Nanodelivery System Research Articles

Apoptosis-targeted gene therapy for non-small cell lung cancer using chitosan-poly-lactic-co-glycolic acid -based nano-delivery system and CASP8 and miRs 29A-B1 and 34A.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with resistance to apoptosis being a major driver of therapeutic resistance and aggressive phenotype. This study aimed to develop a novel gene therapy approach for NSCLC by targeting resistance to apoptosis. Loss of function mutations of caspase 8 (CASP8) and downregulation of microRNAs (miRs) 29A-B1 and 34A were identified as key contributors to resistance to apoptosis in NSCLC. A biodegradable polymeric nano-gene delivery system composed of chitosan-poly-lactic-co-glycolic acid was formulated to deliver initiator CASP8 and miRs 29A-B1 and 34A. The nano-formulation efficiently encapsulated the therapeutic genes effectively internalized into NSCLC cells and induced significant apoptosis. Evaluation of the nano-formulation in A549 tumor spheroids showed a significant increase in apoptosis within the core of the spheroids, suggesting effective penetration into the spheroid structures. We provide a novel nano-formulation that demonstrate therapeutic potential for suicidal gene therapy in NSCLC.

A Triple-Targeted Rutin-Based Self-Assembled Delivery Vector for Treating Ischemic Stroke by Vascular Normalization and Anti-Inflammation via ACE2/Ang1-7 Signaling.

Changes in the cerebral microenvironment caused by acute ischemic stroke-reperfusion are the main obstacle to the recovery of neurological function and an important cause of stroke recurrence after thrombolytic therapy. The intracerebral microenvironment after ischemia-reperfusion reduces the neuroplasticity of the penumbra and ultimately leads to permanent neurological damage. To overcome this challenge, we developed a triple-targeted self-assembled nanodelivery system, which combines the neuroprotective drug rutin with hyaluronic acid through esterification to form a conjugate, and then connected SS-31, a small peptide that can penetrate the blood brain barrier and target mitochondria. Brain targeting, CD44-mediated endocytosis, hyaluronidase 1-mediated degradation, and the acidic environment synergistically promoted the enrichment of nanoparticles and drug release in the injured area. Results demonstrate that rutin has a high affinity for ACE2 receptors on the cell membrane and can directly activate ACE2/Ang1-7 signaling, maintain neuroinflammation, and promote penumbra angiogenesis and normal neovascularization. Importantly, this delivery system enhanced the overall plasticity of the injured area and significantly reduced neurological damage after stroke. The relevant mechanism was expounded from the aspects of behavior, histology, and molecular cytology. All results suggest that our delivery system may be an effective and safe strategy for the treatment of acute ischemic stroke-reperfusion injury.

Modulation of cancer-associated fibroblasts by nanodelivery system to enhanceefficacy of tumor therapy.

Cancer-associated fibroblasts (CAFs) are the most common cells in the tumor stroma and are essential for tumor development and metastasis. While decreasing the release and infiltration of nanomedicine through nonspecific internalization, CAFs specifically increase solid tumor pressure and interstitial fluid pressure by secreting tumor growth- and migration-promoting cytokines, which increases vascular and organ pressure caused by solid tumor pressure. Nanoparticles have good permeability and can penetrate tumor tissue to reach the lesion area, inhibiting tumor growth. Thus, CAFs are used as modifiable targets. Here, the authors review the biological functions, originsand biomarkers of CAFs andsummarize strategies for modulating CAFs in nanodelivery systems. This study provides a prospective guide to modulating CAFs to enhance oncology treatment.

HSC-targeted delivery of shRNA-TGFβ1 by vitamin A-functionalized polyaminoglycoside for hepatic fibrosis therapy

Liver fibrosis is a scar repair response to liver injury and is a key aspect of liver disease. Transforming growth factor (TGFβ1), one of the most potent pro-fibrotic cytokines known, is involved in almost all critical dimensions of liver fibrosis development. Currently, attenuating the pro-fibrotic effect of TGFβ1 is a promising treatment for liver fibrosis. However, the key to applying this approach is to find a more reliable and effective targeting regulation. In this work, a targeting degradable nucleic acid delivery carrier (SS-HPVA) was constructed based on branched polyaminoglycoside (SS-HPT) modified by hepatic stellate cells (HSCs) targeting molecule vitamin A (VA) for the delivery of the TGFβ1 gene silencing plasmid pshRNA-TGFβ1. The reductive responsiveness and VA modification conferred SS-HPVA with high gene transfection ability and specific targeting properties to HSCs. Multispectral photoacoustic tomography and in vivo fluorescence imaging verified that the SS-HPVA/pshRNA-TGFβ1 system showed superior liver targeting ability, especially in the hepatic fibrosis model.On this basis, it was demonstrated that this system could exhibit good therapeutic effects on liver fibrosis by down-regulating TGFβ1 expression through non-invasive assays and histopathological analysis. Therefore, this gene silencing targeting delivery nanosystem is expected to provide a new strategy for the clinical treatment of liver fibrosis.

Nano Delivery Chitosan-Protein/Hydrolysate of Green Peas Bromelain (PHGPB) Synthesized by Colloidal-Spray Drying Method.

Patients with chronic kidney disease (CKD) suffer persistent decreased kidney function. Previous study of protein hydrolysate of green pea (Pisum sativum) bromelain (PHGPB) has shown promising results as an antifibrotic in glucose-induced renal mesangial culture cells, by decreasing their TGF-β levels. To be effective, protein derived from PHGPB must provide adequate protein intake and reach the target organs. This paper presents a drug delivery system for the formulation of PHGPB using chitosan as polymeric nanoparticles. A PHGPB nano delivery system was synthesized by precipitation with fixed chitosan 0.1 wt.%, followed by a spray drying process at different aerosol flow rates of 1, 3, and 5 L/min. FTIR results showed that the PHGPB was entrapped in the chitosan polymer particles. Homogeneous size and spherical morphology of NDs were obtained for the chitosan-PHGPB with a flow rate of 1 L/min. Our in vivo study showed that the highest entrapment efficiency, solubility, and sustained release were achieved by the delivery system method at 1 L/min. It was concluded that the chitosan-PHGPB delivery system developed in this study improves pharmacokinetics compared to pure PHGPB.

Supramolecular Cyclic Dinucleotide Nanoparticles for STING-Mediated Cancer Immunotherapy.

Activation of stimulator of interferon genes (STING) can reprogram the immunosuppressive tumor microenvironment (TME) by initiating innate and adaptive immunity. As natural STING agonists, clinical translation of cyclic dinucleotides (CDNs) has been challenged by their short half-life in circulation, poor stability, and low membrane permeability. Herein, we use the natural endogenous small molecules oleic acid and deoxycytidine to construct a ligand for the STING agonist c-di-GMP (CDG), a hydrophobic nucleotide lipid (3',5'-diOA-dC), which can assemble with CDG into stable cyclic dinucleotide nanoparticles (CDG-NPs) through various supramolecular forces driven by molecular recognition. CDG-NPs are homogeneous and stable spherical nanoparticles with an average diameter of 59.0 ± 13.0 nm. Compared with free CDG, CDG-NPs promote the retention and intracellular delivery of CDG in the tumor site, boost STING activation and TME immunogenicity, and potentiate STING-mediated anti-tumor immunity when administered by either intratumoral or systemic routes in melanoma-bearing mice. We propose a flexible supramolecular nanodelivery system for CDG by using endogenous small molecules, which provides a CDN delivery platform for STING-mediated cancer immunotherapy.

Antineoplastic effect of paclitaxel-loaded polymeric nanocapsules on malignant human ovarian carcinoma cells (SKOV-3)

Drug resistance is the main responsible for chemotherapy failure in ovarian cancer treatment. In this study, we looked at increasing the anticancer effect of paclitaxel (PTX) through its encapsulation in novel polymeric nanocapsules to develop a novel, less invasive PTX-loaded nano-delivery system. These were synthesized by a microemulsion-based methodology, and their particle size and shapes determined using dynamic light scattering (DLS) and field emission scanning electron microscopy (FESEM). The synthesized PTX-loaded polymeric nanocapsules showed spherical morphology with approximately ca. 18 nm. In vitro cytotoxicity analysis of free administered PTX, bare and PTX-loaded polymeric nanocpasules by means of the MTT assay showed that much lower concentration of PTX loaded inside polymeric nanocapsules (2.2 µg/ml) were needed to achieve a similar therapeutic activity than the free administered drug (14.4 µg/ml). Polymer nanocapsule encapsulation of PTX then improved the therapeutic efficacy as shown by the reduction of IC50 concentration. MYC, MECOM, PRKCl gene and caspases-3, −8, and −9 protein expressions involved in the apoptotic pathway after the treatment of SKOV-3 cells with PTX-loaded polymeric nanocapsules were assessed by qRT-PCR and fluorometric assay, respectively. The expression level of MECOM increased 1.67 times upon administration of PTX-loaded polymeric nanocapsules compared with untreated SKOV-3 cancer cells as the control group (P < 0.001); conversely, MYC and PRKCl gene expressions were 0.40 and 0.45 times lower compared to control cancerous cells (p < 0.001). The expression of caspase-3, caspase-8, and caspase-9 proteins also significantly increased after the administration of PTX-loaded polymeric nanocapsules to cancer cells (p ≤ 0.001). On the other hand, fluorescence microscopy analysis showed nuclei fragmentation after administration of 24.1 μg/mL of PTX-loaded polymeric nanocapsules, which is accompanied by morphological cell alterations, confirming the cytostatic activity of the nanoformulation. Therefore, the synthesized PTX-loaded polymer nanocapsules could be promise and potential nano-delivery system for PTX delivery in ovarian cancer chemotherapy.

Synthesis, cytotoxicity, and biomacromolecule binding: Three isomers of nitrosylruthenium complexes with bidentate bioactive molecules as co-ligands

Three isomeric nitrosylruthenium complexes [RuNO(Qn)(PZA)Cl] (P1, P2, and P3) with bioactive small molecules 8-hydroxyquinoline (Qn) and pyrazinamide (PZA) as co-ligands were synthesized, and their crystal structures were determined using X-ray diffraction technique. The cellular toxicity of the isomeric complexes was compared to understand the effects of the geometries on the biological activity of the complexes. Both the complexes and the human serum albumin (HSA) complex adducts affected the extent of proliferation of HeLa cells (IC50: 0.77–1.45 μM). P2 showed prominent activity-induced cell apoptosis and arrested cell cycles at the G1 phase. The binding constants (Kb) of the complex with calf thymus DNA (CT-DNA) and HSA were quantitatively evaluated using fluorescence spectroscopy in the range of 0.17–1.56 × 104 M−1 and 0.88–3.21 × 105 M−1, respectively. The average binding site (n) number was close to 1. Moreover, the structure of HSA and the P2 complex adduct solved at the resolution of 2.48 Å revealed that one PZA-coordinated nitrosylruthenium complex bound at the subdomain I of HSA via a noncoordinative bond. HSA could serve as a potential nano-delivery system. This study provides a framework for the rational design of metal-based drugs.

Fabrication of egg white protein/phosphatidylcholine-EGCG co-assembled nanoparticles with sustained release in simulated gastrointestinal digestion and their transcellular permeability in Caco-2 cultures

Epigallocatechin-3-gallate (EGCG) is a kind of polyphenol with various biological activities but poor stability and bioavailability. The encapsulation of EGCG in a nano-delivery system effectively improves its shortcomings. In this research, co-assembled nanoparticles of egg white protein, phosphatidylcholine (PC), and EGCG (EW/PE1:5 NPs) were prepared by antisolvent precipitation to improve their bioavailability. The constructed EW/PE1:5 NPs had an average particle size of 172 nm, a ζ-potential of −26.1 mV, and a polymerization dispersion index (PDI) of 0.33. The encapsulation efficiency (EE) of EGCG was 88.09% and the loading capacity (LC) was 20.10%. UV spectra, FTIR, XRD and intermolecular force results indicated that hydrophobic, electrostatic and hydrogen bonding interactions contributed to the formation of EW/PE1:5 NPs. EW/PE1:5 NPs exhibited Fick diffusion and sustained release characteristics in simulated gastrointestinal digestion. In addition, the transcellular permeability of EW/PE1:5 NPs was significantly increased compared with free EGCG. At the same time, EW/PE1:5 NPs increased EGCG absorption transport and inhibited MRP2 and P-gp-mediated efflux transport. These results suggest that EW/PE1:5 NPs play a key role in improving the bioavailability of EGCG. Therefore, EW/PE1:5 NPs are expected to provide a theoretical basis for the design and development of functional foods or dietary supplements that synergistically enhance the bioavailability of EW, PC and other flavonoids.

Tumor microenvironment-responsive spherical nucleic acid nanoparticles for enhanced chemo-immunotherapy

Certain chemotherapeutics can induce tumor cells’ immunogenic cell death (ICD), release tumor antigens, and thereby trigger personalized antitumor immune responses. Co-delivery of adjuvants using nanocarriers could amplify the ICD-induced tumor-specific immunity achieving a synergistic chemo-immunotherapeutic effect. However, complicated preparation, low drug loading efficiency, and potential carrier-associated toxicity are the major challenges that limited its clinical applications. Herein, a carrier-free core–shell nanoparticle (MPLA-CpG-sMMP9-DOX, MCMD NPs) was constructed by facile self-assembly of spherical nucleic acids (SNA) with two adjuvants of CpG ODN and monophosphoryl lipid A (MPLA) as a core and doxorubicin (DOX) radially around the dual-adjuvants SNA as a shell. The results demonstrated that MCMD NPs could enhance drugs accumulation in tumors, and release DOX upon enzymatic degradation of matrix metalloproteinase-9 (MMP-9) peptide in the tumor microenvironment (TME), which enhanced the direct-killing effect of DOX on tumor cells. The core of MPLA-CpG SNA efficiently boosted the ICD-induced antitumor immune response to further attack tumor cells. Thus, MCMD NPs achieved a synergistic therapeutic effect of chemo-immunotherapy with reduced off-target toxicity. This study provided an efficient strategy for the development of a carrier-free nano-delivery system for enhanced cancer chemo-immunotherapy.

Macrophage Hitchhiking Nanoparticles for the Treatment of Myocardial Infarction: An In Vitro and In Vivo Study

AbstractMyocardial infarction (MI) is the leading cause of death worldwide. However, current therapies are unable to restore the function of the injured myocardium. Advanced approaches, such as stimulation of cardiomyocyte (CM) proliferation are promising, but suffer from poor pharmacokinetics and possible systemic adverse effects. Nanomedicines can be a solution to the above‐mentioned drawbacks. However, targeting the cardiac tissue still represents a challenge. Herein, a MI‐selective precision nanosystem is developed, that relies on the heart targeting properties of atrial natriuretic peptide (ANP) and lin‐TT1 peptide‐mediated hitchhiking on M2‐like macrophages. The system based on pH‐responsive putrescine‐modified acetalated dextran (Putre‐AcDEX) nanoparticles, shows biocompatibility with cultured cardiac cells, and ANP receptor‐dependent interaction with CMs. Moreover, treatment with nanoparticles (NPs) loaded with two pleiotropic cellular self‐renewal promoting compounds, CHIR99021 and SB203580, induces a 4‐fold increase in bromodeoxyuridine (BrdU) incorporation in primary cardiomyocytes compared to control. In vivo studies confirm that M2‐like macrophages targeting by lin‐TT1 peptide enhances the heart targeting of ANP. In addition, NP administration does not alter the immunological profile of blood and spleen, showing the short‐term safety of the developed system in vivo. Overall, the study results in the development of a peptide‐guided precision nanosystem for delivery of therapeutic compounds to the infarcted heart.

Redox-Responsive Lipidic Prodrug Nano-Delivery System Improves Antitumor Effect of Curcumin Derivative C210.

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives.

Synthesis of Chitosan Oligosaccharide-Loaded Glycyrrhetinic Acid Functionalized Mesoporous Silica Nanoparticles and In Vitro Verification of the Treatment of APAP-Induced Liver Injury.

the study was to find a suitable treatment for acute drug-induced liver injury. The use of nanocarriers can improve the therapeutic effect of natural drugs by targeting hepatocytes and higher loads. firstly, uniformly dispersed three-dimensional dendritic mesoporous silica nanospheres (MSNs) were synthesized. Glycyrrhetinic acid (GA) was covalently modified on MSN surfaces through amide bond and then loaded with COSM to form drug-loaded nanoparticles (COSM@MSN-NH2-GA). The constructed drug-loaded nano-delivery system was determined by characterization analysis. Finally, the effect of nano-drug particles on cell viability was evaluated and the cell uptake in vitro was observed. GA was successfully modified to obtain the spherical nano-carrier MSN-NH2-GA (≤200 nm). The neutral surface charge improves its biocompatibility. MSN-NH2-GA has high drug loading (28.36% ± 1.00) because of its suitable specific surface area and pore volume. In vitro cell experiments showed that COSM@MSN-NH2-GA significantly enhanced the uptake of liver cells (LO2) and decreased the AST and ALT indexes. this study demonstrated for the first time that formulation and delivery schemes using natural drug COSM and nanocarrier MSN have a protective effect on APAP-induced hepatocyte injury. This result provides a potential nano-delivery scheme for the targeted therapy of acute drug-induced liver injury.

Targeted Drug Administration onto Cancer Cells Using Hyaluronic Acid-Quercetin-Conjugated Silver Nanoparticles.

Quercetin (QtN) displays low systemic bioavailability caused by poor water solubility and instability. Consequently, it exerts limited anticancer action in vivo. One solution to increase the anticancer efficacy of QtN is the use of appropriate functionalized nanocarriers that preferentially target and deliver the drug to the tumor location. Herein, a direct advanced method was designed to develop water-soluble hyaluronic acid (HA)-QtN-conjugated silver nanoparticles (AgNPs). HA-QtN reduced silver nitrate (AgNO3) while acting as a stabilizing agent to produce AgNPs. Further, HA-QtN#AgNPs served as an anchor for folate/folic acid (FA) conjugated with polyethylene glycol (PEG). The resulting PEG-FA-HA-QtN#AgNPs (further abbreviated as PF/HA-QtN#AgNPs) were characterized both in vitro and ex vivo. Physical characterizations included UV-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), particle size (PS) and zeta potential (ZP) measurements, and biopharmaceutical evaluations. The biopharmaceutical evaluations included analyses of the cytotoxic effects on the HeLa and Caco-2 cancer cell lines using the MTT assay; cellular drug intake into cancer cells using flow cytometry and confocal microscopy; and blood compatibility using an automatic hematology analyzer, a diode array spectrophotometer, and an enzyme-linked immunosorbent assay (ELISA). The prepared hybrid delivery nanosystem was hemocompatible and more oncocytotoxic than the free, pure QtN. Therefore, PF/HA-QtN#AgNPs represent a smart nano-based drug delivery system (NDDS) and could be a promising oncotherapeutic option if the data are validated in vivo.

Preparation of Melatonin-Loaded Nanoparticles with Targeting and Sustained Release Function and Their Application in Osteoarthritis.

(1) The vicious cycle of innate immune response and reactive oxygen species (ROS) generation is an important pathological process of osteoarthritis (OA). Melatonin may be a new hope for the treatment of OA because of its antioxidant capacity. However, the mechanism of melatonin in the treatment of OA is still not completely clear, and the physiological characteristics of articular cartilage make melatonin unable to play a long-term role in OA. (2) The effects of melatonin on ROS and the innate immune response system in OA chondrocytes and the therapeutic effect in vivo were evaluated. Then, a melatonin-loaded nano-delivery system (MT@PLGA-COLBP) was prepared and characterized. Finally, the behavior of MT@PLGA-COLPB in cartilage and the therapeutic effect in OA mice were evaluated. (3) Melatonin can inhibit the activation of the innate immune system by inhibiting the TLR2/4-MyD88-NFκB signal pathway and scavenging ROS, thus improving cartilage matrix metabolism and delaying the progression of OA in vivo. MT@PLGA-COLBP can reach the interior of cartilage and complete the accumulation in OA knee joints. At the same time, it can reduce the number of intra-articular injections and improve the utilization rate of melatonin in vivo. (4) This work provides a new idea for the treatment of osteoarthritis, updates the mechanism of melatonin in the treatment of osteoarthritis, and highlights the application prospect of PLGA@MT-COLBP nanoparticles in preventing OA.

Development of Novel Chimeric Endolysin Conjugated with Chitosan-Zn-Metal-Organic Framework Nanocomposites with Antibacterial Activity.

Bacterial diseases have been considered the most crucial issue and are threatening human health all around the world. Also, resistance to antimicrobial drugs has become a big hurdle against efficient therapy. As a result, recombinant chimeric endolysin was produced in E. coli host to use as a potential antibacterial agent against bacteria resistance and replacement to conventional antibiotics in this study. Then, chitosan (C)-coated nanoscale metal-organic frameworks (CS-NMOFs) nanocomposite was synthesized as a novel nano delivery system to further improve the antibacterial activity of endolysin. After characterization of nanocomposite with analytical devices such as FT-IR, DLS, and TEM and determining the nanometric size of samples (30nm to 90nm), endolysin was covalently (endolysin-CS-NMOFs (C)) and non-covalently (endolysin-CS-NMOFs (NC)) conjugated to nanocomposite. Thereafter, the lytic ability, synergistic interaction, and biofilm reduction manner of endolysin-containing CS-NMOF nanocomposites were evaluated on E. coli, S. aureus, and P. aeruginosa strains. The results depicted an excellent lytic ability of nanocomposites after 24h and 48h of treatment, especially endolysin-CS-NMOFs (NC) on E. coli and P. aeruginosa strains. The synergistic interaction between nanocomposite and vancomycin did not attain for P. aeruginosa strain whereas the reverse was true for E. coli and S. aureus strains at 8ng/mL concentration. Next, nanocomposites demonstrated potential biofilm reduction activities in various strains, especially in S. aureus and P. aeruginosa. Ultimately, our outputs demonstrate an efficient performance of the synthesized nanocomposite as an appropriate substitution for conventional antibiotics against bacteria.

Liposome Formulations for the Strategic Delivery of PARP1 Inhibitors: Development and Optimization.

The development of a lipid nano-delivery system was attempted for three specific poly (ADP-ribose) polymerase 1 (PARP1) inhibitors: Veliparib, Rucaparib, and Niraparib. Simple lipid and dual lipid formulations with 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1'-glycerol) sodium salt (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocoline (DPPC) were developed and tested following the thin-film method. DPPG-encapsulating inhibitors presented the best fit in terms of encapsulation efficiency (>40%, translates into concentrations as high as 100 µM), zeta potential values (below -30 mV), and population distribution (single population profile). The particle size of the main population of interest was ~130 nm in diameter. Kinetic release studies showed that DPPG-encapsulating PARP1 inhibitors present slower drug release rates than liposome control samples, and complex drug release mechanisms were identified. DPPG + Veliparib/Niraparib presented a combination of diffusion-controlled and non-Fickian diffusion, while anomalous and super case II transport was verified for DPPG + Rucaparib. Spectroscopic analysis revealed that PARP1 inhibitors interact with the DPPG lipid membrane, promoting membrane water displacement from hydration centers. A preferential membrane interaction with lipid carbonyl groups was observed through hydrogen bonding, where the inhibitors' protonated amine groups may be the major players in the PARP1 inhibitor encapsulation mode.

Metformin and curcumin co-encapsulated chitosan/alginate nanoparticles as effective oral carriers against pain-like behaviors in mice

Nanotechnology plays an integral role in multimodal analgesia. In this study, we co-encapsulated metformin (Met) and curcumin (Cur) into chitosan/alginate (CTS/ALG) nanoparticles (NPs) at their synergistic drug ratio by applying response surface methodology. The optimized Met-Cur-CTS/ALG-NPs were achieved with Pluronic® F-127 2.33 % (w/v), Met 5.91 mg, and CTS:ALG mass ratio 0.05:1. The prepared Met-Cur-CTS/ALG-NPs had 243 nm particle size, −21.6 mV zeta potential, 32.6 and 44.2 % Met and Cur encapsulations, 19.6 and 6.8 % Met and Cur loading, respectively, and 2.9:1 Met:Cur mass ratio. Met-Cur-CTS/ALG-NPs displayed stability under simulated gastrointestinal (GI) fluid conditions and during storage. In vitro release study of Met-Cur-CTS/ALG-NPs in simulated GI fluids showed sustained release, with Met exhibiting Fickian diffusion and Cur demonstrating non-Fickian diffusion following the Korsmeyer-Peppas model. Met-Cur-CTS/ALG-NPs exhibited increased mucoadhesion and improved cellular uptake in Caco-2 cells. Additionally, Met-Cur-CTS/ALG-NPs exhibited better anti-inflammatory effects in lipopolysaccharide-stimulated RAW 264.7 macrophage and BV-2 microglial cells than the equivalent amount of the Met-Cur physical mixture, indicating a greater ability to modulate peripheral and central immune mechanisms of pain. In the mouse formalin-induced pain model, Met-Cur-CTS/ALG-NPs administered orally exhibited better attenuation of pain-like behaviors and proinflammatory cytokine release compared to the Met-Cur physical mixture. Furthermore, Met-Cur-CTS/ALG-NPs did not induce significant side effects in mice at therapeutic doses. Altogether, the present study establishes a CTS/ALG nano-delivery system for Met-Cur combination against pain with improved efficacy and safety.

Enhanced anti-cancer effect of artemisinin- and curcumin-loaded niosomal nanoparticles against human colon cancer cells.

Colorectal cancer (CRC) is the third broadly identified cancer in the world. The ineffectiveness of colorectal cancer treatment is redundantly reported. Natural bioactive compounds have gained popularity in reducing the drawback of conventional anti-cancer agents. Curcumin (Cur) and Artemisinin (Art) are materials of a natural source that have been utilized to treat numerous kinds of cancers. Although the benefits of bioactive materials, their utilization is limited because of poor solubility, bioavailability, and low dispersion rate in aqueous media. Nano delivery system such as niosome can improve the bioavailability and stability of bioactive compounds within the drug. In current work, we used Cur-Art co-loaded niosomal nanoparticles (Cur-Art NioNPs) as an anti-tumor factor versus colorectal cancer cell line. The synthesized formulations were characterized using dynamic light scattering, scanning electron microscopy, and FTIR. The proliferation ability of the cells and expression of apoptosis-associated gene were MTT assay and qRT-PCR, respectively. Cur-Art NioNPs exhibited well distributed with an encapsulation efficiency of 80.27% and 85.5% for Cur and Art. The NioNPs had good release and degradation properties, and had no negative effect on the survival and proliferation ability of SW480 cells. Importantly, nanoformulation form of Cur and Art significantly displayed higher toxicity effect against SW480 cells. Furthermore, Cur-Art NioNPs increased Bax, Fas, and p53 gene expressions and suppressed Bcl2, Rb, and Cyclin D 1 gene expressions. In summary, these results display the niosome NPs as a first report of nano-combinational application of the natural herbal substances with a one-step fabricated co-delivery system for effective colorectal cancer.

Syphilis mimetic nanoparticles for cuproptosis-based synergistic cancer therapy via reprogramming copper metabolism

Small cell lung cancer (SCLC) is one of the most devastating type of human lung cancer and has a high propensity to metastasize into the brain. Cuproptosis recently has been defined as a copper dependent cell death, offers a new lens to develop the novel copper-based nanostructure inducing cuproptosis for suppressing tumor growth and metastasis. Here, we report a syphilis mimetic TP0751-peptide decorated stem cell membrane-coated copper-based metal organic framework (Cu-MOF) nanodelivery system for SCLC brain metastasis. The Cu-MOF is employed as nanocarrier to support siRNA with high loading efficiency, and its pH sensitivity facilitates endosomal disruption upon cellular uptake. Furthermore, the cell membrane coating Cu-MOF presents a good biocompatibility, high BBB transcytosis, and specific uptake by tumor cells within the brain. In vitro and in vivo trials have shown that TP-M−Cu−MOF/siATP7a exhibited high silencing efficiency against target gene, specifically blocked copper trafficking, increased copper intake, triggered cuproptosis, and improved therapeutic efficacy in SCLC brain metastasis tumor-bearing mice. Overall, the biomimetic nanodelivery platform presented here further offers a promising way of orchestrating gene therapy to target copper-dependent signalling for reprogramming copper metabolism and cuproptosis-based synergistic therapy in mice bearing brain metastases.