Dual Delivery of TGF-ß3 and Ghrelin in Microsphere/Hydrogel Systems for Cartilage Regeneration.

Articular cartilage (AC) damage is quite common, but due to AC's poor self-healing ability, the damage can easily develop into osteoarthritis (OA). To solve this problem, we developed a microsphere/hydrogel system that provides two growth factors that promote cartilage repair: transforming growth factor-ß3 (TGF-ß3) to enhance cartilage tissue formation and ghrelin synergy TGF-ß to significantly enhance the chondrogenic differentiation. The hydrogel and microspheres were characterized in vitro, and the biocompatibility of the system was verified. Double emulsion solvent extraction technology (w/o/w) is used to encapsulate TGF-ß3 and ghrelin into microspheres, and these microspheres are encapsulated in a hydrogel to continuously release TGF-ß3 and ghrelin. According to the chondrogenic differentiation ability of mesenchymal stem cells (MSCs) in vitro, the concentrations of the two growth factors were optimized to promote cartilage regeneration.

Fabrication of nanoparticles from a synthesized peptide amphiphile as a versatile therapeutic cargo for high antiproliferative activity in tumor cells.

Nanoparticles with encapsulated small molecules have attained vital importance in anticancer research. Peptide-based nanoparticles show their versatility in drug delivery due to their excellent biocompatibility and nontoxic nature. We demonstrate here the design and fabrication of peptide-based nanoparticles as dual-therapeutic cargo for the controlled release of hydrophilic 5-Fluorouracil (5Fu) and hydrophobic camptothecin (CPT), simultaneously. The covalent conjugation of 5Fu with the peptide, through a stimuli-responsive linker, provided better control over the release of 5Fu and dramatically reduced the possibility of leaching of the small molecule. As anticipated, the peptide-5Fu nanoparticles were efficient to encapsulate a second chemotherapeutic molecule CPT in its hydrophobic region. The stimuli-responsive release of 5Fu was carefully monitored by HPLC, NMR, and UV-visible spectroscopy. On the other hand, the release of the hydrophobic drug CPT from the nanoparticles was determined to be in a diffusion-controlled fashion. Assessment of performance in human cervical HeLa cell lines demonstrated the peptide-drug nanoparticles to be highly nontoxic. Whereas, the simultaneous release of the two antitumor agents, in a controlled manner, resulting in rapid antiproliferation of the tumor cells.

Novel PEI/Poly-γ-Gutamic Acid Nanoparticles for High Efficient siRNA and Plasmid DNA Co-Delivery.

The efficient delivery of sufficient amounts of nucleic acids into target cells is critical for successful gene therapy and gene knockdown. The DNA/siRNA co-delivery system has been considered a promising approach for cancer therapy to simultaneously express and inhibit tumor suppressor genes and overexpressed oncogenes, respectively, triggering synergistic anti-cancer effects. Polyethylenimine (PEI) has been identified as an efficient non-viral vector for transgene expression. In this study, we created a very high efficient DNA/siRNA co-delivery system by incorporating a negatively-charged poly-γ-glutamic acid (γ-PGA) into PEI/nucleic acid complexes. Spherical nanoparticles with about 200 nm diameter were formed by mixing PEI/plasmid DNA/siRNA/γ-PGA (dual delivery nanoparticles; DDNPs) with specific ratio (N/P/C ratio) and the particles present positive surface charge under all manufacturing conditions. The gel retardation assay shows both nucleic acids were effectively condensed by PEI, even at low N/P ratios. The PEI-based DDNPs reveal excellent DNA/siRNA transfection efficiency in the human hepatoma cell line (Hep 3B) by simultaneously providing high transgene expression efficiency and high siRNA silencing effect. The results indicated that DDNP can be an effective tool for gene therapy against hepatoma.

Enhanced Sensitivity of Cancer Stem Cells to Chemotherapy Using Functionalized Mesoporous Silica Nanoparticles.

Cancer stem cells (CSCs) are responsible for cancer drug resistance with high expression of ABCG2, which pumps the internalized chemotherapeutic out to escape drug-induced cytotoxicity. Here, we established a functionalized mesoporous silica nanoparticle (MSN) system to deliver shABCG2 and doxorubicin (Dox) synergistically. With excellent cell uptake and endosomal escape capacities, the dual-delivery carriers internalized shABCG2 and Dox into CSCs efficiently. ABCG2 depletion increased intracellular and intranuclear Dox enrichment, drove vigorous Dox-induced cell death, and impaired the self-renewal of CSCs. Additionally, the nanoparticles eliminated tumors efficiently and reduced tumor initiation by CSCs in vivo, with negligible side effects. Our findings suggest that well-designed delivery systems for conventional chemotherapeutic agents are promising for CSC therapy.

Bilaterally Aligned Electroosmotic Flow Generated by Porous Microneedle Device for Dual-Mode Delivery.

Here, a novel porous microneedle (PMN) device with bilaterally aligned electroosmotic flow (EOF) enabling controllable dual-mode delivery of molecules is developed. The PMNs placed at anode and cathode compartments are modified with anionic poly-2-acrylamido-2-methyl-1-propanesulfonic acid and cationic poly-(3-acrylamidopropyl) trimethylammonium, respectively. The direction of EOF generated by PMN at the cathode compartment is, therefore, reversed from cathode to anode, countering the unwanted cathodal suctioning of interstitial fluid caused by reverse iontophoresis. With the bilateral alignment of EOF, the versatility of the proposed device is evaluated by delivering molecules with different charges and sizes using Franz cell. In addition, a 3D printed probe device is developed to ease practical handling and minimize electrical stimulation by integrating two PMNs in closed proximity. Finally, the performance of the integrated probe device is demonstrated by dual delivery of a variety of molecules (methylene blue, rhodamine B, and fluorescein isothiocyanate-dextran) using pig skin and vaccination using mice with delivered ovalbumin.

Enhancing anti-inflammatory effect of brucine nanohydrogel using rosemary oil: a promising strategy for dermal delivery in arthritic inflammation.

Brucine (BRU), an active constituent of Strychnos nux-vomica L., is one of the potential agents to control subside swelling in arthritis. However, its hydrophobic nature, poor permeation, shorter half-life, narrow therapeutic window, and higher toxicity impede its clinical applications. Hence, this investigation was aimed to develop and evaluate novel BRU loaded ß-cyclodextrin (ß-CD) nanosponges (BRUNs) hydrogel consisting rosemary essential oil (RO), which have been tailored for delayed release, enhanced skin permeation, and reduced irritation, while retaining anti-oxidant and anti-inflammatory activities of this bioactive. Firstly, BRUNs were fabricated by melt technique and characterized appropriately. BRUNs6 demonstrated two fold enhancement in BRU solubility (441.692 ± 38.674) with minimum particle size (322.966 ± 54.456) having good PDI (0.571 ± 0.091) and zeta potential (-14.633 ± 6.357). In vitro release results demonstrated delayed release of BRU from BRUNs6 (67 ± 4.25%) over 24 h through molecular diffusion mechanism. Further, preserved anti-inflammatory (53.343 ± 0.191%) and antioxidant potential (60.269 ± 0.073%) of bioactive was observed in BRUNs6. Hence, this Ns batch was engrossed with Carbopol®934 hydrogel with RO and characterized. In vitro (release and anti-inflammatory activity), ex-vivo (skin permeability) and in vivo (carrageenan-induced inflammation) assays along with irritation study were conducted for fabricated hydrogels. Results revealed that in vitro release of BRU was further delayed from Ns hydrogel with RO (56.45 ± 3.01%) following Fickian mechanism. Considerable enhancement in skin permeability (60.221 ± 0.322 µg/cm2/h) and preservation of anti-inflammatory activity (94.736 ± 2.002%) was also observed in BRUNs6 hydrogel containing RO. The irritation of BRU was found reduced (half) after its entrapped in Ns. Further, as a proof of concept, BRUNs6 hydrogel with RO effectively reduced (75.757 ± 0.944%) carrageenan-induced inflammation in rat model in comparison to pure BRU (54.914 ± 1.081%). Hence, BRUNs hydrogel with RO can be considered as a promising alternative for dermal delivery of BRU in arthritis.

Dendrimers as Modifiers of Inorganic Nanoparticles for Therapeutic Delivery in Cancer.

The formulation of nanoscale systems with well-defined sizes and shapes is of great interest in applications such as drug and gene delivery, diagnostics and imaging. Dendrimers are polymers that have attracted interest due to their size, shape, branching length, amine density, and surface functionalities. These unique characteristics of dendrimers set them apart from other polymers, their ability to modify nanoparticles (NPs) for biomedical applications. Dendrimers are spherical with multiple layers over their central core, each representing a generation. Their amphiphilic nature and hollow structure allow for the incorporation of multiple drugs or genes, in addition to enabling easy surface modification with cellular receptor-targeting moieties to ensure site-specific delivery of therapeutics. Dendrimers are employed in chemotherapeutic applications for the delivery of anticancer drugs. There are many inorganic NPs currently being investigated for cancer therapy, each with their own unique biological, chemical, and physical properties. To favor biomedical applications, inorganic NPs require suitable polymers to ensure stability, biodegradability and target specificity. The success of dendrimers is dependent on their unique structure, good bioavailability and stability. In this review, we describe the properties of dendrimers and their use as modifiers of inorganic NPs for enhanced therapeutic delivery. Herein, we review the significant developments in this area from 2015 to 2022. Databases including Web of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), and PubMed were searched for articles using dendrimers, inorganic nanoparticles and cancer as keywords.

Co-delivery of simvastatin and microRNA-21 through liposome could accelerates the wound healing process.

The gene delivery approach, mainly microRNAs (miRNA) as key wound healing mediators, has recently received extensive attention. MicroRNA-21 (miR-21) has strongly impacted wound healing by affecting the inflammation and proliferation phases. Previous studies have also demonstrated the beneficial effect of simvastatin on wound healing. Therefore, we designed a dual-drug/gene delivery system using PEGylated liposomes that could simultaneously attain the co-encapsulation and co-delivery of miRNA and simvastatin (SIM) to explore the combined effect of this dual-drug delivery system on wound healing. The PEG-liposomes for simvastatin and miR-21 plasmid (miR-21-P/SIM/Liposomes) were prepared using the thin-film hydration method. The liposomes showed 85 % entrapment efficiency for SIM in the lipid bilayer and high physical entrapment of miR-21-P in the inner cavity. In vitro studies demonstrated no cytotoxicity for the carrier on normal human dermal fibroblast cells (NHDF) and 97 % cellular uptake over 2 h incubation. The scratch test revealed excellent cell proliferation and migration after treatment with miR-21-P/SIM/Liposomes. For the in vivo experiments, a full-thickness cutaneous wound model was used. The wound closure on day 8 was higher for Liposomal formulation containing miR-21-P promoting faster re-epithelialization. On day 12, all treated groups showed complete wound closure. However, following histological analysis, the miR-21-P/SIM/Liposomes revealed the best tissue regeneration, similar to normal functional skin, by reduced inflammation and increased re-epithelialization, collagen deposition and angiogenesis. In conclusion, the designed miR-21-P/SIM/Liposomes could significantly accelerate the process of wound healing, which provides a new strategy for the management of chronic wounds.

Magnetic graphene oxide nanoflakes for dual RNA interfering delivery and gene knockdown in prostate and liver cancers.

The development of synthetic carriers for small interfering RNA (siRNA) and plasmids is crucial for effective gene therapy. In this study, we synthesized magnetic graphene oxide nanoflakes as carriers for siRNA delivery, with the goal of knockdown specific genes such as the green fluorescence protein (GFP). Our approach combined magnetically reduced graphene oxide with polyethylenimine (PEI) crosslinked to its surface using carbonyl diimidazole. To evaluate the adsorption capacity of the PEI-modified nanocomposite, we investigated its ability to bind two types of nucleic acids: short-hairpin (sh)RNA plasmids and siRNA targeting GFP. The nanocomposite exhibited significant adsorption, with maximum capacities of 426 ng/µg for shRNA and 71 ng/µg for siRNA, respectively. Simultaneous delivery of siRNA and shRNA using our designed nanocomposites was successfully achieved in human hepatoma and prostate cancer cells. Under magnetic guidance, the knockdown efficiencies reached 73.5 % in hepatoma cells for dual delivery of siRNA and shRNA. Our findings revealed that the nanocomplexes were internalized by the cells through a caveolae-dependent endocytosis mechanism. The demonstrated ability of the nanoflakes to efficiently transport siRNA and shRNA, with high loading capacity, controlled release, and magnetic targeting, resulted in effective GFP knockdown in vitro. These findings highlight the potential of magnetic graphene oxide nanoflakes as promising carriers for siRNA delivery and gene knockdown in therapeutic applications.

Merging konjac glucomannan with other copolymeric hydrogels as a cutting-edge liquid raft system for dual delivery of etoricoxib and famotidine.

This study aimed to formulate and evaluate a floating raft system for the co-delivery of etoricoxib (ETO) and famotidine (FAM) using a combination of glucomannan with natural/semi-synthetic polysaccharides. Formulation variables affect gelation lag time (GLT), floating lag time (FLT), and release percentage of drugs after 1-8 h, Stability, and viscosity parameters were evaluated. In vivo X-ray studies, followed by the pharmacokinetic study, were performed on human volunteers. Formulations exhibited pseudoplastic behavior for ease of swallowing. The optimum raft system (ORS) comprised 1% Na alginate, 0.1% Low Methoxyl (LM) pectin, 0.8% Konjac glucomannan (KGL), 1% Precirol, and 1% CaCO3. ORS exhibited rapid GLT and FLT (around 42 and 8 sec respectively) in 0.1 N HCl as well as controlled release of ETO (15% in 1 h and 82% in 8 h) and FAM (29% in 1 h and 85% in 8 h). Formulation stability with the absence of any drug-excipient interactions was observed. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. Compared with marketed products, ORS showed superior relative bioavailability for both drugs. These findings revealed the successful preparation of a promising raft system with improved dual drug delivery.

Dual scaffold delivery of miR-210 mimic and miR-16 inhibitor enhances angiogenesis and osteogenesis to accelerate bone healing.

Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis: miR-210 acts as an activator by silencing EFNA3 & AcvR1b, while miR-16 inhibits both pathways by silencing VEGF & Smad5. It was thus hypothesized that dual delivery of both a miR-210 mimic and a miR-16 inhibitor from a collagen-nanohydroxyapatite scaffold system may hold significant potential for bone repair. Therefore, this systems potential to rapidly accelerate bone repair by directing enhanced angiogenic-osteogenic coupling in host cells in a rat calvarial defect model at a very early 4 week timepoint was assessed. In vitro, the treatment significantly enhanced angiogenic-osteogenic coupling of human mesenchymal stem cells, with enhanced calcium deposition after just 10 days in 2D and 14 days on scaffolds. In vivo, these dual-miRNA loaded scaffolds showed more than double bone volume and vessel recruitment increased 2.3 fold over the miRNA-free scaffolds. Overall, this study demonstrates the successful development of a dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair for the first time, and the possibility of extending this 'off-the-shelf' platform system to applications beyond bone offers immense potential to impact a myriad of other tissue engineering areas. STATEMENT OF SIGNIFICANCE: miRNAs have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. However, angiogenic-osteogenic coupling is critical for successful bone repair. Therefore, this study harnesses the delivery of miR-210, known to be an activator of both angiogenesis and osteogenesis, and miR-16 inhibitor, as miR-16 is known to inhibit both pathways, from a collagen-nanohydroxyapatite scaffold system to rapidly enhance osteogenesis in vitro and bone repair in vivo in a rat calvarial defect model. Overall, it describes the successful development of the first dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair. This 'off-the-shelf' platform system offers immense potential to extend beyond bone applications and impact a myriad of other tissue engineering areas.

Combinational Growth Factor and Gas Delivery for Thrombosis Prevention.

Cardiovascular stents enable the rapid re-endothelialization of endothelial cells (ECs), and the constant suppression of smooth muscle cell (SMC) proliferation has been proved to effectively prevent thrombosis. However, the development and application of such stents are still insufficient due the delayed re-endothelialization progress, as well as the poor durability of the SMC inhibition. In this paper, we developed a mussel-inspired coating with the ability for the dual delivery of both growth factor (e.g., platelet-derived growth factor, PDGF) and therapeutic gas (e.g., nitric oxide, NO) for thrombosis prevention. We firstly synthesized the mussel-inspired co-polymer (DMHM) of dopamine methacrylamide (DMA) and hydroxyethyl methacrylate (HEMA) and then coated the DMHM on 316L SS stents combined with CuII. Afterwards, we immobilized the PDGF on the DMHM-coated stent and found that the PDGF could be released in the first 3 days to enhance the recruitment, proliferation, and migration of human umbilical vein endothelial cells (HUVECs) to promote re-endothelialization. The CuII could be "sealed" in the DMHM coating, with extended durability (2 months), with the capacity for catalyzed NO generation for up to 2 months to suppress the proliferation of SMCs. Such a stent surface modification strategy could enhance the development of the cardiovascular stents for thrombosis prevention.

Development of tobacco rattle virus-based platform for dual heterologous gene expression and CRISPR/Cas reagent delivery.

A large number of viral delivery systems have been developed for characterizing functional genes and producing heterologous recombinant proteins in plants, and but most of them are unable to co-express two fusion-free foreign proteins in the whole plant for extended periods of time. In this study, we modified tobacco rattle virus (TRV) as a TRVe dual delivery vector, using the strategy of gene substitution. The reconstructed TRVe had the capability to simultaneously produce two fusion-free foreign proteins at the whole level of Nicotiana benthamiana, and maintained the genetic stability for the insert of double foreign genes. Moreover, TRVe allowed systemic expression of two foreign proteins with the total lengths up to ∼900 aa residues. In addition, Cas12a protein and crRNA were delivered by the TRVe expression system for site-directed editing of genomic DNA in N. benthamiana 16c line constitutively expressing green fluorescent protein (GFP). Taker together, the TRV-based delivery system will be a simple and powerful means to rapidly co-express two non-fused foreign proteins at the whole level and facilitate functional genomics studies in plants.

Enhanced Efficacy of Thiosemicarbazone Derivative-Encapsulated Fibrin Liposomes against Candidiasis in Murine Model.

Candida albicans is the most studied species for the candidiasis infection and is becoming resistant towards existing antifungal drugs. Considering this, in the current study, we developed and characterized a fibrin liposome-based formulation encapsulating a novel thiosemicarbazone derivative, 2C, and evaluated its antifungal efficacy against murine candidiasis. The 2C-containing formulation was prepared by encapsulating 2C within the liposomes (2C-L) that were further encapsulated in the fibrin beads (2C-FL). The in-house synthesized 2C-FLs were spherical with a zeta potential of -34.12 ± 0.3 mV, an entrapment efficiency of 72.6 ± 4.7%, and a loading efficiency of 9.21 ± 2.3%, and they showed a slow and sustained release of 2C. Compared to free 2C, the formulation was non-toxic and exhibited serum stability, increased tissue specificity, and penetration. The 2C-FL formulation had a minimum inhibitory concentration (MIC) value of 4.92 ± 0.76 µg/mL and was able to induce apoptosis and necrosis in C. albicans in vitro. The administration of 2C-FL in C. albicans-infected mice prolonged their survival and antifungal effects when compared with the free 2C. The 2C-FL antifungal therapy significantly reduced the fungal burden and displayed an improved survival rate. In conclusion, the 2C thiosemicarbazone derivative possesses a potent antifungal activity that became more advantageous upon its encapsulation in the fibrin liposome delivery system.

Local dual delivery therapeutic strategies: Using biomaterials for advanced bone tissue regeneration.

Bone development is a complex process involving a vast number of growth factors and chemical substances. These factors include transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and most importantly, the bone morphogenetic protein, which exhibits excellent therapeutic value in bone repair. However, the spatial-temporal relationship in the expression of these factors during bone formation makes the bone repair a more complicated process to address. Thus, using a single therapeutic agent to address bone formation does not seem to provide a clinically effective option. Conversely, a dual delivery approach facilitating the co-delivery of agents has proved to be a dynamic alternative since such a strategy can provide more efficient spatial-temporal action. Such delivery systems can smartly target more than one pathway or differentiation lineage and thus offer more efficient bone regeneration. This review discusses various dual delivery strategies reported in the literature employed to achieve improved bone regeneration. These include concurrent use of different therapeutic agents (including growth factors and drugs), enhancing bone formation and cell recruitment, and improving the efficiency of bone healing.

Understanding dual delivery of doxorubicin and paclitaxel with boron nitride and phosphorene nanosheets as highly efficient drug delivery systems.

Dual delivery of Doxorubicin (DOX) and Paclitaxel (PTX) anticancer drug molecules with boron nitride (BN) and phosphorene (PH) nanosheets are investigated using molecular dynamics (MD) simulation. Several quantities are employed to examine the adsorption mechanism of DOX and PTX on the carriers. The obtained results indicate that the drug molecules spontaneously move toward the carriers and form stable complexes. In the interaction of the drugs and BN, the contribution of van der Walls (vdW) is higher than electrostatic energy which can be related to the formation of strong π-π interactions between the drugs and the carrier. Moreover, in the same manner, in the adsorption of drugs on the PH surface, the role of vdW interaction is more than electrostatic energy. Moreover, the oxidative properties of BN and PH nanosheets are examined. The obtained results indicated that the diffusion coefficient values of PTX and DOX molecules in the presence of hydroxyl groups are increased, which can attribute to the blocking effect of functional groups.Communicated by Ramaswamy H. Sarma.

Cryogenic 3D printing of dual-delivery scaffolds for improved bone regeneration with enhanced vascularization.

Three-dimensional (3D) printing has been increasingly employed to produce advanced bone tissue engineering scaffolds with biomimetic structures and matched mechanical strengths, in order to induce improved bone regeneration in defects with a critical size. Given that the successful bone regeneration requires both excellent osteogenesis and vascularization, endowing scaffolds with both strong bone forming ability and favorable angiogenic potential would be highly desirable to induce improved bone regeneration with required vascularization. In this investigation, customized bone tissue engineering scaffolds with balanced osteoconductivity/osteoinductivity were produced via cryogenic 3D printing of ß-tricalcium phosphate and osteogenic peptide (OP) containing water/poly(lactic-co-glycolic acid)/dichloromethane emulsion inks. The fabricated scaffolds had a hierarchically porous structure and were mechanically comparable to human cancellous bone. Angiogenic peptide (AP) containing collagen I hydrogel was then coated on scaffold surface to further provide scaffolds with angiogenic capability. A sequential release with a quick AP release and a slow but sustained OP release was obtained for the scaffolds. Both rat endothelial cells (ECs) and rat bone marrow derived mesenchymal stem cells (MSCs) showed high viability on scaffolds. Improved in vitro migration and angiogenesis of ECs were obtained for scaffolds delivered with AP while enhanced osteogenic differentiation was observed in scaffolds containing OP. The in vivo results showed that, toward scaffolds containing both AP and OP, the quick release of AP induced obvious angiogenesis in vivo, while the sustained OP release significantly improved the new bone formation. This study provides a facile method to produce dual-delivery scaffolds to achieve multiple functions.

Enhanced Synergistic-Antioxidant Activity of Melatonin and Tretinoin by Co-encapsulation into Amphiphilic Chitosan Nanocarriers: During Mice In Vitro Matured Oocyte/Morula-Compact Stage Embryo Culture Model.

The use of exogenous antioxidants or the combination of them during in vitro oocyte/embryo culture media is reasonable. Co-delivery by nanocarrier has been designed to overcome the limitations of combining them traditionally. In this work, amphiphilic chitosan nanocarrier (ACN) was applied to co-encapsulate melatonin (Mel) and tretinoin (TTN) by the self-assembled method and evaluate their synergistic antioxidant efficacy in mice oocytes/embryos. The formation of single/dual-ACN was confirmed by Fourier-transformed infrared spectroscopy (FT-IR). The average particle diameter, size distribution, polydispersity index (PDI), and zeta potential of them were measured by dynamic light scattering (DLS), and the morphology was evaluated by TEM and SEM technologies. Also, the encapsulation efficiency (EE%) and drug loading content (DL%) of the nanocapsules were determined by UV-vis spectrophotometry. Studies of the in vitro release showed a continued drug release without any bursting effect of Mel+TTN-ACNs compared with single Mel/TTN-ACNs. Then, in both experiments, nuclear staining (Aceto-orcein and Hoechst 33342), fluorescent staining of H2DCFDA, chemiluminescence test, and qRT-PCR technique were performed as in vitro toxicity studies. The results of all these evaluations demonstrated that the dual delivery of Mel and TTN could accumulate a safety (without high-dose toxicity) synergistic anti-oxidative effect in oocyte/embryo by passive controlled, and inhibit intra/extracellular ROS levels by an enhanced intracellular penetration.

New insights into Hexakis macrocycles as a novel nano-carrier for highly potent anti-cancer treatment: A new challenge in drug delivery.

The purpose of this study is to design and evaluate a new tubular assembly structure of Hexakis (m-phenylene ethynylene) (m-PE) macrocycles and to explore its potential application as an innovative drug delivery system. First, we focused on how (m-PE) macrocycles can be self-assembled in both chloroform (CHCl3) and water solvents for the formation of the assembled nanotube using molecular dynamics (MD) simulations. In contrast to their behavior in water solvent, all ten (m-PE) macrocycles remain aggregated at low concentrations of CHCl3. We found that these macrocycles carrying chiral side chains and capable of H-bonded self-association, assemble into tubular stacks. Then, the dual delivery strategy for the transport of doxorubicin (DOX) and curcumin (Cur) on the self-assembly system of hexakis (m-PE) nanocarrier is examined using molecular dynamics (MD) simulation and free energy calculation. The obtained results indicated that the binding energy of DOX (- 298.9 kJ/mol) on hexakis (m-PE) in the presence of Cur is higher than free DOX (- 247.7 kJ/mol). Furthermore, in the interaction of the DOX and hexakis m-PE, the contribution of van der Walls (vdW) energy is higher than electrostatic (elec) energy, which can be related to the strong π-π interactions between the drug molecules with the carrier surface. In general, the results indicated that the simultaneous delivery of DOX and Cur through DOX/Cur/hexakis (m-PE) could be a promising vehicle in tumor therapy. Based on the obtained results of the present research, hexakis (m-PE) macrocycle can be used as a drug delivery vehicle for targeted or systemic delivery.

Co-delivery of doxorubicin and epacadostat via heparin coated pH-sensitive liposomes to suppress the lung metastasis of melanoma.

High metastasis is responsible for the failure in the treatment of melanoma. Chemoimmunotherapy has shown conspicuous inhibition effects not only on the growth of tumor in situ, but also on the metastasis to distant organs. Given that the indoleamine-2,3 dioxygenase (IDO) overexpressed in the microenvironment of tumor leads to the immune escape, the combination of chemotherapeutic drug and IDO inhibitor might be a promising chemoimmunotherapy. Besides, the hematogenous metastasis mediated by platelets was supposed to be blocked by the heparin (HP). Therefore, a drug delivery system with all these elements involved might be a potential treatment for melanoma. Here, we developed a pH-sensitive liposomal dual-delivery system for doxorubicin (DOX) and epacadostat (EPA) with HP coated (HP/LDE). It was confirmed to enhance cytotoxicity and apoptosis, reverse the platelets-activated epithelial mesenchymal transformation (EMT) and prevent the invasion and migration in vitro. After systemic administration, HP/LDE provided the optimum anti-metastasis effect on the melanoma. The results of evaluation on DC maturation, CD8+ cytotoxic T lymphocytes (CTLs) activation and T cell mediated cytotoxicity were consistent in vitro and in vivo. Taken together, our study established a functional liposomal dual-delivery system with ideal anti-metastasis efficacy on melanoma.