Bacterial outer membrane vesicle-cancer cell hybrid membrane-coated nanoparticles for sonodynamic therapy in the treatment of breast cancer bone metastasis.

Breast cancer bone metastasis is a terminal-stage disease and is typically treated with radiotherapy and chemotherapy, which causes severe side effects and limited effectiveness. To improve this, Sonodynamic therapy may be a more safe and effective approach in the future. Bacterial outer membrane vesicles (OMV) have excellent immune-regulating properties, including modulating macrophage polarization, promoting DC cell maturation, and enhancing anti-tumor effects. Combining OMV with Sonodynamic therapy can result in synergetic anti-tumor effects. Therefore, we constructed multifunctional nanoparticles for treating breast cancer bone metastasis. We fused breast cancer cell membranes and bacterial outer membrane vesicles to form a hybrid membrane (HM) and then encapsulated IR780-loaded PLGA with HM to produce the nanoparticles, IR780@PLGA@HM, which had tumor targeting, immune regulating, and Sonodynamic abilities. Experiments showed that the IR780@PLGA@HM nanoparticles had good biocompatibility, effectively targeted to 4T1 tumors, promoted macrophage type I polarization and DC cells activation, strengthened anti-tumor inflammatory factors expression, and presented the ability to effectively kill tumors both in vitro and in vivo, which showed a promising therapeutic effect on breast cancer bone metastasis. Therefore, the nanoparticles we constructed provided a new strategy for effectively treating breast cancer bone metastasis.

Multifunctional Nanocarrier for Synergistic Treatment of Alzheimer's Disease by Inhibiting ß-Amyloid Aggregation and Scavenging Reactive Oxygen Species.

The excessive depositions of ß-amyloid (Aß) and abnormal level of reactive oxygen species (ROS) are considered as the important pathogenic factors of Alzheimer's disease (AD). Strategies targeting only one of them have no obvious effects in clinic. In this study, a multifunctional nanocarrier CICe@M-K that crosses the blood-brain barrier (BBB) efficiently was developed for inhibiting Aß aggregation and scavenging ROS synchronously. Antioxidant curcumin (Cur) and photosensitizer IR780 were loaded in mesoporous silica nanomaterials (MSNs). Their surfaces were grafted with cerium oxide nanoparticles (CeO2 NPs) and a short peptide K (CKLVFFAED). Living imaging showed that CICe@M-K was mainly distributed in the brain, liver, and kidneys, indicating CICe@M-K crossed BBB efficiently and accumulated in brain. After the irradiation of 808 nm laser, Cur was continuously released. Both of Cur and the peptide K can recognize and bind to Aß through multiple interaction including π-π stacking interaction, hydrophobic interaction, and hydrogen bond, inhibiting Aß aggregation. On the other hand, Cur and CeO2 NPs cooperate to relieve the oxidative stress in the brains by scavenging ROS. In vivo assays showed that the CICe@M-K could diminish Aß depositions, alleviate oxidative stress, and improve cognitive ability of the APP/PS1 AD mouse model, which demonstrated that CICe@M-K is a potential agent for AD treatment.

Hyaluronic acid targeted and pH-responsive multifunctional nanoparticles for chemo-photothermal synergistic therapy of atherosclerosis.

Atherosclerosis is a global disease with an extremely high morbidity and fatality rate, so it is necessary to develop effective treatments to reduce its impact. In this work, we successfully prepared a multifunctional drug-loaded nano-delivery system with pH-responsive, CD44-targeted, and chemical-photothermal synergistic treatment. Dendritic mesoporous silica nanoparticles capped with copper sulfide (CuS) were synthesized via an oil-water biphase stratification reaction system; these served as the carrier material and encapsulated the anticoagulant drug heparin (Hep). The pH-sensitive Schiff base bond was used as a gatekeeper and targeting agent to modify hyaluronic acid (HA) on the surface of the nanocarrier. HA coating endowed the nanocomposite with the ability to respond to pH and target CD44-positive inflammatory macrophages. Based on this multifunctional nanocomposite, we achieved precise drug delivery, controlled drug release, and chemical-photothermal synergistic treatment of atherosclerosis. The in vitro drug release results showed that the nanocarriers exhibited excellent drug-controlled release properties, and could release drugs in the weakly acidic microenvironment of atherosclerotic inflammation. Cytotoxicity and cell uptake experiments indicated that nanocarriers had low cytotoxicity against RAW 264.7 cells. Modification of HA to nanocarriers can be effectively internalized by RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Combining CuS photothermal treatment with anti-atherosclerosis chemotherapy showed better effects than single treatment in vitro and in vivo. In summary, our research proved that H-CuS@DMSN-NC-HA has broad application prospects in anti-atherosclerosis.

Real-Time Simultaneous Imaging of Acidification and Proteolysis in Single Phagosomes Using Bifunctional Janus-Particle Probes.

The digestion of pathogens inside phagosomes by immune cells occurs through a sequence of reactions including acidification and proteolysis, but how the reactions are orchestrated in the right order is unclear due to a lack of methods to simultaneously measure more than one reaction in phagosomes. Here we report a bifunctional Janus-particle probe to simultaneously monitor acidification and proteolysis in single phagosomes in live cells. Each probe consists of a pH reporter and a proteolysis reporter that are spatially separated but function concurrently. Using the Janus probes, we found the acidic pH needed to initiate and maintain proteolysis, revealing the mechanism for the sequential occurrence of both reactions during pathogen digestion. We showed how bacterium-derived lipopolysaccharides alter the acidification and proteolysis in phagosomes. This study showcases Janus-particle probes as a generally applicable tool for monitoring multiple reactions in intracellular vesicles.

Blood-Brain Barrier Permeable and NO-Releasing Multifunctional Nanoparticles for Alzheimer's Disease Treatment: Targeting NO/cGMP/CREB Signaling Pathways.

The development of novel therapeutic strategies for combating Alzheimer's disease (AD) is challenging but imperative. Multifunctional nanoparticles are promising tools for regulating complex pathological dysfunctions for AD treatment. Herein, we constructed multifunctional nanoparticles consisting of regadenoson (Reg), nitric oxide (NO) donor, and YC-1 in a single molecular entity that can spontaneously self-assemble into nanoparticles and load donepezil to yield Reg-nanoparticles (Reg-NPs). The Reg moiety enabled the Reg-NPs to effectively regulate tight junction-associated proteins in the blood-brain barrier, thus facilitating the permeation of donepezil through the barrier and its accumulation in the brain. Moreover, the released NO and YC-1 activated the NO/cGMP/CREB signaling pathway by stimulating soluble guanylyl cyclase and inhibiting phosphodiesterase activity, which finally reduced cytotoxicity induced by aggregated Aß in the neurons and was beneficial for synaptic plasticity and memory formation.

Oral Administration of Resveratrol-Selenium-Peptide Nanocomposites Alleviates Alzheimer's Disease-like Pathogenesis by Inhibiting Aß Aggregation and Regulating Gut Microbiota.

Alzheimer's disease (AD) is a neurodegenerative disease associated with amyloid-ß (Aß) deposition, leading to neurotoxicity (oxidative stress and neuroinflammation) and gut microbiota imbalance. Resveratrol (Res) has neuroprotective properties, but its bioavailability in vivo is very low. Herein, we developed a small Res-selenium-peptide nanocomposite to enable the application of Res for eliminating Aß aggregate-induced neurotoxicity and mitigating gut microbiota disorder in aluminum chloride (AlCl3) and d-galactose(d-gal)-induced AD model mice. Res functional selenium nanoparticles (Res@SeNPs) (8 ± 0.34 nm) were prepared first, after which the surface of Res@SeNPs was decorated with a blood-brain barrier transport peptide (TGN peptide) to generate Res-selenium-peptide nanocomposites (TGN-Res@SeNPs) (14 ± 0.12 nm). Oral administration of TGN-Res@SeNPs improves cognitive disorder through (1) interacting with Aß and decreasing Aß aggregation, effectively inhibiting Aß deposition in the hippocampus; (2) decreasing Aß-induced reactive oxygen species (ROS) and increasing activity of antioxidation enzymes in PC12 cells and in vivo; (3) down-regulating Aß-induced neuroinflammation via the nuclear factor kappa B/mitogen-activated protein kinase/Akt signal pathway in BV-2 cells and in vivo; and (4) alleviating gut microbiota disorder, particularly with respect to oxidative stress and inflammatory-related bacteria such as Alistipes, Helicobacter, Rikenella, Desulfovibrio, and Faecalibaculum. Thus, we anticipate that Res-selenium-peptide nanocomposites will offer a new potential strategy for the treatment of AD.

Hitchhiking Nanoparticles: Mesenchymal Stem Cell-Mediated Delivery of Theranostic Nanoparticles.

Nanotechnology has emerged as a promising solution to permanent elimination of cancer. However, nanoparticles themselves lack specificity to tumors. Due to enhanced migration to tumors, mesenchymal stem cells (MSCs) were suggested as cell-mediated delivery vehicles of nanoparticles. In this study, we have constructed a complex composed of photoluminescent quantum dots (QDs) and a photosensitizer chlorin e6 (Ce6) to obtain multifunctional nanoparticles, combining cancer diagnostic and therapeutic properties. QDs serve as energy donors-excited QDs transfer energy to the attached Ce6 via Förster resonance energy transfer, which in turn generates reactive oxygen species. Here, the physicochemical properties of the QD-Ce6 complex and singlet oxygen generation were measured, and the stability in protein-rich media was evaluated, showing that the complex remains the most stable in protein-free medium. In vitro studies on MSC and cancer cell response to the QD-Ce6 complex revealed the complex-loaded MSCs' potential to transport theranostic nanoparticles and induce cancer cell death. In vivo studies proved the therapeutic efficacy, as the survival of tumor-bearing mice was statistically significantly increased, while tumor progression and metastases were slowed down.

Micromotor-based localized electroporation and gene transfection of mammalian cells.

Herein, we studied localized electroporation and gene transfection of mammalian cells using a metallodielectric hybrid micromotor that is magnetically and electrically powered. Much like nanochannel-based, local electroporation of single cells, the presented micromotor was expected to increase reversible electroporation yield, relative to standard electroporation, as only a small portion of the cell's membrane (in contact with the micromotor) is affected. In contrast to methods in which the entire membrane of all cells within the sample are electroporated, the presented micromotor can perform, via magnetic steering, localized, spatially precise electroporation of the target cells that it traps and transports. In order to minimize nonselective electrical lysis of all cells within the chamber, resulting from extended exposure to an electrical field, magnetic propulsion was used to approach the immediate vicinity of the targeted cell, after which short-duration, electric-driven propulsion was activated to enable contact with the cell, followed by electroporation. In addition to local injection of fluorescent dye molecules, we demonstrated that the micromotor can enhance the introduction of plasmids into the suspension cells because of the dielectrophoretic accumulation of the plasmids in between the Janus particle and the attached cell prior to the electroporation step. Here, we chose a different strategy involving the simultaneous operation of many micromotors that are self-propelling, without external steering, and pair with cells in an autonomic manner. The locally electroporated suspension cells that are considered to be very difficult to transfect were shown to express the transfected gene, which is of significant importance for molecular biology research.

Guided accumulation of active particles by topological design of a second-order skin effect.

Collective guidance of out-of-equilibrium systems without using external fields is a challenge of paramount importance in active matter, ranging from bacterial colonies to swarms of self-propelled particles. Designing strategies to guide active matter and exploiting enhanced diffusion associated to its motion will provide insights for application from sensing, drug delivery to water remediation. However, achieving directed motion without breaking detailed balance, for example by asymmetric topographical patterning, is challenging. Here we engineer a two-dimensional periodic topographical design with detailed balance in its unit cell where we observe spontaneous particle edge guidance and corner accumulation of self-propelled particles. This emergent behaviour is guaranteed by a second-order non-Hermitian skin effect, a topologically robust non-equilibrium phenomenon, that we use to dynamically break detailed balance. Our stochastic circuit model predicts, without fitting parameters, how guidance and accumulation can be controlled and enhanced by design: a device guides particles more efficiently if the topological invariant characterizing it is non-zero. Our work establishes a fruitful bridge between active and topological matter, and our design principles offer a blueprint to design devices that display spontaneous, robust and predictable guided motion and accumulation, guaranteed by out-of-equilibrium topology.

Imaging application and radiosensitivity enhancement of pectin decorated multifunctional magnetic nanoparticles in cancer therapy.

In this contribution, we report the fabrication of multifunctional nanoparticles with gold shell over an iron oxide nanoparticles (INPs) core. The fabricated system combines the magnetic property of INPs and the surface plasmon resonance of gold. The developed nanoparticles are coated with thiolated pectin (TPGINs), which provides stability to the nanoparticles dispersion and allows the loading of hydrophobic anticancer drugs. Curcumin (Cur) is used as the model drug and an encapsulation efficiency of approximately 80% in TPGINs is observed. Cytotoxicity study with HeLa cells shows that Cur-loaded TPGINs have better viability percent (~30%) than Cur alone (~40%) at a dose of 30 µg of TPGINs. Further, annexin V-PI assay demonstrated the enhanced anticancer activity of Cur-loaded TPGINs via induction of apoptosis. The use of TPGINs leads to a significant enhancement in generating reactive oxygen species (ROS) in HeLa cells through improved radiosensitization by gamma irradiation (0.5 Gy). TPGINs are further evaluated for imparting contrast in magnetic resonance imaging (MRI) with the r2 relaxivity in the range of 11.06-13.94 s-1 µg-1 mL when measured at 7 Tesla. These experimental results indicate the potential of TPGINs for drug delivery and MR imaging.

Functional Nanomaterials and 3D-Printable Nanocomposite Hydrogels for Enhanced Cell Proliferation and for the Reduction of Bacterial Biofilm Formation.

Biomaterial-associated infections are a major cause of biomaterial implant failure. To prevent the initial attachment of bacteria to the implant surface, researchers have investigated various surface modification methods. However, most of these approaches also prevent the attachment, spread, and growth of mammalian cells, resulting in tissue integration failure. Therefore, the success of biomaterial implants requires an optimal balance between tissue integration (cell adhesion to biomaterial implants) and inhibition of bacterial colonization. In this regard, we synthesize bifunctional nanomaterials by functionalizing the pores and outer surfaces of periodic mesoporous organosilica (PMO) with antibacterial tetracycline (Tet) and antibacterial and cell-adhesive bipolymer poly-d-lysine (PDL), respectively. Then, the fabricated TetPMO-PDL nanomaterials are incorporated into alginate-based hydrogels to create injectable and 3D-printable nanocomposite (NC) hydrogels (AlgL-TetPMO-PDL). These bifunctional nanomaterial and 3D-printable NC hydrogel show pH-dependent release of Tet over 7 days. They also enhance the proliferation of eukaryotic cells (fibroblasts). TetPMO-PDL is inactive in reducing Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis biofilms. However, AlgL-TetPMO-PDL shows significant antibiofilm activity against P. aeruginosa. These results suggest that the incorporation of TetPMO-PDL into AlgL may have a synergistic effect on the inhibition of the Gram-negative bacterial (P. aeruginosa) biofilm, while this has no effect on the reduction of the Gram-positive bacterial (S. aureus and E. faecalis) biofilm.

RGD-modified multifunctional nanoparticles encapsulating salvianolic acid A for targeted treatment of choroidal neovascularization.

BACKGROUND: The development of alternative anti-angiogenesis therapy for choroidal neovascularization (CNV) remains a great challenge. Nanoparticle systems have emerged as a new form of drug delivery in ocular diseases. Here, we report the construction and characterization of arginine-glycine-aspartic acid (RGD)-conjugated polyethyleneimine (PEI) as a vehicle to load antioxidant salvianolic acid A (SAA) for targeted anti-angiogenesis therapy of CNV. In this study, PEI was consecutively modified with polyethylene glycol (PEG) conjugated RGD segments, 3-(4'-hydroxyphenyl) propionic acid-Osu (HPAO), and fluorescein isothiocyanate (FI), followed by acetylation of the remaining PEI surface amines to generate the multifunctional PEI vehicle PEI.NHAc-FI-HPAO-(PEG-RGD) (for short, RGD-PEI). The formed RGD-PEI was utilized as an effective vehicle platform to load SAA. RESULTS: We showed that RGD-PEI/SAA complexes displayed desirable water dispersibility, low cytotoxicity, and sustainable release of SAA under different pH conditions. It could be specifically taken up by retinal pigment epithelium (RPE) cells which highly expressed ɑvß5 integrin receptors in vitro and selectively accumulated in CNV lesions in vivo. Moreover, the complexes displayed specific therapeutic efficacy in a mouse model of laser induced CNV, and the slow elimination of the complexes in the vitreous cavity was verified by SPECT imaging after 131I radiolabeling. The histological examinations further confirmed the biocompatibility of RGD-PEI/SAA. CONCLUSIONS: The results suggest that the designed RGD-PEI/SAA complexes may be a potential alternative anti-angiogenesis therapy for posterior ocular neovascular diseases.

Novel Multifunctional Stimuli-Responsive Nanoparticles for Synergetic Chemo-Photothermal Therapy of Tumors.

In this study, a novel class of multifunctional responsive nanoparticles is designed and fabricated as drug nanocarriers for synergetic chemo-photothermal therapy of tumors. The proposed nanoparticles are composed of a thermo-/pH-responsive poly(N-isopropylacrylamide-co-acrylic acid) (PNA) nanogel core, a polydopamine (PDA) layer for photothermal conversion, and an outer folic acid (FA) layer as a targeting agent for the folate receptors on tumor cells. The fabricated nanoparticles show good biocompatibility and outstanding photothermal conversion efficiency. The proposed nanoparticles loaded with doxorubicin (DOX) drug molecules are stable under physiological conditions with low leakage of drugs, while rapidly release drugs in environments with low pH conditions and at high temperature. The experimental results show that the drug release process is mainly governed by Fickian diffusion. In vitro cell experimental results demonstrate that the PNA-DOX@PDA-FA nanoparticles can be phagocytized by 4T1 tumor cells and release drugs in tumor cell acidic environments, and confirm that the combined chemo and photothermal therapeutic efficacy of PNA-DOX@PDA-FA nanoparticles is higher than the photothermal therapeutic efficacy or the chemotherapeutic efficacy alone. The proposed multifunctional responsive nanoparticles in this study provide a novel class of drug nanocarriers as a promising tool for synergetic chemo-photothermal therapy of tumors.

Co-biomembrane-coated Fe3O4/MnO2 multifunctional nanoparticles for targeted delivery and enhanced chemodynamic/photothermal/chemo therapy.

Here, the co-membrane system of MCF-7 breast cancer cell membrane (MM) and Escherichia coli membrane (EM)-coated Fe3O4/MnO2 multifunctional composite nanoparticles loaded with DOX (Fe3O4/MnO2/MM/EM/D) was used for targeted drug delivery and biological imaging.

Photodynamic therapy synergizes with PD-L1 checkpoint blockade for immunotherapy of CRC by multifunctional nanoparticles.

Checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have been shown to be extraordinarily effective, but their durable response rate remains low, especially in colorectal cancer (CRC). Recent studies have shown that photodynamic therapy (PDT) could effectively enhance PD-L1 blockade therapeutic effects, although the reason is still unclear. Here, we report the use of multifunctional nanoparticles (NPs) loaded with photosensitized mTHPC (mTHPC@VeC/T-RGD NPs)-mediated PDT treatment to potentiate the anti-tumor efficacy of PD-L1 blockade for CRC treatment and investigate the underlying mechanisms of PDT enhancing PD-L1 blockade therapeutic effect in this combination therapy. In this study, the mTHPC@VeC/T-RGD NPs under the 660-nm near infrared (NIR) laser could kill tumor cells by inducing apoptosis and/or necrosis and stimulating systemic immune response, which could be further promoted by the PD-L1 blockade to inhibit primary and distant tumor growth, as well as building long-term host immunological memory to prevent tumor recurrence. Furthermore, we detected that mTHPC@VeC/T-RGD NP-mediated PDT sensitizes tumors to PD-L1 blockade therapy mainly because PDT-mediated hypoxia could induce the hypoxia-inducible factor 1α (HIF-1α) signaling pathway that upregulates PD-L1 expression in CRC. Taken together, our work demonstrates that mTHPC@VeC/T-RGD NP-mediated PDT is a promising strategy that may potentiate the response rate of anti-PD-L1 checkpoint blockade immunotherapies in CRC.

Proof-of-Concept Study of Multifunctional Hybrid Nanoparticle System Combined with NIR Laser Irradiation for the Treatment of Melanoma.

The global impact of cancer emphasizes the importance of developing innovative, effective and minimally invasive therapies. In the context of superficial cancers, the development of a multifunctional nanoparticle-based system and its in vitro and in vivo safety and efficacy characterization are, herein, proposed as a proof-of-concept. This multifunctional system consists of gold nanoparticles coated with hyaluronic and oleic acids, and functionalized with epidermal growth factor for greater specificity towards cutaneous melanoma cells. This nanoparticle system is activated by a near-infrared laser. The characterization of this nanoparticle system included several phases, with in vitro assays being firstly performed to assess the safety of gold nanoparticles without laser irradiation. Then, hairless immunocompromised mice were selected for a xenograft model upon inoculation of A375 human melanoma cells. Treatment with near-infrared laser irradiation for five minutes combined with in situ administration of the nanoparticles showed a tumor volume reduction of approximately 80% and, in some cases, led to the formation of several necrotic foci, observed histologically. No significant skin erythema at the irradiation zone was verified, nor other harmful effects on the excised organs. In conclusion, these assays suggest that this system is safe and shows promising results for the treatment of superficial melanoma.

Multifunctional nanoparticles as theranostic agents for therapy and imaging of breast cancer.

Over the last decade, there has been significant developments in nanotechnology, in particular for combined imaging and therapeutic applications (theranostics). The core or shell of nanoemulsions (NEs) can be loaded with various therapeutic agents, including drugs with low solubility for effective treatment, or various imaging agents for specific imaging modalities (e.g., MRI, fluorescence). In this work, perfluorohexane (PFH) NEs were synthesized for theranostic applications and were coupled to silica coated gold nanoparticles (scAuNPs) to increase the generation of PFH bubbles upon laser induced vaporization (i.e., optical droplet vaporization). The localized heat generated from the absorption properties of these nanoparticles (used to provide photoacoustic signals) can also be used to treat cancer without significantly damaging nearby healthy tissues. The theranostic potential of these PFH-NEs for contrast imaging of tumors and as a drug-delivery vehicle for therapeutic purposes were demonstrated for both in vitro and in vivo systems using a combination of photoacoustic, ultrasound and fluorescence imaging modalities. The ability of PFH-NEs to couple with scAuNPs, attach to the membranes of cancer cells and internalize within cancer cells, are encouraging for targeted chemotherapeutic applications for directly inducing cancer cell death via vaporization in clinical settings.

A Smart Multifunctional Nanoparticle for Enhanced Near-Infrared Image-Guided Photothermal Therapy Against Gastric Cancer.

BACKGROUND: Surgery is considered to be a potentially curative approach for gastric cancer. However, most cases are diagnosed at a very advanced stage for the lack of typical symptoms in the initial stage, which makes it difficult to completely surgical resect of tumors. Early diagnosis and precise personalized intervention are urgent issues to be solved for improving the prognosis of gastric cancer. Herein, we developed an RGD-modified ROS-responsive multifunctional nanosystem for near-infrared (NIR) imaging and photothermal therapy (PTT) against gastric cancer. METHODS: Firstly, the amphiphilic polymer was synthesized by bromination reaction and nucleophilic substitution reaction of carboxymethyl chitosan (CMCh) and 4-hydroxymethyl-pinacol phenylborate (BAPE). Then, it was used to encapsulate indocyanine green (ICG) and modified with RGD to form a smart multifunctional nanoparticle targeted to gastric cancer (CMCh-BAPE-RGD@ICG). The characteristics were determined, and the targeting capacity and biosafety were evaluated both in vitro and in vivo. Furthermore, CMCh-BAPE-RGD@ICG mediated photothermal therapy (PTT) effect was studied using gastric cancer cells (SGC7901) and SGC7901 tumor model. RESULTS: The nanoparticle exhibited suitable size (≈ 120 nm), improved aqueous stability, ROS-responsive drug release, excellent photothermal conversion efficiency, enhanced cellular uptake, and targeting capacity to tumors. Remarkably, in vivo studies suggested that CMCh-BAPE-RGD@ICG could accurately illustrate the location and margin of the SGC7901 tumor through NIR imaging in comparison with non-targeted nanoparticles. Moreover, the antitumor activity of CMCh-BAPE-RGD@ICG-mediated PTT could effectively suppress tumor growth by inducing necrosis and apoptosis in cancer cells. Additionally, CMCh-BAPE-RGD@ICG demonstrated excellent biosafety both in vitro and in vivo. CONCLUSION: Overall, our study provides a biocompatible theranostic nanoparticle with enhanced tumor-targeting ability and accumulation to realize NIR image-guided PTT in gastric cancer.

Enhancement of target toxin neutralization effect in vivo by PEGylation of multifunctionalized lipid nanoparticles.

Protein-protein (e.g., antibody-antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.

Electrospun Janus Beads-On-A-String Structures for Different Types of Controlled Release Profiles of Double Drugs.

A side-by-side electrospinning process characterized by a home-made eccentric spinneret was established to produce the Janus beads-on-a-string products. In this study, ketoprofen (KET) and methylene blue (MB) were used as model drugs, which loaded in Janus beads-on-a-string products, in which polyvinylpyrrolidone K90 (PVP K90) and ethyl cellulose (EC) were exploited as the polymer matrices. From SEM images, distinct nanofibers and microparticles in the Janus beads-on-a-string structures could be observed clearly. X-ray diffraction demonstrated that all crystalline drugs loaded in Janus beads-on-a-string products were transferred into the amorphous state. ATR-FTIR revealed that the components of prepared Janus nanostructures were compatibility. In vitro dissolution tests showed that Janus beads-on-a-string products could provide typical double drugs controlled-release profiles, which provided a faster immediate release of MB and a slower sustained release of KET than the electrospun Janus nanofibers. Drug releases from the Janus beads-on-a-string products were controlled through a combination of erosion mechanism (linear MB-PVP sides) and a typical Fickian diffusion mechanism (bead KET-EC sides). This work developed a brand-new approach for the preparation of the Janus beads-on-a-string nanostructures using side-by-side electrospinning, and also provided a fresh idea for double drugs controlled release and the potential combined therapy.