pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC resistance to GEM could be due to ERK1/2 activity. However, successful ERKi therapy is hindered due to low ligand efficiency, poor drug delivery, and toxicity. In this study, to overcome these limitations, we have designed pH-responsive nanoparticles (pHNPs) with a size range of 100-150 nm for the simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses. These pHNPs are polyethylene glycol (PEG)-containing amphiphilic polycarbonate block copolymers with tertiary amine side chains. They are systemically stable and capable of improving in vitro and in vivo drug delivery at the cellular environment's acidic pH. The functional analysis indicates that the nanomolar doses of ERKi or GEM significantly decreased the 50% growth inhibition (IC50) of PDAC cells when encapsulated in pHNPs compared to free drugs. The combination of ERKi with GEM displayed a synergistic inhibitory effect. Unexpectedly, we uncover that the minimum effective dose of ERKi significantly promotes GEM activities on PDAC cells. Furthermore, we found that pHNP-encapsulated combination therapy of ERKi with GEM was superior to unencapsulated combination drug therapy. Our findings, thus, reveal a simple, yet efficient, drug delivery approach to overcome the limitations of ERKi for clinical applications and present a new model of sensitization of GEM by ERKi with no or minimal toxicity.

Quality by design (Qbd) assisted development of phytosomal gel of aloe vera extract for topical delivery.

The aim of the current study was to develop the phytosomal gel of aloe vera extract for improved topical delivery. Aloe vera extract loaded phytosomal system was developed by fixing the amount of aloe vera extract and ethanol and by varying the concentration of lecithin (0.15-0.25% w/v) and speed of rotation (80-120 rpm). Different formulation batches were prepared as per the Design expert software. A 22 Factorial design was applied to optimize the formulation on the basis of vesicular size and entrapment efficiency. Developed formulations were evaluated for vesicular size, entrapment efficiency, PDI, zeta potential and in-vitro release. Further stability studies were also performed. For the optimized formulation (F09), vesicular size, entrapment efficiency and PDI were found as 123.1 ± 1.44 nm, 95.67 ± 0.27% and 0.98 ± 0.06. Zeta potential of -11.9 mV and drug release of 56.91 ± 4.1% obtained in 24 h. Drug release kinetics from the phytosomes follows Higuchi model. TEM micrograph confirms the uniform structure of phytosomes. Phytosomal gel of optimized phytosomal formulation (F09) was developed with 1% Carbopol 934 and physically characterized on the basis of pH, viscosity, homogeneity and drug content. Ex-vivo permeation study showed the better permeation and flux profile of phytosomal gel with the conventional aloe vera extract gel. Also, studies on phytosomal formulation and gel showed stability up-to 3 months. Thus overall, it can be concluded that the phytosomal gel is a good carrier for topical delivery of herbal extract such as aloe vera.

Preparation of levofloxacin loaded in situ gel for sustained ocular delivery: in vitro and ex vivo evaluations.

The major drawback of the eye drops is rapid elimination of drug from the precorneal region, thus ensuing poor bioavailability as well as therapeutic efficacy. To conquer these limitations, a pH triggered in situ gel was developed for sustained delivery of levofloxacin. Two polymers namely hydroxypropyl methylcellulose (HPMC) and sodium alginate along with the boric acid buffer were used to formulate the in situ gel. Based on the various physicochemical evaluation parameters like pH, clarity and gelling capacity placebo formulations were selected and further characterized for viscosity, in vitro release, ex vivo corneal permeation, and histopathological studies. The optimized in situ gel (F28) showed sustained release of 93 ± 4.23% for 24 h and cumulative drug permeation of 71.81 ± 4.7% for 72 h. Additionally, ocular irritation study and histopathology of the formulation treated cornea confirm the non-irritancy of the optimized formulation. Based on all the above performed studies, it can be concluded that the in situ gel would present a fruitful alternative for the ocular infections.

Three-dimensional eco-friendly bacterial nanocellulose (BNC) scaffold for regenerative dentistry: Characterization, cytocompatibility and differentiation potential.

OBJECTIVE: Regenerative dentistry (RD) is an innovative strategy for treating necrotic teeth and regenerating damaged dental tissue. Biocompatible materials are pivotal for the advancement of RD, and the rising interest in environmental sustainability drives exploration of sustainable materials for dentistry. Bacterial nanocellulose (BNC) has emerged as a promising eco-friendly option and this study aims to assess BNC's suitability as scaffolds for regenerative dentistry applications. METHODS: Different in vitro methods have been utilized to characterize the properties of BNC scaffolds in regenerative dentistry, such as scanning electron microscopy (SEM) to analyse surface property and porosity, as well as examining their absorption behaviour using phosphate-buffered saline and bovine serum. Dental pulp stem cell (DPSCs) attachment, viability, and proliferation were evaluated using SEM, live and dead, and tetrazolium reduction assays. The odontogenic potential of the scaffold was evaluated using Alizarin Red staining and qPCR (14 and 21 days). RESULTS: Scanning electron microscopy (SEM) images and ethanol displacement method demonstrated the porous architecture of the BNC scaffold with an average porosity of 70.02 ± 4.74% and 50.26 ± 1.43% respectively. The scaffold absorbed 2846.54 ± 258.95 of BSA and 1648.63 ± 50.37% PBS after immersion in solution for 1 h, following pseudo first and second order kinetics. The biocompatibility assay indicated that cell density increased with time and that the scaffold was appropriate for cell adhesion and migration. Moreover, the BNC led to significantly higher mineralization and odontogenic expression compared to the control (BNC in conditioned media). SIGNIFICANCE: BNC showed fast adsorption of bovine serum, allowed DPSC attachment, migration, and odontogenic differentiation. This suggests its suitability as a biocompatible scaffold for triggering in situ mineralized tissue regeneration for regenerative dental applications.

An Overview of the Dichotomous Role of Microbiota in Cancer Progression and Management.

It is a well-known fact that cancer is considered the second leading cause of mortality across the globe. Although the human oral cavity and intestine are the natural habitat of thousands of microbes, dysbiosis results in malignancies, such as oral squamous cell carcinoma and colorectal cancer. Amongst the intestinal microbes, H. pylori is a deadly carcinogen. Also, causative pathogens for the development of pancreatic and colorectal cancer are found in the oral cavity, such as Fusobacterium nucleatum and Porphyromonas gingivalis. Many periodontopathic micro- organisms, like Streptococcus sp., Peptostreptococcus sp., Prevotella sp., Fusobacterium sp., Porphyromonas gingivalis, and Capnocytophaga gingivalis, strongly have an impact on the development of oral cancers. Three basic mechanisms are involved in pathogen-mediated cancer development, like chronic inflammation-mediated angiogenesis, inhibition of cellular apoptosis, and release of carcinogenic by-products. Microbiota has a dichotomous role to play in cancer, i.e., microbiota can be used for cancer management too. Shreds of evidence are there to support the fact that microbiota enhances the chemotherapeutic drug efficacy. This review presents the possible mechanism of the oncogenic effect of microbiota with emphasis on the oral microbiome and also attempts to explain the intricate role of microbiota in cancer management.

QbD-Assisted Development and Optimization of Doxycycline Hyclate- and Hydroxyapatite-Loaded Nanoparticles for Periodontal Delivery.

The current research aims to develop a carrier system for the delivery of a matrix metalloproteinase (MMP) inhibitor along with a bioceramic agent to the periodontal pocket. It is proposed that the present system, if given along with a systemic antibiotic, would be a fruitful approach for periodontitis amelioration. To fulfill the aforementioned objective, a doxycycline hyclate- and hydroxyapatite-adsorbed composite was prepared by a physical adsorption method and successfully loaded inside sodium alginate-chitosan nanoparticles and optimized based on particle size and drug content. Optimized formulation was then subjected to different evaluation parameters like encapsulation efficiency, hydroxyapatite content, ζ potential, surface morphology, in vitro drug release, cell line studies, and stability studies. For the optimized formulation, particle size, polydispersity index (PDI), entrapment efficiency, ζ potential, and drug content were found to be 336.50 nm, 0.23, 41.77%, -13.85 mV, and 14.00%, respectively. The surface morphology of the placebo and adsorbed composite-loaded nanoparticles as observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed the spherical shape and rough surface of the particles. In gingival crevicular fluid (GCF) 7.6, a sustained drug release profile was obtained up to 36 h. In vitro % viability studies performed on murine fibroblast cells (NIH3T3) and human periodontal ligament (hPDL) cell lines confirmed the proliferative nature of the formulation. Also, when subjected to stability studies for 4 weeks, particle size, PDI, and drug content did not vary considerably, thereby ensuring the stable nature of nanoparticles. Henceforth, sodium alginate-chitosan nanoparticles appeared to be a good carrier system for doxycycline hyclate and hydroxyapatite for periodontal therapy. If given along with a system antibiotic, the system will serve as a fruitful tool for infection-mediated periodontal regeneration and healing.

In-silico Validation of the Proposed Treatment Strategy of Periodontitis.

OBJECTIVE: The present study aims to assess a proposed treatment approach or therapy for periodontitis by using the in-silico technique. The proposed treatment strategy offers a singular vehicular system consisting of minocycline (antibiotic), celecoxib (selective COX-II inhibitor), doxycycline hyclate (matrix metalloproteinase inhibitor), and hydroxyapatite (osteogenic agent). MATERIAL AND METHODS: Molecular docking studies of drugs were performed using Maestro version 9.4 software Schrödinger, and 3-Dimensional Crystallographic X-ray protein structures of targeted proteins were downloaded from RCSB protein data bank in .pdb file format. These agents were docked, and their affinities towards the receptors/protein/enzyme were calculated. Furthermore, their affinities were compared with the standard drug. RESULTS: The study suggests that minocycline and metronidazole possess equal affinity towards the RGPB and Inlj protein of P.gingivalis. Celecoxib, a well-known inhibitor of the COX-II enzyme, showed very high affinity. Selective inhibitor of MMP-8 possessed higher affinity than doxycycline, whereas CMT-3 showed equal affinity as doxycycline for MMP-13. Similarly, hydroxyapatite and simvastatin also showed a comparatively similar affinity for osteopontin receptor. CONCLUSION: Based upon molecular docking results, it can be concluded that the proposed treatment strategy would be a suitable approach for periodontitis and all the selected therapeutic agents have potential similar to the standard drugs, thereby constituting a reliable system for periodontitis.

Assessment of Postoperative Pain after Single-Visit Root Canal Treatment using Wave One® and One Shape® Single File System: A Clinical Study.

BACKGROUND: Wave One® (WO) and One Shape® (OS) are among the common endodontic file systems having rotary and reciprocating movement of instrument, respectively. The study evaluated the postoperative pain after single-visit root canal treatment using single file rotary and reciprocating system. MATERIALS AND METHODS: The present study was conducted in the department of conservative dentistry and endodontics on 68 teeth of patients aged between 20 and 45 years. Sixty-eight teeth were divided into two study groups. In Group A, instrumentation with OS file systems (n = 34) was done with subgroup A1 having patients without periapical lesion (n = 17) and subgroup A2 having patients with periapical lesion (n = 17). In Group B, instrumentation with WO file systems (n = 34) was done with subgroup B1 having patients without periapical lesion (n = 17) and subgroup B2 having patients with periapical lesion (n = 17). The root canal shaping procedures were performed according to the manufacturer's instructions for each instrument system. Presence of postobturation pain was accessed by visual analog scale (VAS) scale (0-10), where 0 showed no pain, 1-3 mild pain, 4-6 moderate pain, 7-9 severe pain, and 10 worst possible pain. RESULTS: The intensity of pain was measured with VAS score in patients without periapical lesions and with periapical lesions using WO and OS file system on the 1st, 2nd, 3rd, and 7th day. VAS score was found to be nonsignificant on the 1st, 2nd, 3rd, and 7th day in both groups (P > 0.05). Intergroup comparison of VAS score was found to be nonsignificant (P > 0.05). CONCLUSION: Both systems were found to have similar effect with respect to postoperative pain. However, WO single file system presented less pain as compared to OS system in cases with periapical lesion. Large sample studies are required to substantiate the result obtained in this study.

Eugenol as a Potential Drug Candidate: A Review.

Eugenol is a bioactive compound widely available in many herbs like clove, cinnamon, tulsi, pepper etc. The compound is known for its antioxidant, antimicrobial, anesthetic, anti-inflammatory, neuroprotective, anti-diabetic, and anti-cancer activities. In pharmaceutical analysis, eugenol is used as a marker for single drugs and drug products. Dental care, household, and personal hygiene products are other areas where it has established its potential. In the food industry, eugenol is used as a flavouring agent in non-alcoholic beverages, baked foods, and chewing gums. Considering the huge potential of eugenol, this review is an attempt to collate the regulatory information, physico-chemical properties, toxicity profile, marketed conventional and novel formulations, analytical methods, extraction procedures, recent patents and clinical trials of the moiety. Based on literature survey a schematic diagram of mechanism of action has also been made.

Design and in vitro/in vivo evaluations of a multiple-drug-containing gingiva disc for periodontotherapy.

In the current work, we set out to develop and evaluate a gingiva disc of cellulose acetate phthalate and poloxamer F-127 for the simultaneous delivery of multiple drugs, namely minocycline, celecoxib, doxycycline hyclate, and simvastatin, to abolish infection, impede inflammation, avert collagen destruction, and promote alveolar bone regeneration, respectively. In vitro release studies revealed the sustained release profiles of the drugs for 12 h and that they were active against Staphylococcus aureus, Escherichia coli and Streptococcus mutans. The in vivo bioactivity levels of these drugs were assessed by comparing the number of colony forming units during different phases of a study on Wistar rats, and the results showed a reduction in the number of bacterial colonies with the applied formulation. A mucosal irritation study conducted on Wistar rat gingiva confirmed the non-irritancy of the optimal gingiva disc. Hence, this customized, non-invasive polymeric gingiva disc displaying a sustained release of drugs can be a useful tool to treat acute to moderate stages of periodontitis.

Exploration of Nanoethosomal Transgel of Naproxen Sodium for the Treatment of Arthritis.

BACKGROUND: The present work aimed to develop an ethosomal gel of naproxen sodium for the amelioration of rheumatoid arthritis. OBJECTIVE: In the present work, we have explored the potential of ethosomes to deliver naproxen into deeper skin strata. Further, the anti-inflammatory efficacy of naproxen ethosomal formulation was assessed using the carrageenan-induced rat paw edema model. METHODS: Naproxen sodium nanoethosomes were prepared using different proportions of lipoid S100 (50mg-200mg), ethanol (20-50%) and water, and were further characterized on the basis of vesicle morphology, entrapment efficiency, zeta potential, in-vitro drug release and ex-vivo permeation studies. RESULTS: The optimized ethosomal formulation was found to have 129 ± 0.01 nm particle size, 0.295 Polydispersity Index (PDI), -3.29 mV zeta potential, 88% entrapment efficiency and 96.573% drug release in 24 hours. TEM and SEM analysis of the optimized formulation showed slightly smooth spherical structures. The Confocal laser scanning microscopy showed that ethosomes could easily infiltrate into deeper dermal layers (upto 104.9µm) whereas the hydroalcoholic solution of the drug could penetrate up to 74.9µm. Further, the optimized ethosomal formulation was incorporated into 1% carbopol 934 gel base and optimized wherein the transdermal flux was found to be approximately 10 times more than the hydroethanolic solution. Also, the in-vivo pharmacodynamic study of the optimized ethosomal gel exhibited a higher percentage inhibition of swelling paw edema than marketed diclofenac gel. CONCLUSION: The ethosomal gel was successfully developed and has shown the potential to be a good option for the replacement of conventional therapies of rheumatoid arthritis.

A 4-D approach for amelioration of periodontitis.

Global prevalence of the severe periodontitis is at the alarming stage and its association with the systemic complications is highly evident which cannot be neglected. An insight into the pathophysiology of the periodontitis reveals that the promising amelioration could only be envisaged with the 4-D/multi-pronged approach of combining antibiotic along with the host modulating agents. The complications of the disease itself suggest that the use of antibiotic alone is not able to cater the symptoms completely. There is a need of other host modulatory agents too, such as Cyclo-oxygenase -II (COX II) enzyme inhibitors, Matrix metalloproteinase's (MMPs) inhibitors and osteo-integrating agents. Also, there is an unmet need of singular treatment modality through which all these agents can be sequentially and directly delivered into the periodontal cavity. The current hypothesis takes it a step forward wherein an antibiotic is combined with other three host modulatory agents in a singular drug delivery system. The encapsulation of multiple therapeutic agents with controlled release would therefore allow for reduced drug dose thus minimizing side effects; contributing to enhanced patient compliance and treatment efficacy. Hence this approach can be presented as a 4-D/multi-pronged approach for circumvention of periodontitis.

Cervicofacial necrotizing fasciitis: an unusual complication of chronic suppurative otitis media.

Necrotizing fasciitis is a rare microbial soft tissue infection characterized by rapidly spreading areas of necrosis and a high mortality rate. It may be of odontogenic or traumatic origin or may arise from insect bites, burns or surgical infections. We present a clinical case of an eight-year-old child with facial and cervical necrotizing fasciitis as a complication of chronic suppurative otitis media. The causes, diagnosis and management of necrotizing fasciitis are reviewed.