Kidney-Targeted Renalase Agonist Prevents Cisplatin-Induced Chronic Kidney Disease by Inhibiting Regulated Necrosis and Inflammation.

BACKGROUND: Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI. METHODS: To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy. RESULTS: In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment. CONCLUSIONS: Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.

The effects of consuming a low-fat yogurt fortified with nano encapsulated vitamin D on serum pro-oxidant-antioxidant balance (PAB) in adults with metabolic syndrome; a randomized control trial.

BACKGROUND AND AIM: The current study aimed to assess the effect of fortified yogurt with nano-encapsulated vitamin D on serum pro-oxidant anti-oxidant balance (PAB) in adults with or without metabolic syndrome. METHODS: In a quadruple blind clinical trial study, 139 adults with an age range of 30-50 years were randomly selected to receive either 1500 IU nano-encapsulated vitamin D fortified yogurt or placebo for ten weeks. Before and after the intervention period, blood sample was taken to determine the serum levels of vitamin D, pro-oxidant-antioxidant balance (PAB), and high-sensitivity C-reactive protein (hs-CRP). The laboratory tests were checked at baseline and at the end of the treatment. RESULTS: Serum vitamin D increased significantly, from 14.47 ± 6.07 ng/mL to 21.39 ± 6.54 ng/mL (P < 0.001) after ten weeks in the intervention group. Serum hs-CRP and PAB were significantly lower following consumption period in intervention group [1.95(0.4-8.15) g/dL vs. 1.35(0.25-3.62) g/dL; P = 0.013] and (135.19 ± 42.4 HK vs. 115.39 ± 44.69) HK; P = 0.018] respectively. There were no significant differences between the intervention and control groups regarding weight and BMI at the end of the intervention period (p > 0.05). CONCLUSION: Low-fat yogurt fortified with nano-encapsulated vitamin D was found to reduce serum PAB levels in adults with metabolic syndrome. PRACTICAL APPLICATION: The findings of the present study indicated that a low-fat yogurt fortified with 1500 IU nano-encapsulated vitamin D for ten weeks, leads to a significant reduction in serum hs-CRP and PAB concentrations highlighted the anti-inflammatory/anti-oxidative effect of vitamin D.

Increasing the Power of Polyphenols through Nanoencapsulation for Adjuvant Therapy against Cardiovascular Diseases.

Polyphenols play a therapeutic role in vascular diseases, acting in inherent illness-associate conditions such as inflammation, diabetes, dyslipidemia, hypertension, and oxidative stress, as demonstrated by clinical trials and epidemiological surveys. The main polyphenol cardioprotective mechanisms rely on increased nitric oxide, decreased asymmetric dimethylarginine levels, upregulation of genes encoding antioxidant enzymes via the Nrf2-ARE pathway and anti-inflammatory action through the redox-sensitive transcription factor NF-κB and PPAR-γ receptor. However, poor polyphenol bioavailability and extensive metabolization restrict their applicability. Polyphenols carried by nanoparticles circumvent these limitations providing controlled release and better solubility, chemical protection, and target achievement. Nano-encapsulate polyphenols loaded in food grade polymers and lipids appear to be safe, gaining resistance in the enteric route for intestinal absorption, in which the mucoadhesiveness ensures their increased uptake, achieving high systemic levels in non-metabolized forms. Nano-capsules confer a gradual release to these compounds, as well as longer half-lives and cell and whole organism permanence, reinforcing their effectiveness, as demonstrated in pre-clinical trials, enabling their application as an adjuvant therapy against cardiovascular diseases. Polyphenol entrapment in nanoparticles should be encouraged in nutraceutical manufacturing for the fortification of foods and beverages. This study discusses pre-clinical trials evaluating how nano-encapsulate polyphenols following oral administration can aid in cardiovascular performance.

Novel Gellan Gum-Based In Situ Nanovesicle Formulation of Docetaxel for Its Localized Delivery Using Depot Formation.

In the present study, different in situ hydrogel formulations of docetaxel (DTX) based on biocompatible polymers such as Hyaluronic Acid (HA), poloxamer-407, chitosan and gellan gum were formulated to increase its therapeutic efficacy and reduce toxicity. DTX was loaded in nanovesicles (20 mg/mL equivalent to commercial strength) and further incorporated into the hydrogel bases to possess a dual rationale of protection against burst release and enhanced solubility of the drug. The optimized hydrogel formulation (NV-TPGS-3-GG-4) showed ideal rheological behavior and in situ characteristics at 37±0.5°C with sustained release of more than 144 h. The optimized formulation had instant in vitro gelation (2.8±0.3 min) with good injectability in comparison to the conventional commercial DTX injectable formulation having instant release (<2 h). Additionally, developed formulation exhibited an improved biodisponibility (25.1±0.2 h) in comparison to the commercially available formulation (1.7±0.1 h). The Solid Tumor Carcinoma model in Swiss albino mice revealed that the optimized formulation (based on gellan gum) showed better tumor reduction (85.7±1.2%) and lower toxicity as compared to the commercial formulation (77.3±1.3%). Pharmacokinetic and biodistribution studies demonstrated 3 to 4 times higher localization of drug in tumors. Our findings suggested that injectable gellan gum-based in situ hydrogel formulation can be an effective delivery system for DTX with enhanced solubility, reduced toxicity, and better targeting to the tumors for improved therapeutics.Graphical abstract.

Multifunctional Spiky Topological Nanocapsules for the Discrimination and Differential Inhibition of Inflammation and Cancer.

Accurate discrimination of inflammations and cancers as well as differential inhibition of cancers are significant for early diagnoses and timely treatments. Nanoparticles have become new modalities for diagnosis and therapy. However, they are still challenged by the efficient delivery of multiple reagents into living cells, discriminating multisignals without any interference, and differential treatments of different diseases. Here, multifunctional spiky topological nanocapsules (STNs) are prepared for the discrimination and differential inhibition of inflammation and cancer. With unique spiky hollow architectures, STNs' advantages including excellent loading capacity, enhanced cellular uptake, DNAs' protection against degradation, target-controlled drug release, and efficient endo-/lysosome escape are demonstrated. Therefore, sequential detection of inflammation-related miR-155 (by external modified hairpin DNAs) and the cancer target of monocarboxylate transporter 1 (MCT1) (by internal loaded pH-sensitive carbon dots and MCT1 inhibitor-AZD3965) are achieved. Furthermore, the release of AZD3965 from the cavities of STNs is controlled by the miR-155 amount (first target). Therefore, the released drug of AZD3965 realizes the stage-dependent differential treatment of diseases via cellular acidosis induced by MCT1 inhibition. Via in vivo evaluations of normal, inflammatory, and liver cancer cells/mice, as well as the efficient inhibition of tumor growth, the possibility of STN-based discrimination and differential treatment is confirmed. This would encourage new strategies for multidiagnosis and differential treatment of early-stage cancer.

Light-assisted anticancer photodynamic therapy using porphyrin-doped nanoencapsulates.

Light activatable porphyrinic photosensitizers (PSs) are essential components of anticancer and antimicrobial therapy and diagnostic imaging. However, their biological applications are quite challenging due to the lack of hydrophilicity and biocompatibility. To overcome such drawbacks, photosensitizers can be doped into a biocompatible polymer such as gelatin and further can be used for biomedical applications. Herein, first, a novel A4 type porphyrin PS [5,10,15,20-tetrakis(4-pyridylamidephenyl)porphyrin; TPyAPP] was synthesized via a rational route with good yield. Further, this porphyrin was encapsulated into the gelatin nanoparticles (GNPs) to develop hydrophilic phototherapeutic nanoagents (PTNAs, A4por-GNPs). Notably, the synthesis of such porphyrin-doped GNPs avoids the use of any toxic chemicals or solvents. The nanoprobes have also shown good fluorescence quantum yield demonstrating their applicability in bioimaging. Further, the mechanistic aspects of the anticancer and antimicrobial efficacy of the developed A4por-GNPs were evaluated via singlet oxygen generation studies. Overall, our results indicated porphyrin-doped biodegradable polymeric nanoparticles act as effective phototherapeutic agents against a broad range of cancer cell lines and microbes upon activation by the low-cost LED light.

Assessment of nanoencapsulated Cananga odorata essential oil in chitosan nanopolymer as a green approach to boost the antifungal, antioxidant and in situ efficacy.

In this study, a comparative efficacy of Cananga odorata EO (CoEO) and its nanoencapsulated formulation into chitosan nanoemulsion (CoEO-CsNe) against a toxigenic strain of Aspergillus flavus (AF-M-K5) were investigated for the first time in order to determine its efficacy in preservation of stored food from fungal, aflatoxin B1 (AFB1) contamination and lipid peroxidation. GC and GC-MS analysis of CoEO revealed the presence of linalool (24.56%) and benzyl acetate (22.43%) as the major components. CoEO was encapsulated into chitosan nanoemulsion (CsNe) through ionic-gelation technique and characterized by High Resolution-Scanning Electron Microscopy (HR-SEM), Fourier Transform Infrared spectroscopy (FTIR), and X-Ray Diffraction (XRD) analysis. The CoEO-CsNe during in vitro investigation against A. flavus completely inhibited the growth and AFB1 production at 1.0 µL/mL and 0.75 µL/mL, respectively. Additionally, CoEO-CsNe showed improved antioxidant activity against DPPH• and ABTS•+ with IC50 value 0.93 and 0.72 µL/mL, respectively. Further, CoEO-CsNe suppressed fungal growth, AFB1 secretion and lipid peroxidation in Arachis hypogea L. during in situ investigation without causing any adverse effect on seed germination. Overall results demonstrated that the CoEO-CsNe has potential of being utilized as a suitable plant based antifungal agent to improve the shelf-life of stored food against AFB1 and lipid peroxidation mediated biodeterioration.

Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni.

BACKGROUND: The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed-dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy. METHODS: Two nanocombinations were prepared to provide 250 mg praziquantel-20 mg miltefosine/kg (higher fixed-dose) or 125 mg praziquantel-10 mg miltefosine/kg (lower fixed-dose), respectively. Their antischistosomal efficacy in comparison with a non-treated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral dose of either formulation was administered on the initial day of infection, and on days 21 and 42 post-infection. Scanning electron microscopic, parasitological, and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukey's post-hoc test for pairwise comparisons. RESULTS: Lipid nanocapsules (~ 58 nm) showed high entrapment efficiency of both drugs (> 97%). Compared to singly loaded praziquantel-lipid nanocapsules, the higher nanocombination dose showed a significant increase in antischistosomal efficacy in terms of statistically significant decrease in mean worm burden, particularly against invasive and juvenile worms, and amelioration of hepatic granulomas (P ≤ 0.05). In addition, scanning electron microscopy examination showed extensive dorsal tegumental damage with noticeable deposition of nanostructures. CONCLUSIONS: The therapeutic profile of praziquantel could be improved by a novel multiple approach integrating drug repurposing, combination therapy and nanotechnology. Multistage activity and amelioration of liver pathology could be achieved by a new praziquantel-miltefosine fixed-dose nanocombination providing 250 mg praziquantel-20 mg miltefosine/kg. To the best of our knowledge, this is the first report of a fixed-dose nano-based combinatorial therapy for schistosomiasis mansoni. Further studies are needed to document the nanocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.

Silica Nanocapsules with Different Sizes and Physicochemical Properties as Suitable Nanocarriers for Uptake in T-Cells.

INTRODUCTION: Adoptive T-cell immunotherapy emerged as a powerful and promising cancer therapy, as the problem regarding the immuno-reaction between different donors and recipients can be avoided. However, this approach is challenging. After long cultivation and expansion under laboratory media conditions, T-cells are losing their viability and function due to immune checkpoint proteins, leading to decreased efficiency in killing cancer cells. Therefore, a new strategy to improve T-cell survival and function is needed. With the advantages of nanotechnology and the biocompatibility of silica-based material, silica nanocapsules (SiNCs) provide an ideal delivery system to transport therapeutic biomolecules to T-cells. Up to now, there is a lack of cellular uptake studies of nanocarriers towards T-cells. METHODS: We systematically studied the influence of various physicochemical properties such as sizes, core hydrophobicities, surface charges, and surface functionalities of SiNC for their impact on cellular uptake and toxicity in CD8+ T-cells by flow cytometry and confocal laser scanning microscopy. Cytokine secretion assay was performed using the enzyme-linked immunosorbent assay. To identify suitable uptake conditions for SiNCs into CD8+ T-cells, the impact of human serum in cell culture medium was also investigated. RESULTS: The major impact on cellular uptake and toxicity was found to be size- and dose-dependent. Smaller sizes of SiNCs than 100 nm caused significant toxicity to the cells. It was found that the formed protein corona reduced the toxicity of the SiNCs. However, it also inhibited their uptake. CONCLUSION: Overall, we present a set of different criteria for a suitable design of nanocarriers and cell culture conditions, which need to be carefully considered for T-cell immunotherapy in vitro to facilitate uptake while avoiding toxicity.

Impact of Reverse Micelle Loaded Lipid Nanocapsules on the Delivery of Gallic Acid into Activated Hepatic Stellate Cells: A Promising Therapeutic Approach for Hepatic Fibrosis.

PURPOSE: Gallic acid (GA) is a polyphenolic compound with proven efficacy against hepatic fibrosis in experimental animals. However, it suffers from poor bioavailability and rapid clearance that hinders its clinical investigation. Accordingly, we designed and optimized reverse micelle-loaded lipid nanocapsules (RMLNC) using Box-Behnken design that can deliver GA directly into activated-hepatic stellate cells (aHSCs) aiming to suppress hepatic fibrosis progression. METHODS: GA-RMLNC was prepared using soft energy, solvent free phase inversion temperature method. Effects of formulation variables on particle size, zeta potential, entrapment efficiency (EE%) and GA release were studied. In-vivo biodistribution of GA-RMLNC in rats and in-vitro activities on aHSCs were also explored. RESULTS: Nano-sized GA-RMLNCs (30.35 ± 2.34 nm) were formulated with high GA-EE% (63.95 ± 2.98% w/w) and physical stability (9 months). The formulated system showed burst GA release in the first 2 h followed by sustained release profile. In-vivo biodistribution imaging revealed that RMLNC-loaded with rhodamine-B accumulated mainly in rats' livers. Relative to GA; GA-RMLNC displayed higher anti-proliferative activities, effective internalization into aHSCs, marked down-regulation in pro-fibrogenic biomarkers' expressions and elevated HSCs' apoptosis. CONCLUSIONS: These findings emphasize the promising application of RMLNC as a delivery system in hepatic fibrosis treatment, where successful delivery of GA into aHSCs was ensured via increased cellular uptake and antifibrotic activities.

Antinociception induced by artemisinin nanocapsule in a model of postoperative pain via spinal TLR4 inhibition.

Artemisinin (ART) was initially described for the control of inflammation and pain. However, the mechanisms involved with its antinociceptive effect are still poorly understood. Thus, this present study aimed to investigate the effect of ART in both free and nanocapsulated form on postoperative pain, as well as the participation of the spinal Toll-like receptor 4 (TLR4) in this process. Postoperative pain was induced using the skin/muscle incision retraction (SMIR) model in male Swiss mice. After 3 and 28 days of SMIR, the animals received an intrathecal injection of free or nanocapsulated ART, and the nociceptive threshold was evaluated by von Frey filament test. To evaluate the involvement of the microglia, astrocytes, and TLR4, minocycline (a microglia inhibitor), fluorocitrate (an astrocyte inhibitor), and Lipopolysaccharide Rhodobacter sphaeroides (LPS-RS), a TLR4 antagonist, were intrathecally injected on the third day of SMIR. The levels of spinal TLR4 protein and proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1ß) were quantified by western blot and enzyme-linked immunosorbent assay, respectively. The results showed that free ART reduced postoperative pain (P < 0.001, F5,30 = 7.49, 16.66% for 1000 ng dose; and P < 0.01, F5,30 = 7.49, 14.58% for 500 ng dose) on the 3rd day of SMIR; while the ART nanocapsule had this effect on both the third (P < 0.001; F5,30 = 4.94; 43.75, 39.58 and 72.91% for the 250, 500 and 1000 ng doses, respectively) and 28th (P < 0.05; F5,30 = 7.71; 29.16 and 33.33% for the 500 and 1000 ng doses, respectively) day. The ART nanocapsule had a more potent and longer antinociceptive effect than free ART or morphine. Postoperative pain was also reduced by minocycline and LPS-RS. The ART nanocapsule also reduced the increased levels of TLR4, TNF-α, and IL-1ß induced by SMIR. These data suggest that the ART nanocapsule has a potent analgesic effect on postoperative pain at the spinal level, and this response involves the inhibition of TLR4 and the proinflammatory cytokines TNF-α and IL-1ß.

Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy.

BACKGROUND: Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy. METHODS: TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake. RESULTS: The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer. CONCLUSION: In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.

Nanocapsule Delivery of IL-12.

Interleukin(IL)-12 is a protein that activates T cells and macrophages to kill tumor cells. However, despite this cytokine showing strong antitumor activity in preclinical settings, translation to patients has been slowed by toxic side effects, poor distribution to peripheral tissues, and improper dosing regimens. Osteosarcoma (OS) is an aggressive primary tumor of bone that has shown particular responsiveness to recombinant (r)IL-12 in preclinical models. Poly(lactic-co-glycolic) acid (PLGA) nanospheres, an FDA-approved drug delivery vector, may be a viable delivery vector for transporting biologically active IL-12 to tissues without disturbing normal homeostasis. In this chapter, we explore the potential for using IL-12-loaded nanospheres (IL-12-NS, <1 µm in diameter) to treat cancer, describe the synthesis process, and examine a typical protein release profile while providing insight and future directions of nanoscale tumor immunotherapeutics.

Healing of dermal wounds property of Caryocar brasiliense oil loaded polymeric lipid-core nanocapsules: formulation and in vivo evaluation.

Cutaneous lesions lead to complications in patients, since they may be recurrent and also represent risk of progression to infection and/or amputation. Therefore, effective, protective, and topical treatments of easy application and removal need to be developed to provide effective alternatives to patients. The Caryocar brasiliense Cambess (CBC) presents important pharmacological activities and proved in the healing process. This paper reports the improvement of the CBC nanostructured (LNCCBC and LNCCBC+) activity in dermal wounds in vivo. The oil was physico-chemically characterized and used in the development of lipid-core nanocapsules (LNCs), coated (LNCCBC+) or without chitosan (LNCCBC), in concentration of 1.0 mg mL-1. Hydrogel (HG) was tested in vivo on lesions in the back of male Wistar rats for 14 days. The oil presented appropriate physico-chemical characteristics for its use, such as moisture 0.76 %, acidity 0.85 % and oleic acid 25.90 %. The LNCs showed nanometric size (around 200 nm), monomodal distribution, slight acid pH and zeta potential of + 22.1 mV in accordance with the composition. The nanostructured oil induced dermal healing in vivo showing significantly better improvement than free oil. LNCCBC+ showed best results showing the higher increase of the production of type 1 collagen, an important protein to the healing repair. These results suggest that development of formulations LNCCBC and LNCCBC+ are promising and important alternative for the treatment of dermal wounds, avoiding complications related to cutaneous lesions.

Sorafenib-Loaded Long-Circulating Nanoliposomes for Liver Cancer Therapy.

A type of sorafenib- (SOR-) loaded long-circulating nanoliposome was constructed, and the targeting performance and antitumor effects of the prepared liposome were evaluated in the present study. Polyethylene glycol- (PEG-) modified long-circulating nanoliposomes (LC-NPs) were designed and prepared using reverse evaporation, and the LC-NPs were used for delivering sorafenib (LC-PEG-SOR-NPs). Then, the anti-VEGFR antibody as a targeting moiety was chemically coupled with LC-PEG-SOR-NPs to form liver cancer-targeted nanoliposomes (anti-VEGFR-LC-PEG-SOR-NPs). The drug entrapment and loading efficiency were measured. And the cancer-targeting performance and therapeutic efficiency were evaluated both in vitro and in vivo. The anti-VEGFR-LC-PEG-SOR-NPs with an average of 119.8 ± 4.2 nm showed a uniform spherical structure. The drug entrapment and loading efficiency were 92.5% and 18.5%, respectively. The killing efficiency of anti-VEGFR-LC-PEG-SOR-NPs was up to 18% after incubating with liver cancer cells for 72 h. Furthermore, the anti-VEGFR-LC-PEG-SOR-NPs could actively target at the tumor region and could efficiently inhibit tumor growth with negligible side effects. This newly designed nanoliposomes had desirable dispersibility, high drug entrapment efficiency, tumor targeting and therapeutic efficiency, and good safety. As a biocompatible nanocomposite, it was promising to become a novel and useful tumor-targeting nanodrug for liver cancer therapy.

Engineering red-emitting multi-functional nanocapsules for magnetic tumour targeting and imaging.

In this work we describe the formulation and characterisation of red-emitting polymeric nanocapsules (NCs) incorporating superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic tumour targeting. The self-fluorescent oligomers were synthesised and chemically conjugated to PLGA which was confirmed by NMR spectroscopy, FT-IR spectroscopy and mass spectrometry. Hydrophobic SPIONs were synthesised through thermal decomposition and their magnetic and heating properties were assessed by SQUID magnetometry and calorimetric measurements, respectively. Magnetic nanocapsules (m-NCs) were prepared by a single emulsification/solvent evaporation method. Their in vitro cytotoxicity was examined in CT26 colon cancer cells. The formulated fluorescent m-NCs showed good stability and biocompatibility both in vitro and in vivo in CT 26 colon cancer models. Following intravenous injection, accumulation of m-NCs in tumours was observed by optical imaging. A higher iron content in the tumours exposed to a magnetic field, compared to the contralateral tumours without magnetic exposure in the same animal, further confirmed the magnetic tumour targeting in vivo. The overall results show that the engineered red-emitting m-NCs have great potential as multifunctional nanocarriers for multi-model bioimaging and magnetic-targeted drug delivery.

Design, Formulation and in vivo Evaluation of Novel Honokiol-Loaded PEGylated PLGA Nanocapsules for Treatment of Breast Cancer.

BACKGROUND: Honokiol (HK) is a common herbal medicine extracted from magnolia plants. Low aqueous solubility and limited bioavailability of HK have hindered its clinical application, especially for cancer treatment. Nano-drug delivery system has the potential to enhance HK delivery and therefore, enhance its anti-cancer activity. PURPOSE: The study's aim is to design novel PEGylated-PLGA polymeric nanocapsules (NCs) for HK delivery to breast tumor-bearing mice after systemic administration. METHODS: Formulation of different HK-loaded NCs and their physio-chemical characterization were optimized through the use of different formulation variables. The antitumor activity of the HK-loaded NCs was investigated both in vitro using MCF-7 and EAC breast cancer cell lines and in vivo using solid Ehrlich carcinoma (SEC) breast cancer model. RESULTS: The optimum HK-loaded NCs were prepared from 15% PEG-PLGA diblock copolymer and exhibited the lowest nano size of 125 nm, smooth spherical morphology, highest drug loading of 94% and highest cellular uptake into breast cancer cells. HK-loaded PEGylated NCs can effectively inhibit the in vitro cell growth of breast cancer cells by 80.2% and 58.1% compared to 35% and 31% with free HK in the case of MCF-7 and EAC, respectively. HK-loaded NCs inhibited SEC tumor growth by 2.3 fold significantly higher than free HK, in vivo. CONCLUSION: The designed drug delivery system encapsulating HK exhibited a pronounced decrease in tumor growth biomarkers meanwhile proved its safety in animals. Therefore, 15% PEGylated HK-loaded NCs may act as a promising new approach for breast cancer treatment.

Virus-mimicking mesoporous organosilica nanocapsules with soft framework and rough surface for enhanced cellular uptake and tumor penetration.

An enveloped virus with soft and rough shells has strong penetration ability for cells. Inspired by the unique structure of virus, we successfully constructed virus-mimicking mesoporous organosilica nanocapsules (denoted as VMONs) for the first time by decorating small-sized silica nanoparticles on soft mesoporous organosilica hollow spheres. TEM and SEM images reveal that the prepared VMONs display uniform diameters (240 nm), a soft framework, a rough surface, and excellent dispersity. Quantitative nanomechanical mapping further demonstrates that the VMONs possess an extremely low Young's modulus (36 MPa) and a scraggly surface. In view of the successful construction of the virus-mimicking nanocapsules, the VMONs are further modified with human serum albumin (HSA) and Cy5.5-maleimide (Mal-Cy5.5) to investigate their cell penetration ability. Flow cytometry analysis reveals that the internalization of VMONs@HSA-Cy5.5 increases 2.74-fold compared to that of the conventional mesoporous nanosphere. Confocal laser scanning microscopy images show that the VMONs@HSA-Cy5.5 diffuses deeper for multicellular spheroids compared to both hard and soft mesoporous organosilica nanospheres. The penetration ability of the VMONs and SMONs increases 18.49 and 6.13-fold compared to that of MONs at the depth of 60 µm. Thanks to the excellent cellular penetration ability, the virus-mimicking VMONs@HSA-Cy5.5 can effectively deliver the anticancer drug doxorubicin (Dox) into drug-resistant MCF-7/ADR human breast cancer cells and significantly enhance the chemotherapeutic efficacy. Taken together, the constructed virus-mimicking organosilica nanocapsules with a soft framework and a rough surface possess strong cellular internalization and tumor penetration abilities, providing a unique and effective nanoplatform for biomedical applications.

Dual-target IL-12-containing nanoparticles enhance T cell functions for cancer immunotherapy.

Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy. A potent tumor immunotherapy may not only require activation of anti-tumor effector cells but also rely on the use of cytokines to create a controlled environment for the development of anti-tumor T cells. In this study, we fabricated a dual-target immunonanoparticle, e.g. poly(d,l-lactide-co-glycolide) nanoparticle, by loading Interleukin-12 (IL-12) and modifying with CD8 and Glypican-3 antibodies on the surface. Our results demonstrate that the fabricated targeting immunonanoparticles bind specifically to the two target cells of interest, i.e. CD8+ T cells and HepG-2 cells via the antibody-antigen interactions and form T cell-HepG-2 cell clusters, which enhances the cytotoxicity of T cells. IL-12-containing dual-target immunonanoparticles delivered IL-12 specifically to CD8+ T cells, and favored the expansion, activation and cytotoxic activity of CD8+ T lymphocytes. These results suggest that dual-target IL-12-encapsulated nanoparticles are a promising platform for cancer immunotherapy.