Stimuli-sensitive biomimetic nanoparticles for the inhibition of breast cancer recurrence and pulmonary metastasis.

Biomimetic nanoparticles represent a promising avenue for mitigating rapid clearance by the reticuloendothelial system (RES); however, current challenges include insufficient tumour targeting, suboptimal adhesion, and inadequate localized drug release within tumour regions. These shortcomings contribute to persistent contests, such as recurrence and pulmonary metastasis, even with advanced breast cancer therapies. Stimuli-sensitive drug release can furbish the membrane coated nanoparticles for their efficiency against the stated problems. To enhance the efficacy of biomimetic nanoparticles in addressing these issues, we proposed a versatile, stimuli-responsive drug delivery system by encapsulating doxorubicin (Dox) and perfluorohexane (PFH) within poly (lactic-co-glycolic acid) (PLGA) nanoparticles, subsequently coated with macrophage-derived cell membranes. Within this framework, PFH serves as the mediator for ultrasonic (US)-irradiation-triggered drug release specifically within tumour microenvironment, while the macrophage-derived cell membrane coating enhances cell adhesion, enables immune evasion, and natural tumour-homing ability. The characterization assays and in vitro evaluations yielded encouraging results, indicating enhanced targeting and release efficiencies. In vivo studies demonstrated marked inhibitory effects on both breast cancer recurrence and pulmonary metastasis. The resulting data indicate that these engineered nanoparticles have notable potential for targeted delivery and controlled release upon US irradiation, thereby offering significant therapeutic efficacy against primary breast cancer, pulmonary metastasis, and recurrent malignancies. Our findings lay the groundwork for a novel clinical approach, representing an intriguing direction for ongoing investigation by oncologists.

Rationalized landscape on protein-based cancer nanomedicine: Recent progress and challenges.

The clinical advancement of protein-based nanomedicine has revolutionized medical professionals' perspectives on cancer therapy. Protein-based nanoparticles have been exploited as attractive vehicles for cancer nanomedicine due to their unique properties derived from naturally biomacromolecules with superior biocompatibility and pharmaceutical features. Furthermore, the successful translation of Abraxane™ (paclitaxel-based albumin nanoparticles) into clinical application opened a new avenue for protein-based cancer nanomedicine. In this mini-review article, we demonstrate the rational design and recent progress of protein-based nanoparticles along with their applications in cancer diagnosis and therapy from recent literature. The current challenges and hurdles that hinder clinical application of protein-based nanoparticles are highlighted. Finally, future perspectives for translating protein-based nanoparticles into clinic are identified.

Albumin-coated green-synthesized zinc oxide nanoflowers inhibit skin melanoma cells growth via intra-cellular oxidative stress.

Zinc oxide (ZnO) has attracted a substantial interest in cancer research owing to their promising utility in cancer imaging and therapy. This study aimed to synthesized ZnO nanoflowers coated with albumin to actively target and the inhibit skin melanoma cells. We synthesized bovine serum albumin (BSA)-coated ZnO nanoflowers (BSA@ZnO NFs) and evaluated it's in vitro and in vivo therapeutic efficacy for skin cancer cells. BSA@ZnO NFs were prepared via single-step reduction method in the presence of plant extract (Heliotropium indicum) act as a capping agent, and further the successful fabrication was established by various physico-chemical characterizations, such as scanning electron microscopy (SEM), Fourier transform infra-red (FT-IR) spectroscopy, and x-rays diffraction (XRD) analysis. The fabricated BSA@ZnO NFs appeared flower like with multiple cone-shaped wings and average hydration size of 220.8 ± 12.6 nm. Further, BSA@ZnO NFs showed enhanced cellular uptake and cytocidal effects against skin cancer cells by inhibiting their growth via oxidative stress compared uncoated ZnO NFs. Moreover, BSA@ZnO NFs showed enhance biosafety, blood circulation time, tumor accumulation and in vivo tumor growth inhibition compared to ZnO NFs. In short, our findings suggesting BSA@ZnO NFs as a promising candidate for various types of cancer treatment along with chemotherapy.

Bio-evaluations of sericin coated hesperidin nanoparticles for gastric ulcer management.

Gastric ulcers are worrying, and their worsening conditions may result in bleeding in the internal lining of the stomach. The problem is annoying, and both patients and professionals are still not satisfied with the available treatment options. Hesperidin, a flavonoid molecule with potent anti-inflammatory and antioxidant effects, can work like witchcraft to repair gastric ulcers and preserve the stomach lining. Here, we employed a strategy that involved covering the surface of the nano-lipid carriers (NLCs) with sericin before encasing the hesperidin within (Se-He-NLC). Sericin, a biodegradable polymer increases the muco-adhesion with stomach lining and deployment of hesperidin in controlled manner. Se-He-NLCs were physico-chemically characterized for drug loading, encapsulation, particle size, morphology, drug release, chemical stability, and chemical bonding. The nanocarriers showed first order drug release in a controlled manner. Se-He-NLCs showed better in vitro permeation and ex vivo mucoadhesion, thereby by promoting the in vivo bioavailability. Se-He-NLCs also promoted the reduced glutathione (GSH) and glutathione-S-transferase (GST) levels by 2.24- and 1.61-folds, respectively in the stomach lining, and also the regulation of superoxide dismutase (SOD) and catalase (CAT) activities parallel to the control group. In addition, tissues lipid hydroperoxides (LOOH) and myeloperoxidase (MPO) activity were reduced significantly with Se-He-NLCs administration. Se-He-NLC therapy of stomach ulcers in vivo demonstrated better binding ratio and ulcer healing potential. This approach reveals huge capacity for delivering therapies to treat gastric ulcers based on the clinical significance of sericin coated hesperidin nanocarriers in gastric ulcer treatment.

Loratadine oral bioavailability enhancement via solid dispersion loaded oro-dispersible films: Formulation, characterization and pharmacokinetics.

Loratadine (LRD) belongs to second-generation tricyclic H1 antihistamine class, known for its non-sedating properties in allergic reactions. H1 antihistamines avoid and block the responses to allergens or histamine in nose and conjunctivae, thereby abolishing itching, congestion and sneezing. LRD is a Biopharmaceutical Class System (BCS) class II drug with dissolution or solubility limited absorption which limited the oral bioavailability and therapeutic efficacy of LRD. To improve the oral bioavailability of LRD for allergic disease (urticaria) treatment, LRD solid dispersions (LRD-SDs) were integrating into oro-dispersible films (ODFs). LRD-SDs were prepared through hot-melt extrusion method (HME) using d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS-1000), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SP). Subsequently, LRD-SDs were incorporated in ODFs by solvent casting method. The physicochemical and mechanical properties of LRD solid dispersions-loaded oro-dispersible films (LRD-SDs-ODFs), were evaluated. The in-vitro dissolution, ex-vivo permeation, oral bioavailability, and pharmacodynamics studies were conducted to evaluate LRD-SDs-ODFs efficiency. LRD-SDs-ODFs showed superior solubility and in-vitro dissolution results compared to that of pure LRD (p < 0.05). The solubility of the LRD-SD coded as LTS-4 was 190 times higher than the pure drug in aqueous media. The average hydrodynamic particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of SD particles were 76 ± 2.1 nm, 0.20 ± 0.08 and - 19.16 ± 1.4 mV, respectively. Moreover, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results confirmed the amorphousness of LRD in LRD-SDs-ODFs. The permeability flux of LRD was 44.6 ± 3.1 µg/cm2/h from DPF-5 formulation. Likewise, in vivo oral bioavailability of DPF-5 in Sprague-Dawley rats was significantly increased (p < 0.05) compared to free LRD. Further, wheal area was reduced 20 % higher than LRD in 8 h (p < 0.05). Overall, LRD-SDs-ODFs considerably enhanced LRD solubility, dissolution rate, bioavailability, and antihistaminic efficacy. Our findings show that SDs-ODFs is an effective carrier system for delivering poorly soluble LRD.

Chitosan/poly (3-hydroxy butyric acid-co-3-hydroxy valeric acid) electrospun nanofibers with cephradine for superficial incisional skin wound infection management.

The belated and compromised incisional skin wound healing caused by the invading of methicillin-resistance staphylococcus aureus is a serious problem in clinic. Designing a new therapeutic strategy to inhibit the growth of invading bacteria at post-surgical site might be helpful in fast healing of post-surgical wounds. In this study, we developed cephradine (Ceph) encapsulated chitosan and poly (3-hydroxy butyric acid-co-3-hydroxy valeric acid, (PHBV)) hybrid nanofibers (Ceph-CHP NFs) employing an electrospinning method to revamp the Ceph bioavailability at the post-surgical wound site to prevent the growth of invading bacteria and trigger the wound healing process. The fabricated nanofibers revealed smooth and uniform surface with a diameter range of 160 ± 25 to 190 ± 55 nm, depending on Ceph concentration. Further, the electrospun hybrid nanofibers exhibited a higher entrapment efficiency (EE) and drug loading capacity (DLC) nearly 72.8 ± 5.2 % and 16.5 ± 3.2 %, respectively. Moreover, the Ceph-CHP NFs showed high swelling rate and biodegradation in presence of lysozyme in contrast to blank CHP NFs. Ceph-CHP NFs exhibited fast drug release in initial few hours followed by slow and controlled drug release drug up to 48 h with a constant rate. In-vitro antimicrobial studies indicated the heightened efficacy of Ceph-CHP NFs against MRSA clinical isolates and exhibited no visible cytotoxicity against keratinocytes, HC11 and L929 cells. Lastly, Ceph-CHP NFs showed the enhanced wound healing and bacterial clearance from post-surgical wound compared to Ceph in C57BL/6 mice skin model. Overall, our results showed that Ceph-CHP NFs might be used as a promising wound dressing material for MRSA-infected post-surgical wounds.

Eco-Friendly Sustainable Nanocarriers to Treat Oxidative Stresses and Skin Aging-Related Ailments, Valorization of a By-Product.

The peel from Citrus-sinensis L. is a medicinally significant food waste, and its extract (O-Ext) could be significant against oxidative stresses and skin aging, However, the penetration barriers, instability in formulation, undefined toxicities, and enzymatic activities make the O-Ext difficult to formulate and commercialize. The goal of this study was to evaluate O-Ext against oxidative stress, prepare O-Ext-loaded nano-lipid carriers (O-NLCs), and load them into topical O/W-emulsion (O-NLC-E) to improve O-Ext permeation and its in vivo antiaging effects. TPC, TFC, DPPH activity, and mineral/metal contents of O-Ext were determined via atomic-absorption spectroscopy. For bioactive compounds profiling, GC-MS analysis was carried out. O-NLCs were prepared and tested for physicochemical attributes, while HaCaT and fibroblast cells were used to study permeation and cytotoxicity. The kinetic characteristics of ex vivo permeation through rat skin were established, following the Higuchi model. Following written consent, safety investigations were conducted on human volunteers for three months, where optimized O-NLC-E and B-NLC-E were regularly applied on cheeks. Non-invasive procedures were used to assess the volunteer's skin erythema, TEWL, sebum level, melanin, hydration, pH, elasticity, and pore sizes after specified intervals. The results demonstrated that applying O-NLC-E formulation to the skin of volunteers directed significant antiaging benefits. The study offers nanotechnology-based sustainability approach against skin ageing.

pH-responsive albumin-coated biopolymeric nanoparticles with lapatinab for targeted breast cancer therapy.

One can enhance the therapeutic index of anti-cancer drugs using albumin as a tumor homing agent for targeted cancer therapy. Herein, we sought to load lapatinib (LAPA) into small albumin-coated biopolymeric (poly-lactic co-glycolic acid (PLGA)) nanoparticles (APL NPs) by an emulsification method to improve the anti-tumor efficacy of lapatinib. The prepared APL NPs exhibited a small spherical core with an average diameter of 120.5 ± 10.2 nm with a narrow particle size distribution, high drug loading capacity (LC of 9.65 ± 1.53 %), good entrapment efficiency (EE of 75.55 ± 3.25 %), enhanced colloidal stability and a pH-responsive controlled drug release profile. Their cell-uptake and cancer cell growth inhibition were significantly higher compared to free LAPA and uncoated PLGA-LAPA (UPL) NPs, most likely because aggressive breast tumor cells over-express albumin receptors and utilize albumin as nutrient source for their growth. In addition, APL NPs possessed enhanced tumor accumulation and prolonged blood residence time compared to free LAPA and UPL NPs, allowing for potent tumor growth inhibition while exhibiting excellent biosafety. In short, the current study exploited a new and simple strategy to concurrently improve the safety and efficacy of LAPA for breast cancer treatment.

Effectiveness of Roflumilast in Treating Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

Background Chronic obstructive pulmonary disease (COPD) is a chronic airflow obstructive condition. The mainstay of treatment is to avoid exacerbation and manage the symptoms. Roflumilast is being used as a part of treatment to reduce the inflammatory process in this disease. Method This systematic review and meta-analysis were conducted following the provided guidelines. PubMed, Cochrane Library, and Cinahl were considered for searching the desired studies selected until 19 June 2021. The eligibility criteria for inclusion and exclusion were set before selecting studies. Result Five hundred eighty (580) studies were identified at the beginning. Removal of duplicates was done using Endnote software. The eligibility criteria, including the randomized controlled trial study design and others, were applied for screening the title and abstracts. Six studies were selected for the qualitative analysis. After assessing the data from these studies, it was found that roflumilast is an effective drug to treat COPD. Roflumilast plays an essential role in improving quality of life, inflammatory process, and clinical improvement. The drug's mild to moderate adverse effects were observed, but no significant severe adverse events were reported, and the drug was well tolerated. Conclusion Roflumilast is a valuable drug that can be used for its beneficial effects on COPD exacerbation. The benefits of the drug outweigh its adverse effects.

Physicochemical Characterizations and Pharmacokinetic Evaluation of Pentazocine Solid Lipid Nanoparticles against Inflammatory Pain Model.

Pentazocine (PTZ), a narcotic-antagonist analgesic, has been extensively used in the treatment of initial carcinogenic or postoperative pain. Hepatic first-pass metabolism results in low oral bioavailability and high dose wastage. Herein, 10 mg (-)-Pentazocine (HPLC-grade) was incorporated to solid lipid nanoparticles (SLNs) using a double water-oil-water (w/o/w) emulsion by solvent emulsification-evaporation technique, followed by high shear homogenization to augment its oral bioavailability, considering the lymphatic uptake. The resulting SLNs were characterized for zeta potential (ZP), particle size (PS), and polydispersity index (PDI) using a zetasizer. The entrapment efficiency (EE) and loading capacity (LC) were calculated. Chemical interactions, through the identification of active functional groups, were assessed by Fourier-transformed infrared (FTIR) spectroscopy. The nature (crystallinity) of the SLNs was determined by X-ray diffractometry (XRD). The surface morphology was depicted by transmission electron microscopy (TEM). In vitro (in Caco-2 cells) and in vivo (in male Wistar rats) investigations were carried out to evaluate the PTZ release behavior and stability, as well as the cellular permeation, cytotoxicity, systemic pharmacokinetics, antinociceptive, anti-inflammatory, and antioxidative activities of PTZ-loaded SLNs, mainly compared to free PTZ (marketed conventional dosage form). The optimized PTZ-loaded SLN2 showed significantly higher in vitro cellular permeation and negligible cytotoxicity. The in vivo bioavailability and pharmacokinetics parameters (t1/2, Cmax) of the PTZ-loaded SLNs were also significantly improved, and the nociception and inflammation, following carrageenan-induced inflammatory pain, were markedly reduced. Concordantly, PTZ-loaded SLNs showed drastic reduction in the oxidative stress (e.g., malonaldehyde (MDA)) and proinflammatory cytokines (e.g., Interleukin (IL)-1ß, -6, and TNF-α). The histological features of the paw tissue following, carrageenan-induced inflammation, were significantly improved. Taken together, the results demonstrated that PTZ-loaded SLNs can improve the bioavailability of PTZ by bypassing the hepatic metabolism via the lymphatic uptake, for controlled and sustained drug delivery.

Two Promising Anti-Cancer Compounds, 2-Hydroxycinnaldehyde and 2- Benzoyloxycinnamaldehyde: Where do we stand?

Natural bioactive compounds with anti-carcinogenic activity are gaining tremendous interest in the field of oncology. Cinnamon, an aromatic condiment commonly used in tropical regions, appeared incredibly promising as an adjuvant for cancer therapy. Indeed, its whole or active parts (e.g., bark, leaf) exhibited significant anti-carcinogenic activity, which is mainly due to two cinnamaldehyde derivatives, namely 2-hydroxycinnaldehyde (HCA) and 2- benzoyloxycinnamaldehyde (BCA). In addition to their anti-cancer activity, HCA and BCA exert immunomodulatory, anti-platelets, and anti-inflammatory activities. The highly reactive α,ßunsaturated carbonyl pharmacophore, called Michael acceptor, contributes to their therapeutic effects. The molecular mechanisms underlying their anti-tumoral and anti-metastatic effects are miscellaneous, strongly suggesting that these compounds are multi-targeting compounds. Nevertheless, unravelling the exact molecular mechanisms of HCA and BCA remains a challenging matter which is necessary for optimal controlled-drug targeting delivery, safety, and efficiency. Eventually, their poor pharmacological properties (e.g., systemic bioavailability and solubility) represent a limitation and depend both on their administration route (e.g., per os, intravenously) and the nature of the formulation (e.g., free, smart nano-). This concise review focused on the potential of HCA and BCA as adjuvants in cancer. We describe their medicinal effects as well as provide an update about their molecular mechanisms reported either in-vitro, ex-vivo, or in animal models.

Orbital mucormycosis - Post SARS-CoV-2 sequelae.

Multisystem involvement has not been uncommon in SARS-CoV-2 infection. There has been reports of devastating neurological complication both during and after the infection. Here we present a rare case of sino-orbital mucormycosis, diagnosis of which was confirmed on histopathology. Our patient presented with headache, 18 days after her recovery from SARS-CoV-2 infection and was extensively worked up for the cause. Initially she was treated as a severe sinusitis but failure to response to antibiotics treatment warranted for further investigations and imaging. Our patient had to undergo right eye enucleation plus debridement under general anesthesia. She is currently on anti-fungal treatment as advised by infectious disease department.

Time to think beyond door to balloon time: significance of total ischemic time in STEMI.

BACKGROUND: Significance of total ischemic time (TIT) in the context of ST-segment elevation myocardial infarction (STEMI) is still controversial. Therefore, in this study, we have evaluate the association of TIT with immediate outcomes in STEMI patients in whom recommended door to balloon (DTB) time of less than 90 min was achieved. RESULTS: A total of 5730 patients were included in this study, out of which 80.9% were male and median age was 55 [61-48] years. The median DTB was observed to be 60 [75-45] min and onset of chest pain to emergency room (ER) arrival time was 180 [300-120] min. Prolonged TIT was associated with poor pre-procedure thrombolysis in myocardial infarction (TIMI) flow grade (p = 0.022), number of diseased vessels (p = 0.002), use of intra-aortic balloon pump (p = 0.003), and in-hospital mortality (p = 0.002). Mortality rate was 4.5%, 5.7%, and 7.8% for the patients with TIT of ≤ 120 min, 121 to 240 min, and > 240 min, respectively. Thirty days' risk of mortality on TIMI score was 4.97 ± 7.09%, 5.01 ± 6.99%, and 7.12 ± 8.64% for the patients with TIT of ≤ 120 min, 121 to 240 min, and > 240 min, respectively. CONCLUSIONS: Prolonged total ischemic was associated with higher in-hospital mortality. Therefore, TIT can also be considered in the matrix of focus, along with DTB time and other clinical determinants to improve the survival from STEMI.

Neurological complications of SARS-CoV-2: A single-center case series authors.

The neurological manifestations of SARS-CoV-2 are wide-ranging from simple headache to severe demyelinating brain disease. This is a review of collected case reports of patients with SARS-CoV-2 with neurological manifestations presenting to the Pakistan Institute of Medical Sciences (PIMS). Neurological manifestations associated with SARS-CoV-2 such as encephalitis, acute cerebrovascular disease, encephalitis with chorea, post-COVID myositis and Guillain-Barré Syndrome (GBS) are of great concern but are often overlooked in the presence of life-threatening abnormal vital signs in severely ill SARS-CoV-2 patients. There is a need to diagnose these manifestations at the earliest opportunity to limit long-term consequences and complications. Much research is needed to explore the role of SARS-CoV-2 in causing these neurological manifestations by isolating it either from the cerebrospinal fluid (CSF) or the brain tissue of the deceased on autopsy. We also recommend exploring the risk factors that lead to the development of these neurological manifestations.

Ocular surface: A route for SARS CoV-2 transmission- a case report.

SARS-CoV-2 infections are transmitted through droplets or through direct contact with secretions from an infected person. The transmission of the virus through tears and other body secretions remains controversial. PCR detection of Covid-19 in the samples/swabs taken from nasopharynx, CSF fluid, and tears, clarifies that the virus may be transmitted through the modes other than aerosol droplets or direct contact. In order to control and prevent this infectious disease, cutting-off the route of transmission will be one of the most important steps. SARS-CoV-2 RNA has been detected in tears and conjunctival samples of patients. The ocular tropism of Covid-19 is still uncertain but contentious.

Breast Cancer Inhibition by Biosynthesized Titanium Dioxide Nanoparticles Is Comparable to Free Doxorubicin but Appeared Safer in BALB/c Mice.

Cancer remains a global health burden prompting affordable, target-oriented, and safe chemotherapeutic agents to reduce its incidence rate worldwide. In this study, a rapid, cost-effective, and green synthesis of titanium dioxide (TiO2) nanoparticles (NPs) has been carried out; Ex vivo and in vivoevaluation of their safety and anti-tumor efficacy compared to doxorubicin (DOX), a highly efficient breast anti-cancer agent but limited by severe cardiotoxicity in many patients.Thereby,TiO2 NPs were eco-friendly synthetized using aqueous leaf extract of the tropical medicinal shrub Zanthoxylum armatum as a reducing agent. Butanol was used as a unique template. TiO2 NPs were physically characterized by ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning electron microscope (SEM), X-ray powder diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR) as routine state-of-the art techniques. The synthesized TiO2 NPs were then evaluated for their cytotoxicity (by MTT, FACS, and oxidative stress assays) in 4T1 breast tumor cells, and their hemocompatibility (by hemolysis assay). In vivo anti-tumor efficacy and safety of the TiO2 NPs were further assessed using subcutaneous 4T1 breast BALB/c mouse tumor model.The greenly prepared TiO2 NPs were small, spherical, and crystalline in nature. Interestingly, they were hemocompatible and elicited a strong DOX-like concentration-dependent cytotoxicity-induced apoptosis both ex vivo and in vivo (with a noticeable tumor volume reduction). The underlying molecular mechanism was, at least partially, mediated through reactive oxygen species (ROS) generation (lipid peroxidation). Unlike DOX (P < 0.05), it is important to mention that no cardiotoxicity or altered body weight were observed in both the TiO2 NPs-treated tumor-bearing mouse group and the PBS-treated mouse group (P > 0.05). Taken together, Z. armatum-derived TiO2 NPs are cost-effective, more efficient, and safer than DOX. The present findings shall prompt clinical trials using green TiO2 NPs, at least as a possible alternative modality to DOX for effective breast cancer therapy.

Evaluation of the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating type 2 diabetes among Chinese Han patients.

Genetic polymorphisms in the MTNR1B gene is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This prospective case-control study was designed to investigate the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating T2DM. We genotyped untreated T2DM patients (N = 200) and healthy controls (N = 200) using the method of the high resolution of melting curve (HRM). Newly diagnosed T2DM patients (n = 60) with CYP2C9*1 and SLCO1B1 521TT genotypes were enrolled and given oral nateglinide (360 mg/d) for 8 weeks. The outcome was measured by collecting the venous blood samples before and at the 8th week of the treatment. The risk G allelic frequency of MTNR1B rs10830963 was higher in T2DM patients than the healthy subjects (P < 0.05). Post 8-week of treatment, newly diagnosed T2DM patients showed a less reduction in fasting plasma glucose levels and less increase in the carriers of genotype CG + GG at rs10830963 when compared with the CC genotype (P < 0.05). MTNR1B rs10830963 polymorphism was associated with the therapeutic efficacy of nateglinide in T2DM patients. Also, the CC homozygotes had a better effect than G allele carriers.Trial registration Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment.

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.

Development of Cephradine-Loaded Gelatin/Polyvinyl Alcohol Electrospun Nanofibers for Effective Diabetic Wound Healing: In-Vitro and In-Vivo Assessments.

Diabetic wound infections caused by conventional antibiotic-resistant Staphylococcus aureus strains are fast emerging, leading to life-threatening situations (e.g., high costs, morbidity, and mortality) associated with delayed healing and chronic inflammation. Electrospinning is one of the most widely used techniques for the fabrication of nanofibers (NFs), induced by a high voltage applied to a drug-loaded polymer solution. Particular attention is given to electrospun NFs for pharmaceutical applications (e.g., original drug delivery systems) and tissue regeneration (e.g., as tissue scaffolds). However, there is a paucity of reports related to their application in diabetic wound infections. Therefore, we prepared eco-friendly, biodegradable, low-immunogenic, and biocompatible gelatin (GEL)/polyvinyl alcohol (PVA) electrospun NFs (BNFs), in which we loaded the broad-spectrum antibiotic cephradine (Ceph). The resulting drug-loaded NFs (LNFs) were characterized physically using ultraviolet-visible (UV-Vis) spectrophotometry (for drug loading capacity (LC), drug encapsulation efficiency (EE), and drug release kinetics determination), thermogravimetric analysis (TGA) (for thermostability evaluation), scanning electron microscopy (SEM) (for surface morphology analysis), and Fourier-transform infrared spectroscopy (FTIR) (for functional group identification). LNFs were further characterized biologically by in-vitro assessment of their potency against S. aureus clinical strains (N = 16) using the Kirby-Bauer test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, by ex-vivo assessment to evaluate their cytotoxicity against primary human epidermal keratinocytes using MTT assay, and by in-vivo assessment to estimate their diabetic chronic wound-healing efficiency using NcZ10 diabetic/obese mice (N = 18). Thin and uniform NFs with a smooth surface and standard size (<400 nm) were observed by SEM at the optimized 5:5 (GEL:PVA) volumetric ratio. FTIR analyses confirmed the drug loading into BNFs. Compared to free Ceph, LNFs were significantly more thermostable and exhibited sustained/controlled Ceph release. LNFs also exerted a significantly stronger antibacterial activity both in-vitro and in-vivo. LNFs were significantly safer and more efficient for bacterial clearance-induced faster chronic wound healing. LNF-based therapy could be employed as a valuable dressing material to heal S. aureus-induced chronic wounds in diabetic subjects.