Drug-loaded Particles Research Articles

The synthesis of hydroxyapatite from artificially grown Red Sea hydrozoan coral for antimicrobacterial drug delivery system applications

The hydrozoan Millepora dichotoma (MD) is a typical Red Sea species containing a porous skeleton in the form of aragonite crystalline calcium carbonate. Due to environmental considerations, the artificial production of coralline species under controlled conditions is pertinent and underway. Artificially grown MD was used as a raw material for the production of calcium phosphate, mainly hydroxyapatite bioceramics, to be used in the drug delivery systems as a drug carrier or in the tissue engineering such as bone graft. DTA-TGA, XRD, FT-IR, Raman, and SEM analysis were carried out to analyze both unconverted and converted artificial corals. Hydrothermally converted coral fine powders were loaded with gentamicin (Gm) antibiotic, and the drug-loaded particles were analyzed by SEM. Unconverted coral was mainly aragonite, while hydrothermally treated coral was completely converted to hydroxyapatite. Hydrothermally treated coral was showing agglomerated nodules up to 1-μm size consisting of nanocrystalline hydroxyapatite platelets in the size range of less than 100 nm. The general macropore size of the coral was found to be appropriate for osteoid growth, which is 100 to 600 μm range. These artificially grown corals can be easily produced and used for bone growth and repair and other biomedical applications.

Are reported methods for synthesizing nanoparticles and microparticles by magnetic stirrer reproducible

One of the most common tools for fabricating different drug-loaded polymeric particles is magnetic stirrer, a widely-used tool in nano-based drug delivery systems. Typically, the revolutions per minute (rpm) or G-Force of the stirrer are reported in related literature, while other parameters generate less attention and must be better understood. Reporting the rpm or G-Force is likely insufficient for producing the same vortex flow intensity and mono-dispersity as having a reliable and reproducible nanoparticle and microparticle synthesis method. We speculate that the magnetic stirrer bar’s length and diameter, and the size of the cylindrical container, affect the qualities of nanoparticles and microparticles. Given the importance of these particle characteristics in the field of nanomedicine, understanding these details would improve reporting method reliability. These data are currently missing in most related papers and must be reported. The purpose of our study is to highlight the importance of these underestimated parameters (magnetic bar’s length, diameter, and the size of the cylindrical container) and the impact on the reproducibility of particle synthesis methods using a magnetic stirrer.

PLA/PLGA-Based Drug Delivery Systems Produced with Supercritical CO2-A Green Future for Particle Formulation?

Supercritical carbon dioxide (SC-CO2) can serve as solvent, anti-solvent and solute, among others, in the field of drug delivery applications, e.g., for the formulation of polymeric nanocarriers in combination with different drug molecules. With its tunable properties above critical pressure and temperature, SC-CO2 offers control of the particle size, the particle morphology, and their drug loading. Moreover, the SC-CO2-based techniques overcome the limitations of conventional formulation techniques e.g., post purification steps. One of the widely used polymers for drug delivery systems with excellent mechanical (Tg, crystallinity) and chemical properties (controlled drug release, biodegradability) is poly (lactic acid) (PLA), which is used either as a homopolymer or as a copolymer, such as poly(lactic-co-glycolic) acid (PLGA). Over the last 30 years, extensive research has been conducted to exploit SC-CO2-based processes for the formulation of PLA carriers. This review provides an overview of these research studies, including a brief description of the SC-CO2 processes that are widely exploited for the production of PLA and PLGA-based drug-loaded particles. Finally, recent work shows progress in the development of SC-CO2 techniques for particulate drug delivery systems is discussed in detail. Additionally, future perspectives and limitations of SC-CO2-based techniques in industrial applications are examined.

Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I.

Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic-co-glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations.

Numerical simulation of magnetic nano drug targeting to atherosclerosis: Effect of plaque morphology (stenosis degree and shoulder length)

Background and objective: Nanoparticle-mediated targeted drug delivery is a promising option for treatment of atherosclerosis. However, the drug targeting may be affected by multiple factors. Considerable attentions have been focused on the influences of external factors, e.g., magnetic field, drug-loaded particle, but internal factors, e.g., plaque morphology (stenosis degree and shoulder length), have not received any attention yet. Therefore, we investigate the impact of plaque morphology on magnetic nanoparticles targeting under the action of an external field. Method: Numerical simulation, based on Eulerian-Lagrangian coupled Fluid-Solid Interaction, is performed in ANSYS Workbench platform. Blood flow is solved by Navier-Stokes equation, particles are tracked by discrete phase model, and the incorporated effect is obtained by two-way method. Plaques with varying stenosis degrees and shoulder lengths are acquired by manually modifying the geometry of patient-specific. The quantified variables include targeted delivery efficiency (deposition+adhesive strength) of particles and plaque injury characterized by temporal-spatial averaged shear stress (TAWSS¯) during the process of drug transport, in which the critical deposition velocity is determined by plaques and particles, the DEFINE_DPM_BC and User Defined Memory are employed to evaluate whether the particles are deposited, and to store the total number and the adhesive strength of particles deposited on the plaque. Results: Results signify that, with an increment of plaque stenosis degree, the deposition of particle and the adhesive strength between particle and plaque decrease, while the TAWSS¯ increases. Furthermore, for the same stenosis degree, with the increase of plaque shoulder length, the deposition and the adhesive strength of particle increase, and the TAWSS¯ decreases. Conclusions: Results demonstrates that the plaque with smaller stenosis degree or longer shoulder length may achieve a better treatment effect in view of the higher targeted delivery efficiency of particles and the lighter shear damage to plaque itself during the process of drug transport.

Water-stable and finasteride-loaded polyvinyl alcohol nanofibrous particles with sustained drug release for improved prostatic artery embolization - In vitro and in vivo evaluation.

Prostatic artery embolization (PAE) has been a well-established treatment for benign prostatic hyperplasia (BPH). To enhance the therapeutic efficacy, a strategy is to use embolic agent preloaded with 5α-reductase inhibitors for localized drug delivery. In this study, finasteride (FNS) was encapsulated into the polyvinyl alcohol (PVA) nanofibers via co-electrospinning technique, followed by heat treatment and cryogenic grinding to convert them into nanofibrous particles as a drug-loaded embolic agent. The FNS was found to be distributed uniformly in PVA nanofibers, and the processed FNS/PVA nanofibrous particles were 272μm in mean particle size. Besides, the studies on the composition, thermal properties, swelling ratio, and water stability of the nanofibers and drug showed that the FNS remained its crystalline state in PVA nanofibers. The heat treatment increased the crystallinity of nanofibers and rendered them water stability. Both FNS and PVA possessed excellent thermal stability at high temperature (150°C). In addition, in vitro drug release studies suggested the FNS followed a favorable sustained release up to 744h. Furthermore, the cell viability and hemocompatibility assays indicated the nanofibers possessed excellent cytocompatibility and with no evidence of hemolysis. More importantly, the in vivo PAE procedures on beagles demonstrated the crosslinked FNS/PVA nanofibrous particles exhibited higher embolization efficacy with more obvious prostate volume (PV) reduction compared to crosslinked PVA nanofibrous particles after embolization for 1, 3, and 6months (P<0.05). Therefore, such drug-loaded PVA nanofibrous particles combined physical embolization and localized medical therapy together, which offer great potential to be used as an effective embolic agent for BPH therapy.

A pH-controlled approach to fabricate electrolyte/non-electrolyte janus particles with low cytotoxicity as carriers of DOX

Seeded emulsion polymerizations of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and methacrylic acid (MAA) were performed in presence of poly(2-hydroxyehtyl methacrylate) (PHEMA) particles as seed to fabricate Janus particles. By tuning the pH value of solution before polymerization, various solutions of protonated and deprotonated monomers were obtained. Then, different morphologies such as core-shell and dumbbell-like were fabricated as a result of pH variations. These composite particles were then used as carriers of DOX in different conditions. All samples showed high loading capacity and long-time release process. Although all morphologies showed insignificant cumulative release at pH = 7.4, release amount was increased to 50–75% at pH = 1. Finally, neat and DOX-loaded particles were introduced to cytotoxicity studies via an MTT assay. According results, PMAA-based particles had no mentionable cell toxicity whereas PDMAEMA-based ones had moderate cytotoxicity. Also, all drug-loaded particles prohibited cell growth significantly. However, DMAEMA-based particles killed more cells than PMAA-based composite particles.

GSK3787-Loaded Poly(Ester Amide) Particles for Intra-Articular Drug Delivery.

Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor δ (PPARδ) in cartilage may attenuate the development or progression of OA. PPARδ antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt.% drug and had mean diameters of about 600 nm. Differential scanning calorimetry indicated the drug was in crystalline domains in the particles. Atomic force microscopy was used to measure the Young’s moduli of individual particles as 2.8 MPa. In vitro drug release studies showed 11% GSK3787 was released over 30 days. Studies in immature murine articular cartilage (IMAC) cells indicated low toxicity from the drug, empty particles, and drug-loaded particles and that the particles were not taken up by the cells. Ex vivo studies on murine joints showed that the particles could be injected into the joint space and resided there for at least 7 days. Overall, these results indicate that GSK3787-loaded PEA particles warrant further investigation as a delivery system for potential OA therapy.

Sustained Release of Levobupivacaine, Lidocaine, and Acemetacin from Electrosprayed Microparticles: In Vitro and In Vivo Studies.

In this study, we explored the release characteristics of analgesics, namely levobupivacaine, lidocaine, and acemetacin, from electrosprayed poly(D,L-lactide-co-glycolide) (PLGA) microparticles. The drug-loaded particles were prepared using electrospraying techniques and evaluated for their morphology, drug release kinetics, and pain relief activity. The morphology of the produced microparticles elucidated by scanning electron microscopy revealed that the optimal parameters for electrospraying were 9 kV, 1 mL/h, and 10 cm for voltage, flow rate, and travel distance, respectively. Fourier-transform infrared spectrometry indicated that the analgesics had been successfully incorporated into the PLGA microparticles. The analgesic-loaded microparticles possessed low toxicity against human fibroblasts and were able to sustainably elute levobupivacaine, lidocaine, and acemetacin in vitro. Furthermore, electrosprayed microparticles were found to release high levels of lidocaine and acemetacin (well over the minimum therapeutic concentrations) and levobupivacaine at the fracture site of rats for more than 28 days and 12 days, respectively. Analgesic-loaded microparticles demonstrated their effectiveness and sustained performance for pain relief in fracture injuries.

Evaluation of particle shape, size and magnetic field intensity for targeted delivery efficiency and plaque injury in treating atherosclerosis

A comprehensive evaluation of therapeutic effects of magnetic nanoparticle therapy for patient-specific atherosclerosis is presented in terms of targeted delivery efficiency (η) and plaque injury. Eulerian-Lagrangian technique is adopted, and an innovative model is first introduced for simulating targeted delivery drug-loaded particles to plaque, in which the shape and size of particles are taken into account in the drag coefficient CD. The impacts of particle shape, size and magnetic field intensity on η and plaque injury characterized by temporal-spatial averaged shear stress (TAWSS¯) are investigated. The results signify that, among drug delivery using the transport particles of different shapes, the sequences of η and TAWSS¯ are platelet>cylinder>blade>sphere>brick, which indicates that the particle with higher drug targeting ability may induce greater plaque injury. Moreover, it is found that increasing the particle size from 300 to 500 nm or the current from 5E4 to 2E5 A enhances η by nearly 9.3% or 18.1%, respectively, but behind this are greater damage to plaque itself. Along with this, the injury discrepancy of plaque induced by particles with different shapes is also amplified. Results obtained can potentially serve as the guideline to optimize the design of transport particle and magnetic field for targeted therapy to atherosclerosis.

Formulation of drug-loaded oligodepsipeptide particles with submicron size.

The size of particulate carriers is key to their transport and distribution in biological systems, and needs to be tailored in the higher submicron range to enable follicular uptake for dermal treatment. Oligodepsipeptides are promising nanoparticulate carrier systems as they can be designed to exhibit enhanced interaction with drug molecules. Here, a fabrication scheme for drug-loaded submicron particles from oligo[3-(S)-sec-butylmorpholine-2,5-dione]diol (OBMD) is presented based on an emulsion solvent evaporation method with cosolvent, surfactant, and polymer concentration as variable process parameters. The particle size (300-950 nm) increased with lower surfactant concentration and higher oligomer concentration. The addition of acetone increased the particle size at low surfactant concentration. Particle size remained stable upon the encapsulation of models compounds dexamethasone (DXM) and Nile red (NR), having different physicochemical properties. DXM was released faster compared to NR due to its higher water solubility. Overall, the results indicated that both drug-loading and size control of OBMD submicron particles can be achieved. When applied on porcine ear skin samples, the NR-loaded particles have been shown to allow NR penetration into the hair follicle and the depth reached with the 300 nm particles was comparable to the one reached with the cream formulation. A potential benefit of the particles compared to a cream is their sustained release profile.

Targeted ErbB3 cancer therapy: A synergistic approach to effectively combat cancer.

Surface modification of nanoparticles with aptamer is gaining popularity lately due to its selective targeting and low immunogenicity. In this study, sorafenib tosylate (SFB) was loaded in biodegradable PLGA nanoparticles prepared by solvent evaporation method. The surfaces of drug deprived and drug-loaded particles (PN and PNS, respectively) were coupled with aptamer to target ErbB3 using EDC/NHS chemical modification. Nanoparticles were characterized with regard to their size, shape and chemical composition by dynamic light scattering, atomic force microscopy, FTIR and elemental analysis respectively. To evaluate the particles in vitro cell culture studies were performed. Cell viability assay, pathway analysis and apoptosis assay showed cellular toxicity in the presence of aptamer in PNS-Apt (p<0.001). Metastatic progression assay showed decreased cell migration in the presence of aptamer and SFB. Confocal laser scanning microscopy was used to visualize the receptor-mediated time-dependent intracellular uptake and distribution of the nanoparticles throughout the cytoplasm. The findings of the current study demonstrated the potential efficacy of the surface modified SFB-loaded particles against ErbB3.

Citrate Association Dramatically Reduces Diameter with Concomitant Increase in Uptake of Drug-Loaded Carbonate Apatite Particles in Breast Cancer Cells.

Inorganic nanoparticles are commonly employed as vectors for delivering drugs into cancer cells while decreasing undesired cytotoxicity in healthy tissues. Carbonate apatite is an attractive nonviral vector that releases drugs at acidic environment inside the cells following endocytosis. However, maintaining the smaller particle size is crucial for enhancing cellular uptake of drugs as well as prolonging their systemic circulation time. We aimed to modify carbonate apatite with citrate for reducing the growth kinetics of carbonate apatite particles and enhancing the cellular uptake of cyclophosphamide via endocytosis. Several concentrations of sodium citrate were used to fabricate citrate-modified carbonate apatite (CMCA) particle complexes in absence or presence of cyclophosphamide. The binding affinity of the drug towards the particles and its cellular uptake were measured by high-performance liquid chromatography (HPLC). The nanoparticles' average size and zeta potential were determined by Malvern Zetasizer. Fourier-transform infrared spectroscopy (FTIR) was performed to justify association of citrate with carbonate apatite. MTT assay was performed to evaluate the cell viability. CMCA exhibited 6% more binding efficiency for cyclophosphamide and promoted fast cellular uptake of cyclophosphamide with enhanced cytotoxicity in MCF-7 cells, compared to unmodified carbonate apatite. Therefore, CMCA nanoparticles have a high potential for intracellular delivery of anti-cancer drugs and demand for further investigated in animal models of cancer.

Smart Targeting To Improve Cancer Therapeutics.

Cancer is the second largest cause of death worldwide with the number of new cancer cases predicted to grow significantly in the next decades. Biotechnology and medicine can and should work hand-in-hand to improve cancer diagnosis and treatment efficacy. However, success has been frequently limited, in particular when treating late-stage solid tumors. There still is the need to develop smart and synergistic therapeutic approaches to achieve the synthesis of strong and effective drugs and delivery systems. Much interest has been paid to the development of smart drug delivery systems (drug-loaded particles) that utilize passive targeting, active targeting, and/or stimulus responsiveness strategies. This review will summarize some main ideas about the effect of each strategy and how the combination of some or all of them has shown to be effective. After a brief introduction of current cancer therapies and their limitations, we describe the biological barriers that nanoparticles need to overcome, followed by presenting different types of drug delivery systems to improve drug accumulation in tumors. Then, we describe cancer cell membrane targets that increase cellular drug uptake through active targeting mechanisms. Stimulus-responsive targeting is also discussed by looking at the intra- and extracellular conditions for specific drug release. We include a significant amount of information summarized in tables and figures on nanoparticle-based therapeutics, PEGylated drugs, different ligands for the design of active-targeted systems, and targeting of different organs. We also discuss some still prevailing fundamental limitations of these approaches, eg, by occlusion of targeting ligands.

Dual drug-loaded biodegradable Janus particles for simultaneous co-delivery of hydrophobic and hydrophilic compounds.

Bicompartmental Janus particles have many advantages in drug delivery, including co-delivery of two compounds with varying solubilities, differential release kinetics, and two surfaces available for targeting ligands. We present a novel strategy using the double emulsion method for the coencapsulation and staggered release of a hydrophobic and hydrophilic drug from anisotropic PLGA/PCL Janus particles, as well as a UV detection method to measure the release of two different compounds from Janus particles. Curcumin and quercetin were chosen as the model hydrophobic compounds for drug loading studies, while acetaminophen (APAP) and naproxen were chosen as the model hydrophilic–hydrophobic drug pair for encapsulation methods and drug loading. Also, a similar double emulsion method was also applied for PLGA/Preicrol® Janus particles containing Doxorubicin and Curcumin. Hydrophobic drugs were encapsulated by the single O/W emulsion technique. Hydrophilic compounds required special modifications due to their poor oil solubility and tendency to escape to the outer aqueous phase during the emulsification and solvent evaporation steps. In total, three different strategies for incorporating hydrophilic drugs were employed: (1) O/W emulsion with partially water miscible solvent, (2) O/W emulsion with co-solvent (i.e. acetone, methanol, ethanol), or (3) W/O/W double emulsion. The encapsulation efficiencies and drug loading percentages were measured using UV/Vis spectroscopy and compared for the different synthesis methods. It was found that the double emulsion method resulted in the highest encapsulation efficiency and drug loading of the hydrophilic drug.

Phospholipid conjugated prodrugs for targeted delivery using ultrasound with microbubbles and nanodroplets

Therapeutic payloads remain a challenge for phospholipid-stabilized microbubbles that are currently used as contrast agents in diagnostic ultrasound imaging. High loading is difficult to achieve due to the metastable phospholipid monolayer that lacks cargo volume, requiring lengthy drug-loaded particle tethering strategies or other sophisticated methods. The purpose of this work is to demonstrate that phospholipid conjugation can anchor chemotherapeutics to the microbubble shell with minimal disruption to phospholipid packing, resulting in an ultrasound theranostic agent that requires minimal preparation prior to administration. Using a Steglich esterification reaction, several potent chemotherapeutics were conjugated to phospholipids and were subsequently incorporated into liposomes, microbubbles, and nanodroplets for biological and particle characterization. Prodrug structures were confirmed with 1H and 13C NMR. Retention of biological activity for each phospholipid prodrug was demonstrated with an MTT cell proliferation assay using liposomes. Loading and stability of nanodroplets and microbubbles were measured with UV-Vis spectroscopy. To demonstrate site-specific delivery potential, these solutions were suspended in a submersible cell culture chamber with adhered HeLa cells. A single element transducer was used to apply a radiation force and fragmentation pulse sequence. Ultrasound-exposed and non-exposed areas treated with prodrug-containing microbubbles and nanodroplets were compared, demonstrating local efficacy.

Encapsulated Carbenoxolone Reduces Lung Metastases

Carbenoxolone is an anti-inflammatory compound and a derivate of a natural substance from the licorice plant. We previously showed that carbenoxolone reduces the metastatic burden in the lungs of mice through its antagonistic effect on high mobility group box 1 (HMGB1). To further enhance carbenoxolone’s activity and localization in the lungs, thereby reducing the potential adverse side effects resulting from systemic exposure, we developed a poly(lactic-co-glycolic acid) (PLGA) slow-release system for pulmonary delivery which maintains drug activity in-vitro, as demonstrated in the anoikis assay. Both systemic and intranasal administrations of carbenoxolone effectively minimize metastatic formation in a lung colonization model in mice. Our results show a decrease in the metastatic burden in the lung tissue. Notably, the therapeutic effect of a single intranasal administration of 25 mg/kg carbenoxolone, in the form of drug-loaded particles, had a similar effect in reducing metastatic lesions in the lungs to that of a 10-fold dose of the free drug via intraperitoneal injections, three times per week over the course of four weeks. These data offer new means to potentiate the anti-cancer activity of carbenoxolone and simultaneously reduce the requirement for high dosage administration; the upshot substantially improves therapeutic effect and avoidance of side effects.

Sustaining Antibiotic Release from a Poly(methyl methacrylate) Bone-Spacer

One of the challenges in using a bone-spacer to cure infection is the fabrication of a material that can continuously release required antibiotics at effective concentrations for at least 4–6 weeks. Poly(methyl methacrylate) (PMMA) impregnated with antibiotics is one of the popularly used bone-spacer materials. Currently, improved sustained release of hydrophobic and hydrophilic antibiotics is needed for this material. Here, hydrophilic vancomycin (VAN) was encapsulated into calcium citrate (CC) particles and natural rice granules, and hydrophobic erythromycin (ERY) was encapsulated into ethyl cellulose and poly(lactic-co-glycolic acid) particles. The four antibiotic-loaded particles were each incorporated into the PMMA cement. The two unencapsulated drugs and all four drug-loaded particles distributed well in the obtained composites. PMMA composited with VAN-loaded CC showed prolonged VAN release at an effective concentration for more than 40 days, but the composite possessed lesser compressive strength than the PMMA with no drug. PMMA composited with unencapsulated ERY showed a better sustainment of drug release than those composited with encapsulated ERY. VAN elution from the VAN–CC–PMMA did not significantly affect the compressive strength of the material, whereas ERY elution from the ERY–PMMA composite significantly decreased the material’s mechanical strength.

Magnetic Janus particles as a multifunctional drug delivery system for paclitaxel in efficient cancer treatment.

Paclitaxel is broad-spectrum anticancer drug which has been widely used in clinic. However, traditional drug delivery often suffers from the scarcity of resources and systemic toxic side effects caused by the localization to non-tumor areas, rendering cancer treatment extremely challenging. To address this problem, we developed a novel multifunctional drug delivery system of a poly(lactic-co-glycolic acid) (PLGA) drug-loaded magnetic Janus particles (DMJPs) using electrohydrodynamic (EDH) co-jetting. The DMJPs were loaded with three compartments each with distinct function, i.e. paclitaxel for killing cancer cell, Fe3O4 nanoparticles for target location, and rhodamine B for fluorescence tracing, respectively. The Janus structure of the DMJPs, as demonstrated by the loaded nano-quantum dots CdS/ZnS and CdSe/ZnS in different compartments, enhanced not only the drug loading and encapsulation efficiency but also the cumulative release rate of the loaded drugs from DMJPs in different media. More importantly, DMJPs exhibited specific and high toxicity only to human breast cancer cells (MDA-MB-231), but not to mouse embryonic fibroblasts (NIH-3 T3). Consistently, DMJPs induced the higher lethal effect on cancer cells than paclitaxel suspension of high concentrations. Under guidance of external magnetic field, DMJPs can readily target and accumulate on and inside cancer cells for cell elimination. The specific targetability, selectivity, and toxicity of DMJPs on cancer cells would greatly avoid any potential side effects and reduce the overdose of drugs for conventional drug delivery. This work hopefully provides a new drug delivery system for the development of anticancer drug systems for clinical and precision medicine treatment.

Ultrasound/microbubble-mediated targeted delivery of anticancer microRNA-loaded nanoparticles to deep tissues in pigs

In this study, we designed and validated a platform for ultrasound and microbubble-mediated delivery of FDA-approved pegylated poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with anticancer microRNAs (miRNAs) to deep tissues in a pig model. Small RNAs have been shown to reprogram tumor cells and sensitize them to clinically used chemotherapy. To overcome their short intravascular circulation half-life and achieve controlled and sustained release into tumor cells, anticancer miRNAs need to be encapsulated into nanocarriers. Focused ultrasound combined with gas-filled microbubbles provides a noninvasive way to improve the permeability of tumor vasculature and increase the delivery efficiency of drug-loaded particles. A single handheld, curvilinear ultrasound array was used in this study for image-guided therapy with clinical-grade SonoVue contrast agent. First, we validated the platform on phantoms to optimize the microbubble cavitation dose based on acoustic parameters, including peak negative pressure, pulse length, and pulse repetition frequency. We then tested the system in vivo by delivering PLGA nanoparticles co-loaded with antisense-miRNA-21 and antisense-miRNA-10b to pig liver and kidney. Enhanced miRNA delivery was observed (1.9- to 3.7-fold increase) as a result of the ultrasound treatment compared to untreated control regions. Additionally, we used highly fluorescent semiconducting polymer nanoparticles to visually assess nanoparticle extravasation. Fluorescent microscopy suggested the presence of nanoparticles in the extravascular compartment. Hematoxylin and eosin staining of treated tissues did not reveal tissue damage. The results presented in this manuscript suggest that the proposed platform may be used to safely and noninvasively enhance the delivery of miRNA-loaded nanoparticles to target regions in deep organs in large animal models.