Nanodelivery System Research Articles

Nanocomposite orthopaedic bone cement combining long-acting dual antimicrobial drugs

Antibiotic loaded bone cements are widely used in total joint replacement (TJR); despite many limitations such as a burst release which leads to antibiotic concentration below inhibitory levels and possibly contributing to the selection of antibiotic resistant strains. In order to address such limitations and to simultaneously address antibiotic resistance and short-term antimicrobial activity, we developed a nanocomposite bone cement capable of providing a controlled release of antimicrobial agents from bone cement to act as prophylaxis or treatment against prosthetic joint infections (PJIs).Gentamicin and chlorhexidine were loaded in combination on silica nanoparticles surface using layer-by-layer coating technique (LbL) combining hydrolysable and non-hydrolysable polymers.The drug release from the nanocomposite continued for >50 days at concentrations higher than the commercial formulation containing the same amount of antimicrobial drugs, where burst release for few days were observed. Moreover, the nanocomposite bone cement showed superior antimicrobial inhibition without adversely affecting the mechanical properties or the ability of osteoblasts to grow. In vivo experiments with an infected bone lesion model along with mass-spectrometric analysis also provided further evidence of efficacy and safety of the implanted nanocomposite material as well as its prolonged drug eluting profile.The developed nanocomposite bone cement has the potential to reduce PJIs and enable treatment of resistant established infections; moreover, the newly developed LbL based nano-delivery system may also have wider applications in reducing the threat posed by antimicrobial resistance.

Smart chitosan-PLGA nanocarriers functionalized with surface folic acid ligands against lung cancer cells

Lung cancer is the second most prevalent and first killer cancer worldwide, and conventional approaches do not have enough ability to suppress it. Therefore, a novel targeted chitosan (CS)-poly lactic-co-glycolic acid (PLGA)-folic acid (FA) nanocarrier was developed for delivery of sorafenib (Sor) to lung cancer cells. The nanocarrier (CPSF) had a size of 30–40 nm with globular shapes. Surface charge and drug content of CPSF were ascertained at about 1.1 mV and 15 %, respectively. Controlled (4 % within 2 h) and pH-sensitive (18 % within 2 h at pH = 5.0) Sor release were observed for the nanocarrier. The MTT assay demonstrated a cell viability of 13 % after 24 h treatment with 400 nM CPSF in A549 cancer cells while it was 78 % in MSC normal cells. The qRT-PCR revealed >8 folds and 11 folds increase for Caspase9 and P53 genes after 5 h treatment with 100 nM (IC50) CPSF; but a reduction of 5 folds was observed for the Bcl2 gene. Besides, 57 % and 20 % apoptosis were attained in cell cycle arrest and apoptosis assays for CPSF, respectively. CPF indicated about 88 % internalization in cancer cells. These data prove that CPSF is a promising nanodelivery system for lung cancer suppression.

Vitamin A-modified ZIF-8 lipid nanoparticles for the therapy of liver fibrosis

Liver fibrosis (LF) is one of the major diseases that threaten human health. Until now, no effective drugs have been approved for clinical anti-liver fibrosis treatment. In this study, zeolitic imidazolate framework-8 (ZIF-8) lipid nanoparticles loaded with pirfenidone (PFD) and modified with vitamin A (VA) were constructed (VA-PFD@ZIF-8@DMPC NPs). PFD was embedded in ZIF-8 by the “one-pot” method, and the prepared ZIF-8 had a small particle size (84.3 nm) and high drug loading (54.46%). Moreover, the inherent pH sensitivity of ZIF-8 makes it stable in a normal physiological environment and collapsed in an acidic environment, thus controlling drug release and preventing drug leakage. Besides, the phospholipid layer makes the nano-drug delivery system dispersible and improves its biocompatibility. More importantly, VA is modified on the surface of nanoparticles (NPs), which can target the highly expressed retinol-binding protein receptor (RBPR) on the surface of hepatic stellate cells (HSCs), thereby accurately increasing the local drug concentration at the site of LF. In vivo experiments showed that VA-PFD@ZIF-8@DMPC NPs can reduce liver injury, improve the degree of LF, and exert specific therapeutic effects on LF. In conclusion, this nano-delivery system may become a novel and effective anti-liver fibrosis treatment.

Developing Nanosuspension Loaded with Azelastine for Potential Nasal Drug Delivery: Determination of Proinflammatory Interleukin IL-4 mRNA Expression and Industrial Scale-Up Strategy.

In order to increase bioavailability and intranasal absorbance, the current work set out to create azelastine nasal spray based on nanosuspension. Chondroitin was utilized as a polymer to prepare azelastine nanosuspension through the precipitation procedure. A size of 500 nm and a polydispersity index of 0.276 with a negative potential (-20 mV) were achieved. X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, thermal analysis including differential scanning calorimetry and thermogravimetric analysis, in vitro release, and diffusion studies were used to characterize the optimized nanosuspension. MTT assay was used to assess the viability of the cells, and hemolysis assay was used to assess the blood compatibility. Using RNA extraction and reverse transcription polymerase chain reaction, the levels of the anti-inflammatory cytokine IL-4, which is most closely related to cytokines in allergic rhinitis, were measured in mouse lungs. The drug dissolution and diffusion study indicated 2.0-fold increase compared to pure reference sample. Therefore, the azelastine nanosuspension could be suggested as a practical and simple nanosystem for intranasal delivery with improved permeability and bioavailability. The outcome obtained in this study indicated that azelastine nanosuspension has great potential to treat allergic rhinitis as intranasal treatment.

PCL/gelatin nanofibers embedded with doxorubicin-loaded mesoporous silica nanoparticles/silver nanoparticles as an antibacterial and anti-melanoma cancer

Melanoma cancer wound healing is critical and complex and poses a significant challenge to researchers. Drug resistance, adverse side effects, and inefficient localization of chemotherapeutic drugs limit common treatment strategies in melanoma cancer. Using drug delivery nanostructures with low side effects and high efficiency, besides having antibacterial and antiseptic properties, can effectively repair the damage caused by the disease. To this end, this study aimed to develop a drug delivery nanosystem based on doxorubicin (DOX)-loaded amine-functionalized mesoporous silica nanoparticles (MSNs), linked with green synthesized silver nanoparticles (AgNPs). Characterization methods including microscopic methods and X-ray diffraction (XRD) confirmed the synthesis and functionalization of the well-dispersed nanoparticles with nanosized and uniform structures. The poly(ε-caprolactone) (PCL) nanofibers as a strong scaffold were produced by the blow spinning method and DOX-loaded nanoparticles were blow spun on PCL nanofibers along with gelatin solution. The resulting nanosystem including nanofibers and nanoparticles (NFs/NPS) showed a fine loading percent with a proper release profile of DOX and AgNPs and low hemolysis activity. Moreover, besides preventing infection by AgNPs, the DOX-loaded NFs/NPs could effectively destroy melanoma cancer cells. The attachment of normal cells to the nanoparticles-loaded nanofibers scaffold revealed the possibility of healing wounds caused by melanoma cancer.

Polymer stabilized, phenytoin-loaded nanomicelles as promising nanocarriers: In silico and in vitro evaluations

Many drugs currently used in clinics to treat different diseases show low solubilities in aqueous solutions and must be then administered with the aid of organic solvents within the designed formulations leading to harmful health effects. For such reason, drug delivery using nanocarriers appears as an excellent alternative since it improves the solubilization and controlled release of many different pharmaceuticals, favoring the decrease of the overall administered therapeutic doses and by diminishing the risk of potential associated adverse side effects. Among the different types of nanocarriers, those based on polymeric micelles are an excellent option since the polymer structure and composition may be tuned in order to regulate the characteristics and properties of the resulting nanoassemblies to maximize drug solubilization and release profiles. For this reason, in this paper a drug delivery nanosystem based on oil-in-water polymeric-based microemulsion used to load the anti-epileptic phenytoin drug (PHT) was developed in the oily phase. Two different biocompatible polymers were evaluated to form the nanomicelles and maximize encapsulation efficiencies and colloidal stability: The amphiphilic triblock copolymer Pluronic F127, which poses the ability to cross the blood brain barrier (BBB), and the natural lipophilic lignin, which bears antipathogenic properties. Density functional theory (DFT) calculations were performed with the 6-31G(d) basis set to elucidate the interactions of PHT with F127 and lignin monomers. Simulation data showed that hydrogen bonding (HB) interactions between PHT, F127 and lignin are the predominant force to allow for drug solubilization and stability. Atoms in molecules (AIM) and natural bond orbital (NBO) analyses were performed to evaluate the strength of such HB. and their drug encapsulation efficiency, release profiles, and antibacterial susceptibility were determined. Moreover, the cytotoxicity of the developed nanoformulations together with a morphological examination of PC12 and NIH cells after drug-loaded nanocarrier administration and subsequent uptake were also investigated. In this manner, the obtained nanocarriers were also characterized by dynamic light scattering (DLS) and zeta potential, showing a nanometer size (between ca. 16 and 22 nm) and surface negative charge. PHT loading into F127 and lignin nanomicelles were ca. 96.7 ± 1.5% and 68.2 ± 3.5%, respectively, and the drug release profile kinetics of F127/PHT-loaded nanomicelles was rather slower compared to that of lignin/PHT-loaded ones. On the other hand, in vitro cytotoxicity data confirmed the lack of any significant cytotoxicity of PHT-loaded nanomicelles in both NIH/3T3 and PC12 cell lines, but a slightly higher cell viability and well-preserved cell morphology was observed for PC12 cells compared to NIH/3T3 ones. After culturing in chocolate blood agar medium inoculated with F127/PHT-loaded and lignin/ PHT-loaded nanomicelles, pathogenic bacteria did not grow despite confirming certain antimicrobial character of the encapsulated drug. Hence, thanks to their excellent encapsulation and biocompatibility properties, these nanocarriers appear as an excellent option to configure new drug delivery nanocarriers of hydrophobic drugs.

A nano-delivery system based on preventing degradation and promoting absorption to improve the oral bioavailability of insulin

Oral insulin delivery can improve patient compliance and simulate the portal-peripheral insulin concentration gradient produced by endogenous insulin, so oral insulin delivery has a broad prospect. However, some characteristics of the gastrointestinal tract, lead to low oral bioavailability. Therefore, a “ternary mutual-assist” nano-delivery system based on poly(lactide-co-glycolide) (PLGA) as the backbone combined with ionic liquids (IL) and vitamin B12-chitosan (VB12-CS) was constructed in this study, the protein protection performance of IL improves the room temperature stability of the loaded insulin during nanocarrier preparation, transportation and storage to a certain extent, and the protein protection function of IL combined with the slow degradation property of PLGA and the pH-responsive function of VB12-CS to prevent the degradation of insulin in the gastrointestinal tract. In addition, the mucosal adhesion function of VB12-CS, VB12 receptor- and clathrin-mediated transcellular transport involving VB12-CS and IL, and paracellular transport mediated by IL and CS can be combined to improve the intestinal epithelial transport efficiency of insulin, thus, the nanocarrier has stronger preventing degradation and promoting absorption effects. Pharmacodynamic studies showed that after oral administration of VB12-CS-PLGA@IL@INS NPs to diabetic mice, the blood glucose level decreased to about 13 mmol/L, below the critical point of 16.7 mmol/L, and the blood glucose reached a normal level, which was 0.4 times of the blood glucose value before administration, its relative pharmacological bioavailability was 31.8 %, higher than the general nanocarriers (10–20 %) and more beneficial to the clinical transformation of oral insulin.

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.