, diverse food proteins provide "choice and variety" to meet the challenges faced by different drugs in oral delivery resulting from low solubility, poor permeability, and gastrointestinal stability. The abundance of hydroxyl, amino, and carboxyl groups in food proteins allows easy surface modification of the nanoparticles to impart unique functions. Albeit being in its infancy, food protein nanoparticles exhibit high capability to enhance oral bioavailability of a wide range of drugs from small molecules to biomacromolecules. Considering the rapid growth of the field, the achievements and mechanisms of food protein nanoparticles in enhancing oral bioavailability are reviewed. Factors affecting the performance of food protein nanoparticles are discussed with the purpose to inspire the development of food protein nanoparticle-based oral drug delivery systems.

Radiolabeled Biodistribution of Expansile Nanoparticles: Intraperitoneal Administration Results in Tumor Specific Accumulation.

Nanoparticle biodistribution in vivo is an essential component to the success of nanoparticle-based drug delivery systems. Previous studies with fluorescently labeled expansile nanoparticles, or "eNPs", demonstrated a high specificity of eNPs to tumors that is achieved through a materials-based targeting strategy. However, fluorescent labeling techniques are primarily qualitative in nature and the gold-standard for quantitative evaluation of biodistribution is through radiolabeling. In this manuscript, we synthesize 14C-labeled eNPs to quantitatively evaluate the biodistribution of these particles in a murine model of intraperitoneal mesothelioma via liquid scintillation counting. The results demonstrate a strong specificity of eNPs for tumors that lasts one to 2 weeks postinjection with an overall delivery efficiency to the tumor tissue of 30% of the injected dose which is congruent with prior reports of preclinical efficacy of the technology. Importantly, the route of administration is essential to the eNP's material-based targeting strategy with intraperitoneal administration leading to tumoral accumulation while, in contrast, intravenous administration leads to rapid clearance via the reticuloendothelial system and low tumoral accumulation. A comparison against nanoparticle delivery systems published over the past decade shows that the 30% tumoral delivery efficiency of the eNP is significantly higher than the 0.7% median delivery efficiency of other systems with sufficient quantitative data to define this metric. These results lay a foundation for targeting intraperitoneal tumors and encourage efforts to explore alternative, nonintravenous routes, of delivery to accelerate the translation of nanoparticle therapies to the clinic.

A mechanistically motivated constitutive model of biopolymer hydrogels with structural evolution

Understanding the deformation behavior of biopolymer hydrogels would aid in the design of artificial hydrogels and nanoparticle-based drug delivery systems, which have been extensively used in the fields of biomedicine. Here, we develop a mechanistically motivated constitutive model to elucidate the structural evolution of biopolymer hydrogels. A free energy function includingconfigurational entropy of biopolymer nanofibers, potential energy of physical crosslinks, and mixing energy of water molecules is formulated. Both the micro/nanostructures and dynamic features of nanofibrous network under stretching are captured investigating the evolution of physical crosslinks and water hydration. In addition, a quantitative relationship correlating the pore size in the nanofibrous network with mechanical stretching is proposed. Different from chemically crosslinked hydrogels, the pore size of physically crosslinked hydrogels could continuously increase under stretching, which is attributed to the straightening and bundling of biopolymer nanofibers. We further find that a low strain rate or a high swelling ratio promotes the structural evolution of biopolymer hydrogels and increases the pore size of the network. The model predictions are in good agreement with the experimental results. This work could shed light on the deformation mechanisms of physically crosslinked biopolymer hydrogels, thus providing guidelines for the design of drug delivery systems translocating within biopolymer hydrogels.

Design of functional nanoparticles by microfluidic platforms as advanced drug delivery systems for cancer therapy.

Nanoparticle systems are functional carriers that can be used in the cancer therapy field for the delivery of a variety of hydrophobic and/or hydrophilic drugs. Recently, the advent of microfluidic platforms represents an advanced approach to the development of new nanoparticle-based drug delivery systems. Particularly, microfluidics can simplify the design of new nanoparticle-based systems with tunable physicochemical properties such as size, size distribution and morphology, ensuring high batch-to-batch reproducibility and consequently, an enhanced therapeutic effect in vitro and in vivo. In this perspective, we present accurate state-of-the-art microfluidic platforms focusing on the fabrication of polymer-based, lipid-based, lipid/polymer-based, inorganic-based and metal-based nanoparticles for biomedical applications.

Transfer-based nuclear magnetic resonance uncovers unique mechanisms for protein-polymer and protein-nanoparticle binding behavior.

Nanoparticle-based drug delivery systems have shown increasing popularity as a means to improve patient outcomes by improving the effectiveness of active pharmaceutical ingredients (APIs). Similarly, nanoparticles have shown success in targeting alternative routes of API administration, such as applying mucoadhesion or mucopenetration to mucosal drug delivery to enhance uptake. While there are many promising examples of mucoadhesive nanomedicines in literature, there are also many examples of contradictory mucoadhesive binding behavior, most prominently in cases using the same nanoparticle materials. We have uncovered mechanistic insights in polymer-protein binding systems using nOe transfer-based NMR and sought to leverage them to explore nanoparticle-protein interactions. We tested several polymer-coated nanoparticles and micellar polymer nanoparticles and evaluated their binding with mucin proteins. We uncovered that the composition and interaction intimacy of polymer moieties that promote mucin binding change when the polymers are incorporated onto nanoparticle surfaces compared to polymer in solution. This change from solution state to nanoparticle coating can enable switching of behavior of these materials from inert to binding, as we observed in polyvinyl pyrrolidone. We also found the nanoparticle core was influential in determining the binding fate of polymer materials, whereas the nanoparticle size did not possess a clear correlation in the ranges we tested (60-270 nm). These experiments demonstrate that identical polymers may switch their binding behavior to mucin as a function of conformational changes that are induced by incorporating the polymers onto the surface of nanoparticles. These NMR-derived insights could be further leveraged to optimize nanoparticle formulations and guide polymer-mediated mucoadhesion.

Cell-Based Drug Delivery Systems with Innate Homing Capability as a Novel Nanocarrier Platform.

Nanoparticle-based drug delivery systems have been designed to treat various diseases. However, many problems remain, such as inadequate tumor targeting and poor therapeutic outcomes. To overcome these obstacles, cell-based drug delivery systems have been developed. Candidates for cell-mediated drug delivery include blood cells, immune cells, and stem cells with innate tumor tropism and low immunogenicity; they act as a disguise to deliver the therapeutic payload. In drug delivery systems, therapeutic agents are encapsulated intracellularly or attached to the surface of the plasma membrane and transported to the desired site. Here, we review the pros and cons of cell-based therapies and discuss their homing mechanisms in the tumor microenvironment. In addition, different strategies to load therapeutic agents inside or on the surface of circulating cells and the current applications for a wide range of disease treatments are summarized.

Nanoparticle-mediated stimulus-responsive antibacterial therapy.

The limitations associated with conventional antibacterial therapies and the subsequent amplification of multidrug-resistant (MDR) microorganisms have increased, necessitating the urgent development of innovative antibacterial techniques. Accordingly, nanoparticle-mediated therapeutics have emerged as potential candidates for antibacterial treatment due to their suitable dimensions, penetration capacity, and high efficiency in targeted drug delivery. However, although nanoparticle-based drug delivery systems have been demonstrated to be effective, they are limited by their overuse and unwanted side effects. Thus, to overcome these drawbacks, stimulus-responsive antibiotic delivery has been extended as a promising strategy for site-specific restricted drug exemption. Nano-formulations that are triggered by various stimuli, such as intrinsic, extrinsic, and bacterial stimuli, have been developed. Thus, by harnessing the physicochemical properties of various nanoparticles, the selective release of therapeutic cargoes can be achieved through the application of a variety of local stimuli such as light, sound, irradiation, pH, and magnetic field. In this review, we also highlight the progress and perspectives of stimulus-responsive combination therapy, with special emphasis on the eradication of MDR strains and biofilms. Hence, this review addresses the advancement and challenges in the applications of stimulus-responsive nanoparticles together with the various future prospects of this technique.

Understanding the rod-to-tube transformation of self-assembled ascorbyl dipalmitate lipid nanoparticles stabilized with PEGylated lipids.

We previously established a nanoparticle-based drug delivery system (DDS) for high-dose ascorbic acid therapy by self-assembly of a lipid-modified ascorbic acid derivative, L-ascorbyl 2,6-dipalmitate (ASC-DP). The particles' morphology should be modified for effective DDSs. Here, we modulated the morphology of self-assembled ASC-DP nanoparticles using two different PEGylated lipids, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and cholesterol-polyethylene glycol (Chol-PEG), with various PEG molecular weights. At the preparation molar ratio of 10 : 1 (ASC-DP/PEGylated lipid), rod-like nanoparticles emerged in the ASC-DP/DSPE-PEG system, whereas the ASC-DP/Chol-PEG system yielded tube-like nanoparticles. The internal structures of both rod-like ASC-DP/DSPE-PEG and tube-like ASC-DP/Chol-PEG nanoparticles were similar to that of repeated ASC-DP bilayers. The particles' surfaces featured PEGylated lipids, which stabilized the structure and dispersion of the nanoparticles. For both systems, the particle size increased slightly with increasing the PEGylated lipid's PEG molecular weight. Increasing the PEG molecular weight decreased the inner tunnel size of tube-like ASC-DP/Chol-PEG nanoparticles. A mechanism has been proposed for the rod-to-tube transformation. Surface-layer free-energy changes owing to the mixing of multiple lipids and PEG chain repulsion are thought to underlie the inner tunnels' formation. The rod-to-tube morphology of self-assembled ASC-DP nanoparticles can be modulated by controlling the PEGylated lipids' structure, including the lipid species and the PEG chain length.

Nanoparticle-based drug delivery systems targeting cancer cell surfaces.

Traditional cancer chemotherapy easily produces serious toxic and side effects due to the lack of specific selection of tumor cells, which restricts its curative effect. Targeted delivery can increase the concentration of drugs in the target site and reduce their toxic and side effects on normal tissues and cells. Biocompatible and surface-modifiable nanocarriers are novel drug delivery systems, which are used to specifically target tumor sites in a controllable way. One of the effective ways to design effective targeting nanocarriers is to decorate with functional ligands, which can bind to specific receptors overexpressed on the surfaces of cancer cells. Various functional ligands, including transferrin, folic acid, polypeptide and hyaluronic acid, have been widely explored to develop tumor-selective drug delivery systems. This review focuses on the research progress of various receptors overexpressed on the surfaces of cancer cells and different nano-delivery systems of anticancer drugs targeted on the surfaces of cancer cells. We believe that through continuous research and development, actively targeted cancer nano-drugs will make a breakthrough and become an indispensable platform for accurate cancer treatment.