Photothermal-controlled NO-releasing Nanogels reverse epithelial-mesenchymal transition and restore immune surveillance against cancer metastasis.

Metastasis leads to high mortality among cancer patients. It is a complex, multi-step biological process that involves the dissemination of cancer cells from the primary tumor and their systemic spread throughout the body, primarily through the epithelial-mesenchymal transition (EMT) program and immune evasion mechanisms. It presents a challenge in how to comprehensively treat metastatic cancer cells throughout the entire stage of the metastatic cascade using a simple system. Here, we fabricate a nanogel (HNO-NG) by covalently crosslinking a macromolecular nitric oxide (NO) donor with a photothermal IR780 iodide-containing hyaluronic acid derivative via a click reaction. This enables stable storage and tumor-targeted, photothermia-triggered release of NO to combat tumor metastasis throughout all stages. Upon laser irradiation (HNO-NG+L), the surge in NO production within tumor cells impairs the NF-κB/Snail/RKIP signaling loop that promotes the EMT program through S-nitrosylation, thus inhibiting cell dissemination from the primary tumor. On the other hand, it induces immunogenic cell death (ICD) and thereby augments anti-tumor immunity, which is crucial for killing both the primary tumor and systemically distributed tumor cells. Therefore, HNO-NG+L, by fully leveraging EMT reversal, ICD induction, and the lethal effect of NO, achieved impressive eradication of the primary tumor and significant prevention of lung metastasis in a mouse model of orthotropic 4T1 breast tumor that spontaneously metastasizes to the lungs, extending the NO-based therapeutic approach against tumor metastasis.

Resveratrol-Loaded Attalea funifera Oil Organogel Nanoparticles: A Potential Nanocarrier against A375 Human Melanoma Cells.

This study aimed to evaluate Attalea funifera seed oil with or without resveratrol entrapped in organogel nanoparticles in vitro against A375 human melanoma tumor cells. Organogel nanoparticles with seed oil (SON) or with resveratrol entrapped in the seed oil (RSON) formed functional organogel nanoparticles that showed a particle size <100 nm, polydispersity index <0.3, negative zeta potential, and maintenance of electrical conductivity. The resveratrol entrapment efficiency in RSON was 99 ± 1%. The seed oil and SON showed no cytotoxicity against human non-tumor cells or tumor cells. Resveratrol at 50 µg/mL was cytotoxic for non-tumor cells, and was cytotoxic for tumor cells at 25 µg/mL. Resveratrol entrapped in RSON showed a decrease in cytotoxicity against non-tumor cells and cytotoxic against tumor cells at 50 µg/mL. Thus, SON is a potential new platform for the delivery of resveratrol with selective cytotoxic activity in the treatment of melanoma.

Synthesis and Characterizations of Bioactive Glass Nanoparticle-Incorporated Triblock Copolymeric Injectable Hydrogel for Bone Tissue Engineering.

Recently, injectable hydrogels have attracted much interest in tissue engineering (TE) applications because of their controlled flowability, adaptability, and easy handling properties. This work emphasizes the synthesis and characterizations of bioactive glass (BAG) nanoparticle-reinforced poly(ethylene glycol) (PEG)- and poly(N-vinylcarbazole) (pNVC)-based minimally invasive composite injectable hydrogel suitable for bone regeneration. First, the copolymer was synthesized from a combination of PEG and pNVC through reversible addition-fragmentation chain-transfer (RAFT) polymerization and nanocomposite hydrogel constructs were subsequently prepared by conjugating BAG particles at varying loading concentrations. Gel permeation chromatography (GPC) analysis confirmed the controlled nature of the polymer. Various physicochemical characterization results confirmed the successful synthesis of copolymer and nanocomposite hydrogels that showed good gelling and injectability properties. Our optimal nanocomposite hydrogel formulation showed excellent swelling properties in comparison to the copolymeric hydrogel due to the presence of hydrophilic BAG particles. The bone cell proliferation rate was found to be evidently higher in the nanocomposite hydrogel than in the copolymeric hydrogel. Moreover, the enhanced level of ALP activity and apatite mineralization for the nanocomposite in comparison to that for the copolymeric hydrogel indicates accelerated in vitro osteogenesis. Overall, our study findings indicate BAG particle-conjugated nanocomposite hydrogels can be used as promising grafting materials in orthopedic reconstructive surgeries complementary to conventional bone graft substitutes in cancellous bone defects due to their 3D porous framework, minimal invasiveness, and ability to form any desired shape to match irregular bone defects.

Effect of temperature-sensitive nanogel combined with angioplasty on sICAM-1 and VE-cadherin in lower extremity arterial occlusion rabbits.

The study was to explore the effect of subintimal angioplasty (SIA) on the levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular endothelial cadherin (VE-cadherin) in the rabbit model of lower extremity arterial occlusion. Specifically, the poly(N-isopropylacrylamide-co-butyl methacrylate) (PIB) temperature-sensitive nanogel was prepared, and the cytotoxicity of direct and indirect contact with PIB temperature-sensitive gel was analyzed then. Subsequently, the PIB temperature-sensitive gel was injected to the New Zealand white rabbit to prepare the lower extremity arterial occlusion model. The healthy control, model group, and SIA group were compared for the serum lipids, fibrinogen (Fbg), fibrinogen (Fbg), and fibrinogen (Fbg) levels. The results showed that the cell proliferation activity and survival rate were always higher than 90% under different concentrations of PIB temperature-sensitive gels. Compared with the model group, the SIA group had increased total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and Fbg levels, but decreased high-density lipoprotein (HDL) level (P < 0.05); decreased TXB2, ET-1, and ICAM-1 levels, but increased levels of 6-Keto-PGF1α and NO (P < 0.05); and decreased sICAM-1 and VE-cadherin levels (P < 0.05). It showed that PIB temperature-sensitive nanogel can elicit vascular embolism, and SIA is suggested in the treatment of lower extremity arterial occlusion.

Nanogel-Facilitated In-Situ Delivery of a Cataract Inhibitor.

Cataracts are a leading cause of blindness worldwide. Surgical removal of cataracts is a safe and effective procedure to restore vision. However, a large number of patients later develop vision loss due to regrowth of lens cells and subsequent degradation of the visual axis leading to visual disability. This postsurgical complication, known as posterior capsular opacification (PCO), occurs in up to 30% of cataract patients and has no clinically proven pharmacological means of prevention. Despite the availability of many compounds capable of preventing early steps in PCO development, there is currently no effective means to deliver such therapies into the eye for a suitable duration. To model a solution to this unmet medical need, we fabricated acrylic substrates as intraocular lens (IOL) mimics scaled to place into the capsular bag of the mouse lens following a mock-cataract surgery. Substrates were coated with a hydrophilic crosslinked acrylate nanogel designed to elute Sorbinil, an aldose reductase inhibitor previously shown to suppress PCO. Insertion of the Sorbinil-eluting device into the lens capsule at the time of cataract surgery resulted in substantial prevention of cellular changes associated with PCO development. This model demonstrates that a cataract inhibitor can be delivered into the postsurgical lens capsule at therapeutic levels.

Chitosan-bovine serum albumin-Carbopol 940 nanogels for mupirocin dermal delivery: ex-vivo permeation and evaluation of cellular binding capacity via radiolabeling.

The goal of this study was to develop and examine the nanogel-based topical delivery system of mupirocin. Nanogels were prepared with chitosan and bovine serum albumin by ionic gelation and Carbopol 940 was added to improve the gelling/adhesive properties. Detailed characterization studies were performed and the cellular binding capacity of radiolabeled nanogels was investigated on CCD-1070Sk cell lines. Results indicate the successful formation of nanogels with particle size and zeta potential ranged between 341.920-603.320 nm and 13.120-24.300 mV, respectively. The mechanical and rheological studies proved pseudoplastic and strong elastic gel behavior (G' > G''). Mupirocin was successfully entrapped into nanogels with a ratio of more than 95% and the loaded drug was slowly released up to 93.89 ± 3.07% within 24 h. The ex vivo penetration and permeation percentages of mupirocin were very low (1.172 ± 0.202% and 0.161 ± 0.136%) indicating the suitability of nanogels for dermal use against superficial skin infections. The microbiological studies pointed out the effectiveness of nanogels against Staphylococcus aureus strains. Nanogels did not show toxicity signs and the cell binding capacity of radiolabeled formulations was found to be higher than [99mTc]NaTcO4 to CCD-1070Sk cell line. Overall, mupirocin nanogels might be considered as a potential and safe topical treatment option for bacterial skin infections.

In vitro and in vivo evaluation of an ionic sensitive in situ gel containing nanotransfersomes for aripiprazole nasal delivery.

In the current study, a composite in-situ gel formulation containing aripiprazole (APZ) loaded transfersomes (TFS) was developed for the intranasal brain targeting of APZ. APZ loaded TFS were prepared by applying the film hydration method and optimized using an irregular factorial design. The prepared formulations were optimized based on different parameters including particle size, polydispersity index (PdI), zeta potential, encapsulation efficiency (EE) and release efficiency (RE). The optimized APZ-TFS were distributed in an ion-triggered deacetylated gellan gum solution (APZ-TFS-Gel) and evaluated in terms of pH, gelling time, rheological properties and in-vitro release study. The therapeutic efficacy of the best APZ-TFS-Gel was then tested in the mice model of schizophrenia induced by ketamine by evaluating various behavioral parameters. The optimized formulation showed the particle size of 72.12 ± 0.72 nm, the PdI of 0.19 ± 0.07, the zeta potential of -55.56 ± 1.9 mV, the EE of 97.06 ± 0.10%, and the RE of 70.84 ± 1.54%. The in-vivo results showed that compared with the other treatment groups, there was a considerable increase in swimming and climbing time and a decrease in locomotors activity and immobility time in the group receiving APZ-TFS-Gel. Thus, APZ-TFS-Gel was found to have desirable characteristics for therapeutic improvement.

Carbonized Lysine-Nanogels Protect against Infectious Bronchitis Virus.

In this study, we demonstrate the synthesis of carbonized nanogels (CNGs) from an amino acid (lysine hydrochloride) using a simple pyrolysis method, resulting in effective viral inhibition properties against infectious bronchitis virus (IBV). The viral inhibition of CNGs was studied using both in vitro (bovine ephemeral fever virus (BEFV) and pseudorabies virus (PRV)) and in ovo (IBV) models, which indicated that the CNGs were able to prevent virus attachment on the cell membrane and penetration into the cell. A very low concentration of 30 µg mL-1 was found to be effective (>98% inhibition) in IBV-infected chicken embryos. The hatching rate and pathology of IBV-infected chicken embryos were greatly improved in the presence of CNGs. CNGs with distinctive virus-neutralizing activities show great potential as a virostatic agent to prevent the spread of avian viruses and to alleviate the pathology of infected avian species.

Nanoemulgel for Improved Topical Delivery of Desonide: Formulation Design and Characterization.

This research aimed to develop a novel drug delivery system to improve treatment of skin disorders. The system is comprised of a Carbopol 980-based nanoemulgel (NE-gel) containing a desonide (DES; 0.05%, w/w) nanoemulsion (NE), which has a small particle size, high encapsulation efficiency, good thermodynamic stability, good permeation ability, and high skin retention. DES-loaded NE (DES-NE) was prepared by high-pressure homogenization. The developed formulation was characterized by differential scanning calorimetry (DSC), X-ray diffraction, drug release, skin permeation, and drug retention. DES in vitro release and skin permeation studies with different formulations of artificial membrane and rat abdominal skin were performed with the Franz diffusion cell system. Confocal laser scanning microscopy (CLSM) was used to detect the localization and permeation pathways of drugs in the skin. Compared with commercially available gel (CA-gel) and NE, the NE-gel release process conformed to the Higuchi release model (R2 = 0.9813). NE-gel prolonged the drug release time and allowed for reduced administration dose and frequency. The unit cumulative permeation of NE and NE-gel through the skin for 12 h was 63.13 ± 2.78 and 42.53 ± 2.06 µg/cm2, respectively, values significantly higher (p < 0.01) than that of the CA-gel (30.65 ± 1.25 µg/cm2) and CA-cream (15.21 ± 0.97 µg/cm2). The DES-NE and DES NE-gel skin drug retention was significantly higher than commercially available formulations (p < 0.01). Hence, the prepared NE-gel is a potential vehicle for improved topical DES delivery for better treatment of skin disorders.

Nanodefensin-encased hydrogel with dual bactericidal and pro-regenerative functions for advanced wound therapy.

Background: Host defense peptides (HDPs) have emerged as a novel therapeutic paradigm for wound management; however, their clinical applications remain a challenge owing to their poor pharmacological properties and lack of suitable pharmaceutical formulations. Nanodefensin (ND), a nanoengineered human α-defensin 5 (HD5), has shown improved pharmacological properties relative to the parent compound. In this study, we engineered a nanodefensin-encased hydrogel (NDEFgel), investigated the effects of NDEFgel on wound healing, and elucidated underlying mechanisms. Method: ND was chemically synthesized and tested functions by in vitro antimicrobial and scratch assays and western blotting. Different NDEFgels were evaluated by in vitro characterizations including degradation, drug release and antimicrobial activity. In full-thickness excisional murine models, the optimal NDEFgel was directly applied onto wound sites, and the efficacy was assessed. Moreover, the underlying mechanisms of pro-regenerative effect developed by NDEFgel were also explored. Results: Apart from bactericidal effects, ND modulated fibroblast behaviors by promoting migration and differentiation. Among the tested hydrogels, the Pluronic F127 (Plu) hydrogel represented the most desirable carrier for ND delivery owing to its favorable controlled release and compatibility with ND. Local treatment of NDEFgel on the wound bed resulted in accelerated wound regeneration and attenuated bacterial burden. We further demonstrated that NDEFgel therapy significantly upregulated genes related to collagen deposition and fibroblasts, and increased the expression of myofibroblasts and Rac1. We therefore found that Rac1 is a critical factor in the ND-induced modulation of fibroblast behaviors in vitro through a Rac1-dependent cytoskeletal rearrangement. Conclusion: Our results indicate that NDEFgel may be a promising dual-action therapeutic option for advanced wound management in the future.

Targeting potential of alginate-glycyl-prednisolone conjugate nanogel to inflamed joints in rats with adjuvant-induced arthritis.

The efficacy of alginate-glycyl-prednisolone conjugate nanogel (AL-GP-NG) was previously reported to be better than that of prednisolone (PD) alone in arthritic rats. In the present study, novel AL-GP-NG was prepared and its targeting potential was investigated. AL-GP-NG with a PD content of 6.3% (w/w) was obtained and had a slightly larger submicron size and similar zeta potential to that of the previous nanogel. Drug release profiles and pharmacokinetic features were similar to those of the previous nanogel. AL-GP-NG showed prolonged release at weakly acidic and neutral pH and the good systemic retention of total (free + conjugated) PD after an intravenous (i.v.) injection in rats. In animal studies using normal and adjuvant-induced arthritic rats, the distribution of total PD was examined after an i.v. injection. AL-GP-NG achieved a markedly higher drug concentration at inflamed joints than PD alone. Furthermore, ALGP-NG showed specific drug localisation to inflamed joints in arthritic rats, but not in normal rats. Furthermore, specific drug localisation to the joints by AL-GP-NG persisted. Collectively, these results demonstrated the good targeting potential of AL-GP-NG to inflamed joints, suggesting its suitability for the treatment of arthritis.

ICG/5-Fu coencapsulated temperature stimulus response nanogel drug delivery platform for chemo-photothermal/photodynamic synergetic therapy.

The multiple diagnosis and treatment mechanisms of chemotherapy combined with photothermal/photodynamic therapy have very large application prospects in the field of cancer treatment. Therefore, in order to achieve effective and safe antitumour treatment, it is necessary to design an intelligent responsive polymer nanoplatform as a drug delivery system. Herein, the thermosensitive poly-N-isopropylacrylamide (PNIPAM) nanogel particles were prepared by soap-free emulsion polymerization and loaded with a large amount of photosensitizer indocyanine green (ICG) and anticarcinogen 5-fluorouracil (5-Fu), which effectively to realize the cooperative chemotherapy and photothermal/photodynamic therapy for tumours. The 5-Fu@ICG-PNIPAM nanogels significantly improved the bioavailability of the drug and achieved controlled release. In addition, under near-infrared laser (NIR) irradiation at 808 nm, 5-Fu@ICG-PNIPAM nanogels generated lots of heat and reactive oxygen, which significantly enhanced cellular uptake and in vitro antitumour treatment effects. The results showed that 5-Fu@ICG-PNIPAM nanogels were effectively endocytosed by HeLa cells, which also enhanced the drug's entrance into the nucleus. Moreover, compared with alone chemotherapy or photothermal/photodynamic therapy, 5-Fu@ICG-PNIPAM nanogels significantly increased cytotoxicity under NIR irradiation, suggesting that chemotherapy and photothermal/photodynamic synergistic therapy had excellent antitumour properties. Therefore, this temperature-responsive nanogel platform probably has great application prospects in clinical antitumour treatment.

Contrasting the efficacy of pulsed dye laser and photodynamic methylene blue nanoemulgel therapy in treating acne vulgaris.

The treatment of acne remains a challenge for dermatologists. A variety of conventional therapies are available for acne treatment such as topical and systemic medications. Although many of these traditional acne treatments are effective, the wide-spread nature of the disease and its sometimes resistant nature delineate the need for alternative therapies. Therefore, over the past decade, phototherapy has been introduced for the treatment of acne, such as pulsed dye lasers (PDLs) and photodynamic therapy (PDT). The aim of this study was to compare the safety and efficacy of PDL and methylene blue-mediated photodynamic therapy (MB-PDT) in the treatment of mild to moderate acne. Split-face clinical trial including fifteen patients presenting with mild to moderate acne were treated with 585 nm PDL on the right side of the face and MB-PDT with 665-nm diode laser on the left side. The photosensitizer MB was prepared in nanoemulgel formulation, and the treatment was carried out for three sessions maximum at 2-weeks intervals. Results revealed that both PDL and MB-PDT were effective therapies in the treatment of acne, as manifested by the reduction of inflammatory and non-inflammatory lesions throughout the treatment period. However, the latter therapy was proven more potent in the reduction of acne severity, and in terms of patients' tolerance. Therefore, it can be concluded that MB in the nanoemulgel form is a promising treatment approach for acne, and can be further experimented in the treatment of other dermatological diseases.

Intra-articular injection of anti-inflammatory peptide-loaded glycol chitosan/fucoidan nanogels to inhibit inflammation and attenuate osteoarthritis progression.

Glycol chitosan/fucoidan nanogels loaded with anti-inflammatory peptide KAFAK (GC/Fu@KAFAK NGs) were fabricated based on the electrostatic interaction and genipin cross-linking methods. The prepared NGs had an average size of 286.3 ± 5.0 nm and positive surface charge of 14.0 ± 0.2 mV. The anti-inflammatory and chondro-protective effects of GC/Fu@KAFAK NGs were evaluated on interlecukin-1ß (IL-1ß)-stimulated rat chondrocytes. We found that GC/Fu@KAFAK NGs not only inhibited the expression of inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), but also enhanced the expression of chondrogenic markers type II collagen, aggrecan, and Sox9. More importantly, in rat osteoarthritis (OA) model, the intra-articular (IA) injection of GC/Fu@KAFAK NGs reduced glycosaminoglycan loss and diminished inflammatory cytokine release. In addition, GC/Fu@KAFAK NGs showed good biocompatibility both in vitro and in vivo. In conclusion, IA inject-able GC/Fu@KAFAK NGs might have great potential in OA treatment.

Rational Design of Nanogels for Overcoming the Biological Barriers in Various Administration Routes.

Nanogels have been identified as outstanding nanocarrier candidates for drug delivery due to their desirable physiochemical properties and versatile applicability for diverse therapeutic molecules and imaging probes. One of the main challenges that hinder the clinical translation of nanogels is the low efficiency of drug delivery to the target sites because of the complex biological barriers during the in vivo journey. The purpose of this review is to examine and summarize the recent advances on the rational design and structural modulation of nanogels to overcome the barriers and challenges on the way to the site of action following various dosing modes. In particular, the functional moieties or domains have been incorporated in the nanogels, allowing them to spontaneously regulate their structure and physiochemical properties to cross one or more of the multifaceted barriers. In addition, the future perspectives are presented with regards to opportunities and challenges for the precise and efficient therapeutic use of nanogel formulations.

Glycyrrhizin mediated liver-targeted alginate nanogels delivers quercetin to relieve acute liver failure.

Acute liver failure is an uncommon and dramatic clinical syndrome with a high risk of mortality. Previous treatments existed some limitations of poor bioavailability and targeting the efficiency of drugs. In this study, a novel glycyrrhizin mediated liver-targeted alginate nanogels, which can deliver the antioxidant quercetin to the liver for the treatment of acute liver injury. In vitro radical scavenging results showed that the antioxidant activity of quercetin was increased 81-fold. The tissue distribution results indicated that glycyrrhizin-mediated nanogels showed stronger fluorescence intensity in the liver, which improved liver targeting and therapeutic efficacy. Quercetin-glycyrrhizin nanogels were more effective at restoring liver injury as indicated on serum markers, including alanine transaminase, aspartate aminotransferase, and total bilirubin. The histopathology result showed that quercetin-glycyrrhizin nanogels reversed liver damage. Oxidative parameters of malondialdehyde and glutathione s-transferase were decreased, which provided supporting evidence of antioxidation. Moreover, quercetin-glycyrrhizin nanogels were more effective in down-regulating the inflammation-related gene expression of tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase and monocyte chemotactic protein-1. In conclusion, the novel glycyrrhizin mediated liver-targeted alginate nanogels might be a promising treatment for acute liver failure.

Folate conjugated hyaluronic acid coated alginate nanogels encapsulated oxaliplatin enhance antitumor and apoptosis efficacy on colorectal cancer cells (HT29 cell line).

Oxaliplatin (OXA) has been widely used for treatment of colorectal cancer. In this study, to enhance antitumor and apoptosis efficacy, OXA was encapsulated in a novel folate conjugated hyaluronic acid coated alginate nanogels (F/HA/AL/OXA). The F/HA/AL/OXA nanogels were prepared by cross-linking process. The physico-chemical properties of F/HA/AL/OXA nanogels were characterized using scanning electron microscopy, transmission electron microscopy, fourier transform infrared spectroscopy, dynamic light scattering, and fluorescent spectrophotometry. The in-vitro antitumor activity of free OXA, AL, HA/AL, HA/AL/OXA and F/HA/AL/OXA nanogels were assessed using MTT assay against colorectal cancer cells (HT29 cell line). Finally, the effect of F/HA/AL/OXA nanogels on genes expression of Bax and Bcl2 was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) technique. The F/HA/AL/OXA nanogels were 200.3 nm in diameter and had a zeta potential of -22.0 mv. Antitumor activity of F/HA/AL/OXA nanogels on HT29 cell line indicated the highest antitumor activity as compared to free OXA and the empty nanogels. Compared to free OXA and the empty nanogels, the expression of Bax in HT29 cells treated with F/HA/AL/OXA nanogels was significantly increased along with suppression of Bcl-2 (p < .01). In general, the present F/HA/AL/OXA nanogels are a promising carrier candidate for OXA to improve the anti-tumor activity.

Contact lenses as drug-delivery systems: a promising therapeutic tool. / Lentes de contacto para vehiculizar principios activos: una prometedora herramienta terapéutica.

The ocular administration of drugs using traditional pharmaceutical forms, including eye drops or ointments, results in low bioavailability, as well as requiring multiple administrations per day, with the consequent danger of therapeutic non-compliance. Although, through the use of pharmaceutical technology, attempts have been made to use various solutions in order to increase bioavailability in the most common pharmaceutical forms, it has not been entirely satisfactory. In this context, contact lenses are presented as drug delivery systems that largely remedy these two major problems and offer other additional advantages. Therefore, the use of contact lenses as drug carrying systems has been increasingly investigated in recent years, as they can increase the bioavailability of these drugs, leading to an increase in therapeutic efficacy and compliance. The main techniques used to achieve this goal are included in this review, including immersion in drug solutions, use of vitamin E barriers, molecular printing, colloidal systems, etc. The most interesting results, depending on the different eye pathologies, are presented. Although the use of contact lenses as a vehicle for the release of active ingredients is a relatively novel strategy, there are already many studies and trials that support it. In any case, further research needs to be carried out to finally reach an effective, safe, and stable product that can be marketed.

Magnesium oil enriched transdermal nanogel of methotrexate for improved arthritic joint mobility, repair, and reduced inflammation.

Aim: Methotrexate (Mtx) is prescribed to reduce pain and inflammation in arthritis patients; however, improved repair and mobility of joints still are the major concerns. Magnesium oil (MO) improves joint mobility and repair; therefore, MO-assisted transdermal delivery of Mtx was aimed.Methods: MO integrated Mtx nanoemulsion (Mtx-MONE) was prepared with uniform size (175 ± 35.4 nm), pH (6.15 ± 0.3) near to skin pH, and high entrapment efficiency (65 ± 8.6%). Mtx-MONE was transformed to nanogel (Mtx-MONEG) with semisolid consistency (43,408 ± 77.72 cP) and good spreadability (3.63 ± 0.033 mJ).Results: Mtx-MONEG showed significant reduction in oedema, arthritic scores, level of inflammatory cytokines, and improved walking as compared to diseased control. MO offered additional improvements in joints, mobility, and repair.Conclusion: Transdermal delivery of Mtx has been successfully achieved by Mtx-MONEG. Tremendous recovery from inflammation, improved joints mobility and repair, and reduced pain strongly support the use of MO as an adjutant of Mtx for improved transdermal application.

NIR- and thermo-responsive semi-interpenetrated polypyrrole nanogels for imaging guided combinational photothermal and chemotherapy.

Versatile, multifunctional nanomaterials for theranostic approaches in cancer treatment are highly on demand in order to increase therapeutic outcomes. Here, we developed thermo-responsive nanogels equipped with the efficient near-infrared (NIR) transducing polymer polypyrrole (PPY) for combinational photothermal and chemotherapeutic therapy along with photoacoustic imaging ability. Long-term stability and water-dispersibility of PPY was achieved using semi-interpenetration method for in situ polymerization of PPY into hydrophilic thermo-responsive nanogels. The semi-interpenetrated nanogels of spherical shape and with hydrodynamic sizes of around 200 nm retained the temperature response behaviour and exhibit excellent photothermal transducing abilities in the NIR region. The PPY nanogels served as photoacoustic contrast agents, which allowed determination of biodistribution profiles ex vivo. In addition, we developed a new method for biodistribution determination based on the photothermal response of the nanogels with an accuracy down to 12.5 µg/mL. We examined the ability of the nanogels as photothermal agents and drug delivery systems in vitro and in vivo. We showed that they efficiently inhibit tumor growth with combinational effects of chemotherapeutics and photothermal treatment. Our work encourages further exploration of nanogels as functional stabilizing matrix for photothermal transducers and their application as drug delivery devices in combination with photothermal therapy and imaging.