Targeted Delivery Vehicles Research Articles

Inhaled tea polyphenol-loaded nanoparticles coated with platelet membranes largely attenuate asthmatic inflammation

BackgroundTea polyphenols (TPs), prominent constituents of green tea, possess remarkable antioxidant and anti-inflammatory properties. However, their therapeutic potential is limited due to low absorption and poor bioavailability. To address this limitation and enhance their efficacy, we developed a biomimetic nanoplatform by coating platelet membrane (PM) onto poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) to create targeted delivery vehicles for TPs (PM@TP/NPs) to the inflamed tissues in asthma.MethodsAfter synthesizing and characterizing PM@TP/NPs, we assessed their biocompatibility and biosafety through cell viability assays, hemolysis tests, and inflammation analysis in vivo and in vitro. The therapeutic effect of PM@TP/NPs on asthma was then evaluated using a mouse model of HDM-induced asthma. Additionally, PM@TP/NPs-mediated reactive oxygen species (ROS) scavenging capacity, as well as the activation of signaling pathways, were analyzed in HBE cells and asthmatic mice via flow cytometry, RT-qPCR, and western blotting.ResultsCompared with free TPs, PM@TP/NPs demonstrated excellent biocompatibility and safety profiles in both in vitro and in vivo, as well as enhanced retention in inflamed lungs. In HDM-induced mouse asthma model, inhaled PM@TP/NPs largely attenuated lung inflammation and reduced the secretion of type 2 pro-inflammatory cytokines in the lungs compared to free TPs. The therapeutic effects of PM@TP/NPs on asthma might be associated with an enhanced ROS scavenging capacity, increased activation of the Nrf2/HO-1 pathway, and decreased activation of the CCL2/MAPK and TLR4/NF-κB pathway in the lungs.ConclusionsOur findings demonstrate that inhalation of PM@TP/NPs largely attenuated lung inflammation in HDM-induced asthmatic mice. These results suggest that PM@TP/NPs might be a novel therapeutic strategy for asthma.

Targeted Polymeric Micelles System, Designed to Carry a Combined Cargo of L-Asparaginase and Doxorubicin, Shows Vast Improvement in Cytotoxic Efficacy.

L-asparaginases (ASP) and Doxorubicin (Dox) are both used in the treatment of leukemia, including in combination. We have attempted to investigate if their combination within the same targeted delivery vehicle can make such therapy more efficacious. We assembled a micellar system, where the inner hydrophobic core was loaded with Dox, while ASP would absorb at the surface due to electrostatic interactions. To make such absorption stronger, we conjugated the ASP with oligoamines, such as spermine, and the lipid components of the micelle-lipoic and oleic acids-with heparin. When loaded with Dox alone, the system yielded about a 10-fold improvement in cytotoxicity, as compared to free Dox. ASP alone showed about a 2.5-fold increase in cytotoxicity, so, assuming additivity of the effect, one could expect a 25-fold improvement when the two agents are applied in combination. But in reality, a combination of ASP + Dox loaded into the delivery system produced a synergy, with a whopping 50× improvement vs. free individual component. Pharmacokinetic studies have shown prolonged circulation of micellar formulations in the bloodstream as well as an increase in the effective concentration of Dox in micellar form and a reduction in Dox accumulation to the liver and heart (which reduces hepatotoxicity and cardiotoxicity). For the same reason, Dox's liposomal formulation has been in use in the treatment of multiple types of cancer, almost replacing the free drug. We believe that an opportunity to deliver a combination of two types of drugs to the same target cell may represent a further step towards improvement in the risk-benefit ratio in cancer treatment.

A Perspective on the Characterization of Early Neural Progenitor Cell-Derived Extracellular Vesicles for Targeted Delivery to Neuroblastoma Cells

As an element of the cellular signaling systems, extracellular vesicles (EVs) exhibit many desirable traits for usage as targeted delivery vehicles. When administered, EVs cause little to no toxic or immune response, stay in circulation for longer periods compared to synthetic carriers, preferentially accumulate in tissues that are the same or similar to their cell-of-origin and can pass through the blood-brain barrier. Combined, these traits make neural EVs a particularly promising tool for delivering drugs to the brain. This study aims to combine tissue and EVs engineering to prepare neural differentiated cells derived EVs that exhibit neural properties, to develop an effective, tissue-homing drug and gene delivery platform for the brain. Early neural differentiated cell-derived EVs were produced with neural characteristics from neural differentiated human neonatal dermal fibroblasts. The EVs carried key neural proteins such as Nestin, Sox2 and Doublecortin. The cellular uptake of early neural differentiated cell-derived EVs was higher compared to non-neural EVs during in vitro uptake assays on neuroblastoma cells. Moreover, eND-EVs were significantly decreased the viability of neuroblastoma cells. In conclusion, this study revealed that early neural differentiated cell-derived EVs have potential as a promising drug carrier for the treatment of various neural disorders.Graphical

Exosome-mediated PROTAC delivery for treatment of RNA viral infections and zoonosis

The increase in diseases caused by RNA viruses, such as influenza, severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and Ebola, presents a growing global health challenge as well as the threat of zoonosis. Traditional antiviral treatments are often undermined by fast-mutating viruses, drug resistance, and newly emerging pathogens. Here, we explore proteolysis-targeting chimeras (PROTACs), a novel protein degradation machinery that has the potential to reshape the way in which RNA viral infections can be managed. PROTACs excel at specifically degrading pathogenic proteins, offering a targeted and efficient antiviral strategy. We also investigate the potential of exosome-based diagnostic technologies, which harness cell-derived nanovesicles for non-invasive sampling and early viral infection detection. Addressing the challenge of PROTAC delivery, we introduce a groundbreaking strategy utilizing exosomes to deliver PROTACs with improved precision and as a targeted delivery vehicle. Integrating these innovative strategies provides a novel approach to combat RNA zoonotic viral diseases, paving the way for a new era in antiviral therapy.

Application of High-Z Nanoparticles to Enhance Current Radiotherapy Treatment.

Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.

Enhanced Efficacy against Drug-Resistant Tumors Enabled by Redox-Responsive Mesoporous-Silica-Nanoparticle-Supported Lipid Bilayers as Targeted Delivery Vehicles.

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.

Functionalized Calcium Carbonate-Based Microparticles as a Versatile Tool for Targeted Drug Delivery and Cancer Treatment.

Nano- and microparticles are increasingly widely used in biomedical research and applications, particularly as specific labels and targeted delivery vehicles. Silica has long been considered the best material for such vehicles, but it has some disadvantages limiting its potential, such as the proneness of silica-based carriers to spontaneous drug release. Calcium carbonate (CaCO3) is an emerging alternative, being an easily available, cost-effective, and biocompatible material with high porosity and surface reactivity, which makes it an attractive choice for targeted drug delivery. CaCO3 particles are used in this field in the form of either bare CaCO3 microbeads or core/shell microparticles representing polymer-coated CaCO3 cores. In addition, they serve as removable templates for obtaining hollow polymer microcapsules. Each of these types of particles has its specific advantages in terms of biomedical applications. CaCO3 microbeads are primarily used due to their capacity for carrying pharmaceutics, whereas core/shell systems ensure better protection of the drug-loaded core from the environment. Hollow polymer capsules are particularly attractive because they can encapsulate large amounts of pharmaceutical agents and can be so designed as to release their contents in the target site in response to specific stimuli. This review focuses first on the chemistry of the CaCO3 cores, core/shell microbeads, and polymer microcapsules. Then, systems using these structures for the delivery of therapeutic agents, including drugs, proteins, and DNA, are outlined. The results of the systematic analysis of available data are presented. They show that the encapsulation of various therapeutic agents in CaCO3-based microbeads or polymer microcapsules is a promising technique of drug delivery, especially in cancer therapy, enhancing drug bioavailability and specific targeting of cancer cells while reducing side effects. To date, research in CaCO3-based microparticles and polymer microcapsules assembled on CaCO3 templates has mainly dealt with their properties in vitro, whereas their in vivo behavior still remains poorly studied. However, the enormous potential of these highly biocompatible carriers for in vivo applications is undoubted. This last issue is addressed in depth in the Conclusions and Outlook sections of the review.

Ultra-fast in vivo directional dark-field x-ray imaging for visualising magnetic control of particles for airway gene delivery

Objective. Magnetic nanoparticles can be used as a targeted delivery vehicle for genetic therapies. Understanding how they can be manipulated within the complex environment of live airways is key to their application to cystic fibrosis and other respiratory diseases. Approach. Dark-field x-ray imaging provides sensitivity to scattering information, and allows the presence of structures smaller than the detector pixel size to be detected. In this study, ultra-fast directional dark-field synchrotron x-ray imaging was utlilised to understand how magnetic nanoparticles move within a live, anaesthetised, rat airway under the influence of static and moving magnetic fields. Main results. Magnetic nanoparticles emerging from an indwelling tracheal cannula were detectable during delivery, with dark-field imaging increasing the signal-to-noise ratio of this event by 3.5 times compared to the x-ray transmission signal. Particle movement as well as particle retention was evident. Dynamic magnetic fields could manipulate the magnetic particles in situ. Significance. This is the first evidence of the effectiveness of in vivo dark-field imaging operating at these spatial and temporal resolutions, used to detect magnetic nanoparticles. These findings provide the basis for further development toward the effective use of magnetic nanoparticles, and advance their potential as an effective delivery vehicle for genetic agents in the airways of live organisms.

Receptor Targeting Using Copolymer-Modified Gold Nanoparticles for pCMV-Luc Gene Delivery to Liver Cancer Cells In Vitro.

The formulation of novel delivery protocols for the targeted delivery of genes into hepatocytes by receptor mediation is important for the treatment of liver-specific disorders, including cancer. Non-viral delivery methods have been extensively studied for gene therapy. Gold nanoparticles (AuNPs) have gained attention in nanomedicine due to their biocompatibility. In this study, AuNPs were synthesized and coated with polymers: chitosan (CS), and polyethylene glycol (PEG). The targeting moiety, lactobionic acid (LA), was added for hepatocyte-specific delivery. Physicochemical characterization revealed that all nano-formulations were spherical and monodispersed, with hydrodynamic sizes between 70 and 250 nm. Nanocomplexes with pCMV-Luc DNA (pDNA) confirmed that the NPs could bind, compact, and protect the pDNA from nuclease degradation. Cytotoxicity studies revealed that the AuNPs were well tolerated (cell viabilities > 70%) in human hepatocellular carcinoma (HepG2), embryonic kidney (HEK293), and colorectal adenocarcinoma (Caco-2) cells, with enhanced transgene activity in all cells. The inclusion of LA in the NP formulation was notable in the HepG2 cells, which overexpress the asialoglycoprotein receptor on their cell surface. A five-fold increase in luciferase gene expression was evident for the LA-targeted AuNPs compared to the non-targeted AuNPs. These AuNPs have shown potential as safe and suitable targeted delivery vehicles for liver-directed gene therapy.

Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.

Enzyme-Responsive Nanoparticles for Dexamethasone Targeted Delivery to Treat Inflammation in Diabetes.

Diabetes is a global epidemic accompanied by impaired wound healing and increased risk of persistent infections and resistance to standard treatments. Therefore, there is an immense need to develop novel methods to specifically target therapeutics to affected tissues and improve treatment efficacy. This study aims to use enzyme-responsive nanoparticles for the targeted delivery of an anti-inflammatory drug, dexamethasone, to treat inflammation in diabetes. These nanoparticles are assembled from fluorescently-labeled, dexamethasone-loaded peptide-polymer amphiphiles. The nanoparticles are injected in vivo, adjacent to labeled collagen membranes sub-periosteally implanted on the calvaria of diabetic rats. Following their implantation, collagen membrane resorption is linked to inflammation, especially in hyperglycemic individuals. The nanoparticles show strong and prolonged accumulation in inflamed tissue after undergoing a morphological switch into microscale aggregates. Significantly higher remaining collagen membrane area and less inflammatory cell infiltration are observed in responsive nanoparticles-treated rats, compared to control groups injected with free dexamethasone and non-responsive nanoparticles. These factors indicate improved therapeutic efficacy in inflammation reduction. These results demonstrate the potential use of enzyme-responsive nanoparticles as targeted delivery vehicles for the treatment of diabetic and other inflammatory wounds.

Bigels as Delivery Systems: Potential Uses and Applicability in Food.

Bigels have been mainly applied in the pharmaceutical sector for the controlled release of drugs or therapeutics. However, these systems, with their intricate structures, hold great promise for wider application in food products. Besides their classical role as carrier and target delivery vehicles for molecules of interest, bigels may also be valuable tools for building complex food structures. In the context of reducing or even eliminating undesirable (but often highly functional) food components, current strategies often critically affect food structure and palatability. The production of solid fat systems that are trans-fat-free and have high levels of unsaturated fatty acids is one of the challenges the food industry currently faces. According to recent studies, bigels can be successfully used as ingredients for total or partial solid fat replacement in complex food matrices. This review aims to critically assess current research on bigels in food and pharmaceutical applications, discuss the role of bigel composition and production parameters on the characteristics of bigels and further expand the use of bigels as solid fat replacers and functional food ingredients. The hydrogel:oleogel ratio, selected gelators, inclusion of surfactants and encapsulation of molecules of interest, and process parameters (e.g., temperature, shear rate) during bigel production play a crucial role in the bigel's rheological and textural properties, microstructure, release characteristics, biocompatibility, and stability. Besides exploring the role of these parameters in bigel production, future research directions for bigels in a food context are explored.

Cell membrane-based biomimetic vehicles for effective central nervous system target delivery: Insights and challenges.

Central nervous system (CNS) disorders, including brain tumor, ischemic stroke, Alzheimer's disease, and Parkinson's disease, threaten human health. And the existence of the blood-brain barrier (BBB) hinders the delivery of drugs and the design of drug targeting delivery vehicles. Over the past decades, great interest has been given to cell membrane-based biomimetic vehicles since the rise of targeting drug delivery systems and biomimetic nanotechnology. Cell membranes are regarded as natural multifunction biomaterials, and provide potential for targeting delivery design and modification. Cell membrane-based biomimetic vehicles appear timely with the participation of cell membranes and nanoparticles, and raises new lights for BBB recognition and transport, and effective therapy with its biological multifunction and high biocompatibility. This review summarizes existing challenges in CNS target delivery and recent advances of different kinds of cell membrane-based biomimetic vehicles for effective CNS target delivery, and deliberates the BBB targeting mechanism. It also discusses the challenges and possibility of clinical translation, and presents new insights for development.

Biomaterials and Encapsulation Techniques for Probiotics: Current Status and Future Prospects in Biomedical Applications.

Probiotics have garnered significant attention in recent years due to their potential advantages in diverse biomedical applications, such as acting as antimicrobial agents, aiding in tissue repair, and treating diseases. These live bacteria must exist in appropriate quantities and precise locations to exert beneficial effects. However, their viability and activity can be significantly impacted by the surrounding tissue, posing a challenge to maintain their stability in the target location for an extended duration. To counter this, researchers have formulated various strategies that enhance the activity and stability of probiotics by encapsulating them within biomaterials. This approach enables site-specific release, overcoming technical impediments encountered during the processing and application of probiotics. A range of materials can be utilized for encapsulating probiotics, and several methods can be employed for this encapsulation process. This article reviews the recent advancements in probiotics encapsulated within biomaterials, examining the materials, methods, and effects of encapsulation. It also provides an overview of the hurdles faced by currently available biomaterial-based probiotic capsules and suggests potential future research directions in this field. Despite the progress achieved to date, numerous challenges persist, such as the necessity for developing efficient, reproducible encapsulation methods that maintain the viability and activity of probiotics. Furthermore, there is a need to design more robust and targeted delivery vehicles.

Front Cover: Self‐Assembly of Hybrid Peptide−DNA Nanostructures using Homotrimeric Coiled‐Coil/Nucleic Acid Building Blocks (ChemBioChem 17/2023)

In our work, we designed a programmable peptide-DNA tetrahedron nanostructure, which incorporated both DNA hybridization and a coiled-coil peptide assembly structure. A homotrimeric peptide was modified with DNA handles, and assembled with a triangular DNA “base” bearing complementary arms to yield the cage shown. This is the first cage to integrate both DNA and peptide self-assembly, and the peptide building block will enable applications like new targeted delivery vehicles (of encapsulated cargoes) or integration with functional proteins. More information can be found in the Research Article by N. Stephanopoulos et al.

Promoting immunity with novel targeting antigen delivery vehicle based on bispecific nanobody.

As the most potent professional antigen presenting cells, dendritic cells (DCs) have been targeted in strategies to enhance vaccination efficacy. To date, targeted delivery has been mainly used for cancer therapy, with few studies focusing on vaccine antigens for animal epidemic diseases. In this study, we selected a series of mouse DC-specific nanobodies from a non-immunized camel. The four candidate nanobodies identified (Nb4, Nb13, Nb17, and Nb25), which showed efficient endocytosis of bone marrow-derived DCs, were evaluated as potential vaccine antigen targeted delivery vehicles. First, green fluorescent protein (GFP) was selected and four corresponding DCNb-GFP fusions were constructed for verification. Nb17-GFP was effective at promoting antibody production, inducing a cellular immune response, and increasing the IL-4 level. Second, foot-and-mouth disease virus (FMDV) and a FMDV-specific nanobody (Nb205) were selected and four bispecific nanobody DCNb-Nb205 fusions were generated to investigate the feasibility of a novel targeting antigen delivery vehicle. The resulting bispecific nanobody, Nb17-Nb205, could not only deliver FMDV particles instead of antigenic peptide, but also induced the production of specific antibodies, a cellular immune response, and IFN-γ and IL-4 levels upon immunization with a single subcutaneous injection. In conclusion, our results demonstrate the potential of bispecific nanobody as a novel and efficient DC-specific antigen delivery vehicle. This highlights the potential to expand targeted delivery to the field of animal epidemic diseases and provides a reference for the general application of nanotechnology in viral diseases.

Functional Mechanism of Mesenchymal Stem Cell-Derived Exosomes in Articular Cartilage Regeneration

As the aging of the population, a chronic degenerative joint disease - Osteoarthritis (OA), its incidence and severity are increasing. Compared with cells, the immunogenicity of the exon is low and the immunomodulatory performance is excellent. Various types of mesenchymal stem cell-derived exosomes (MSC-EXOs) are now being used to treat cartilage injury and disease as target drugs or delivery vehicles. A thorough examination of the existing evidence is required in light of the emerging evidence on the effective mechanism and method of MSC-EXOs in OA. This article reviews the specific mechanism and latest research progress of MSCs derived exosomes in OA treatment. It mainly summarizes three mechanisms of action of exosomes: a. Enhancing extracellular matrix (ECM) and preventing cartilage degradation; b. Promoting chondrocyte migration, proliferation, migration, and inhibiting chondrocyte apoptosis, c. Influencing immune protection or immune destruction signals. In addition, the difficulties of exosomes in the clinical treatment of OA are briefly reviewed, with the hope of providing ideas for developing biomaterials scaffolds and clinical treatment of MSC-EXOs.

Alginate-inulin-chitosan based microspheres alter metabolic fate of encapsulated quercetin, promote short chain fatty acid production, and modulate pig gut microbiota

Quercetin loaded alginate microspheres, fabricated with the inclusion of inulin as a prebiotic source and chitosan as protective coating (ALINCH-Q), were subjected to in vitro colonic fermentation using pig fecal microbiota, with empty microspheres ALINCH-E, unencapsulated quercetin UQ and media only Blank as parallel studies. ALINCH-Q altered quercetin biotransformation towards higher production of 3-hydroxyphenylpropionic acid and 3-hydroxyphenylacetic acid, and further metabolism of 3,4-dihydroxyphenylacetic acid and 4-hydroxyphenylacetic acid compared to UQ. In addition, ALINCH-Q but not ALINCH-E or UQ significantly promoted SCFAs production compared to Blank. Furthermore, the ALINCH-Q microspheres altered the microbial compositions, increased the relative abundance of Lactobacillus, Turicibacter, Eubacterium, and Clostridium, while decreased that of the potentially pathogenic Enterococcus. The results suggest an interplay between the dietary fiber matrix and quercetin in producing these effects, and that ALINCH-Q could serve as a potential targeted delivery vehicle for quercetin to exert beneficial biological effects in the colon.

Fabrication, properties and applications of xerogels in food processing

Food gels are one of the fascinating areas of research in the field of food science due to their wide range of properties and applications. Most of the biopolymer-based gels are biocompatible, environment-friendly, and safe to use in food and pharmaceutical applications. The xerogels due to their larger surface area, denser structure, and swelling nature, they can be used in 4D printed foods, encapsulating agents, target delivery vehicles, and many other applications. The larger surface area of the xerogels makes them compatible for biosensor applications which are environment-friendly, rapid, and sensitive. The current review focuses on the fabrication of xerogels, their properties, and their application in food processing.

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).