Organogels: "GelVolution" in Topical Drug Delivery - Present and Beyond.

Topical drug delivery holds immense significance in dermatological treatments due to its non-invasive nature and direct application to the target site. Organogels, a promising class of topical drug delivery systems, have acquired substantial attention for enhancing drug delivery efficiency. This review article aims to explore the advantages of organogels, including enhanced drug solubility, controlled release, improved skin penetration, non-greasy formulations, and ease of application. The mechanism of organogel permeation into the skin is discussed, along with formulation strategies, which encompass the selection of gelling agents, cogelling agents, and additives while considering the influence of temperature and pH on gel formation. Various types of organogelators and organogels and their properties, such as viscoelasticity, non-birefringence, thermal stability, and optical clarity, are presented. Moreover, the biomedical applications of organogels in targeting skin cancer, anti-inflammatory drug delivery, and antifungal drug delivery are discussed. Characterization parameters, biocompatibility, safety considerations, and future directions in optimizing skin permeation, ensuring long-term stability, addressing regulatory challenges, and exploring potential combination therapies are thoroughly examined. Overall, this review highlights the immense potential of organogels in redefining topical drug delivery and their significant impact on the field of dermatological treatments, thus paving the way for exciting prospects in the domain.

Recent advancements in nanomaterial-mediated ferroptosis-induced cancer therapy: Importance of molecular dynamics and novel strategies.

Ferroptosis is a novel type of controlled cell death resulting from an imbalance between oxidative harm and protective mechanisms, demonstrating significant potential in combating cancer. It differs from other forms of cell death, such as apoptosis and necrosis. Molecular therapeutics have hard time playing the long-acting role of ferroptosis induction due to their limited water solubility, low cell targeting capacity, and quick metabolism in vivo. To this end, small molecule inducers based on biological factors have long been used as strategy to induce cell death. Research into ferroptosis and advancements in nanotechnology have led to the discovery that nanomaterials are superior to biological medications in triggering ferroptosis. Nanomaterials derived from iron can enhance ferroptosis induction by directly releasing large quantities of iron and increasing cell ROS levels. Moreover, utilizing nanomaterials to promote programmed cell death minimizes the probability of unfavorable effects induced by mutations in cancer-associated genes such as RAS and TP53. Taken together, this review summarizes the molecular mechanisms involved in ferroptosis along with the classification of ferroptosis induction. It also emphasized the importance of cell organelles in the control of ferroptosis in cancer therapy. The nanomaterials that trigger ferroptosis are categorized and explained. Iron-based and noniron-based nanomaterials with their characterization at the molecular and cellular levels have been explored, which will be useful for inducing ferroptosis that leads to reduced tumor growth. Within this framework, we offer a synopsis, which traverses the well-established mechanism of ferroptosis and offers practical suggestions for the design and therapeutic use of nanomaterials.

Nano-Innovations in Cancer Therapy: The Unparalleled Potential of MXene Conjugates.

MXenes are two-dimensional transition metal carbides, nitrides, and carbonitrides that have become important materials in nanotechnology because of their remarkable mechanical, electrical, and thermal characteristics. This review emphasizes how crucial MXene conjugates are for several biomedical applications, especially in the field of cancer. These two-dimensional (2D) nanoconjugates with photothermal, chemotherapeutic, and photodynamic activities have demonstrated promise for highly effective and noninvasive anticancer therapy. MXene conjugates, with their distinctive optical capabilities, have been employed for bioimaging and biosensing, and their excellent light-to-heat conversion efficiency makes them perfect biocompatible and notably proficient nanoscale agents for photothermal applications. The synthesis and characterization of MXenes provide a framework for an in-depth understanding of various fabrication techniques and their importance in the customized formation of MXene conjugates. The following sections explore MXene-based conjugates for nanotheranostics and demonstrate their enormous potential for biomedical applications. Nanoconjugates, such as polymers, metals, graphene, hydrogels, biomimetics, quantum dots, and radio conjugates, exhibit unique properties that can be used for various therapeutic and diagnostic applications in the field of cancer nanotheranostics. An additional layer of understanding into the safety concerns of MXene nanoconjugates is provided by detailing their toxicity viewpoints. Furthermore, the review concludes by addressing the opportunities and challenges in the clinical translation of MXene-based nanoconjugates, emphasizing their potential in real-world medical practices.

Predictors of elaborated perineal or a combined abdominoperineal approach during repair for pelvic fracture urethral injury.

PURPOSE: A step-based anastomotic urethroplasty is a standard technique for repairing the posterior urethra in patients with pelvic fracture urethral injury (PFUI). We aim to identify pre-operative factors, including results of conventional radiological imaging, for prediction of elaborated perineal or a combined abdominoperineal procedure. METHODS: Retrospective observational study on 114 consecutive patients undergoing urethroplasty for PFUI between January 2020 and December 2022 was conducted. Surgical procedures were categorized according to the Webster classification into two groups: steps 1-2 (group 1) and steps 3-4 or a combined abdominoperineal repair (group 2). Pre-operative pattern results of RGU/VCUG were categorized regarding the relation between the proximal urethral stump with the pubic symphysis: posterior urethral stump below (pattern 1) or above (pattern 2) the lower margin of the pubic symphysis. Patient demographics were assessed. Univariate and multivariate logistic regression analyses were utilized. RESULTS: Overall, 102 patients were enrolled in the study for data analysis. On the multivariate logistic regression analysis, the presence of erectile dysfunction (OR 4.5; p = 0.014), prior combined treatment (endoscopic and urethroplasty) (OR 6.4; p = 0.018) and RGU/VCUG pattern 2 (OR 66; p < 0.001) significantly increased the likelihood of the need of step 3 or higher. CONCLUSIONS: The need of step 3 or higher during urethroplasty for PFUI can be predicted pre-operatively with conventional imaging (RGU/VCUG). Patients with proximal urethral stump above the lower margin of pubic symphysis were about 66 times more likely to need step 3 or higher during urethroplasty.

Nano-tracers for sentinel lymph node detection: current trends in technique and application.

Sentinel lymph node (SLN) detection and biopsy is a critical staging component for several cancers. Apart from established methods using dyes or radiolabeled colloids, newer techniques are emerging, like near-infrared fluorescent compounds, targeted molecular radiopharmaceuticals and magnetic nano-tracers. In the overview section of this review, we categorize SLN detection tracers based on their principle of use. We discuss the merits of existing tracers and provide a glimpse of in-development formulations. A subsequent clinical section explores the expanded role of SLN detection in management of various cancers, citing current medical guidelines and the leading conclusions of long-term clinical trials. The concluding section tries to provide a perspective of promising developments and the work required to bring them to clinical fruition.

Anti-CD4 antibody and dendrimeric peptide based targeted nano-liposomal dual drug formulation for the treatment of HIV infection.

AIMS: Development and characterization of LAM and DTG loaded liposomes conjugated anti-CD4 antibody and peptide dendrimer (PD2) to improve the therapeutic efficacy and to achieve targeted treatment for HIV infection. MAIN METHODS: A 2-level full factorial design was used to optimize the preparation of dual drug loaded liposomes. Optimized dual drug loaded ligand conjugated liposomes were assessed for their cytotoxicity and cell internalization on TZM-bl cells. Anti-HIV efficiency of the dual drug loaded liposomes were screened for their inhibitory potential in TZM-bl cells and the activities were confirmed using Peripheral Blood Mononuclear Cells (PBMCs). KEY FINDINGS: The particle size of the optimized dual drug-loaded liposomes was 133.7 ± 4.04 nm, and the spherical morphology of the liposomes was confirmed by TEM analysis. The entrapment efficiency was 34 ± 4.9 % and 54 ± 1.8 % for LAM and DTG, respectively, and a slower in vitro release of LAM and DTG was observed when entrapped into liposomes. The cytotoxicity of the dual drug loaded liposomes was similar to the cytotoxicity of free drug solutions. Conjugation of anti-CD4 antibody and PD2 did not significantly influence the cytotoxicity but it enhanced the uptake of liposomes into the cells. Conjugated dual drug loaded liposomes exhibited better HIV inhibition with lower IC50 values (0.0003 ± 0.0002 µg/mL) compared to their free drug solutions (0.002 ± 0.001 µg/mL). The liposomal formulations have shown similar activities in both screening and confirmatory cell-based assays. SIGNIFICANCE: The results demonstrated the cell targeting ability of dual drug loaded liposomes conjugated with anti-CD4 antibody and peptide dendrimer. Conjugated liposomes also improved anti-HIV efficiency of LAM and DTG.

Targeted Delivery of 5-Fluorouracil and Sonidegib via Surface-Modified ZIF-8 MOFs for Effective Basal Cell Carcinoma Therapy.

The therapeutic effectiveness of the most widely used anticancer drug 5-fluorouracil (5-FU) is constrained by its high metabolism, short half-life, and rapid drug resistance after chemotherapy. Although various nanodrug delivery systems have been reported for skin cancer therapy, their retention, penetration and targeting are still a matter of concern. Hence, in the current study, a topical gel formulation that contains a metal-organic framework (zeolitic imidazole framework; ZIF-8) loaded with 5-FU and a surface modified with sonidegib (SDG; acting as a therapeutic agent as well as a targeting ligand) (5-FU@ZIF-8 MOFs) is developed against DMBA-UV-induced BCC skin cancer in rats. The MOFs were prepared using one-pot synthesis followed by post drug loading and SDG conjugation. The optimized MOFs were incorporated into hyaluronic acid-hydroxypropyl methyl cellulose gel and further subjected to characterization. Enhanced skin deposition of the 5-FU@ZIF-8-SDG MOFs was observed using ex vivo skin permeation studies. Confocal laser microscopy studies showed that 5-FU@ZIF-8-SDG MOFs permeated the skin via the transfollicular pathway. The 5-FU@ZIF-8-SDG MOFs showed stronger cell growth inhibition in A431 cells and good biocompatibility with HaCaT cells. Histopathological studies showed that the efficacy of the optimized MOF gels improved as the epithelial cells manifested modest hyperplasia, nuclear pleomorphism, and dyskeratosis. Additionally, immunohistochemistry and protein expression studies demonstrated the improved effectiveness of the 5-FU@ZIF-8-SDG MOFs, which displayed a considerable reduction in the expression of Bcl-2 protein. Overall, the developed MOF gels showed good potential for the targeted delivery of multifunctional MOFs in topical formulations for treating BCC cancer.

Novel single-stage preputial spiral graft for panurethral stricture: a step-by-step description of the technique.

PURPOSE: To report the 12-month results of a novel urethroplasty technique relying on a spiral preputial graft for panurethral stricture disease. MATERIALS AND METHODS: Twenty consecutive patients were treated between May and October 2021 at our center. A spiral preputial mucocutaneous graft is a foreskin-based graft, developed from a 5-cm-wide preputial skin, which is harvested using a helicoidal shape and can reach up to 20 cm in length. Stricture characteristics were assessed through preoperative retrograde and voiding cystourethrogram and maximum uroflowmetry data (Qmax). Complications were collected up to 30 days after surgery and graded using the Clavien-Dindo (C-D) classification. The patients were followed up to 12 months. RESULTS: Preoperative median Qmax was 6.5 ml/s [interquartile range (IQR): 4.0-8.7]. After a median follow-up of 12 months (IQR 12-13), six patients experienced at least one complication. Of them, two patients had grade 2 C-D complications, while only one developed a grade 3a C-D complication. The median postoperative Qmax was 16 ml/s (IQR: 13-18). Only one patient had early urethral stricture recurrence treated with dilatation after catheter removal. At one-year follow-up, no other patients had urethral stricture recurrence with an overall median Qmax of 15.1 ml/s (IQR 13.5-16.4). CONCLUSIONS: Our novel single-stage spiral preputial graft urethroplasty for panurethral stricture treatment appears to be safe and could be used as a valid alternative to two-stage procedures or even to single-stage buccal mucosa graft augmentation.

Management of Pelvic Fracture Urethral Injury: Is Supracrural Urethral Rerouting (Step 4) Becoming Anecdotical or Does It Remain in Force?

Webster described a step-based perineal approach for repairing the posterior urethra in patients with pelvic fracture urethral injury (PFUI). The higher the complexity of the step, the higher the morbidity for the patient and the lower the surgical outcomes. We evaluated the outcomes of anastomotic urethroplasty (especially Step 4 or higher) or substitution urethroplasty in patients with PFUI at our center. Between 2013 to 2021, we retrospectively collected data on patients with PFUI. Surgical procedures were categorized according to the Webster classification and rates of each step were reported. The success rate was defined as Qmax above 10 mL/s and no need for further treatment. In this period, 737 male patients with PFUI were surgically treated. Notably, 18.8%, 17.6%, 46%, 1.8%, and 5.6% of included patients received steps 1, 2, 3, and 4 and the abdominoperineal approach, respectively. In 68 (9.2%) patients, the substitution of urethroplasty with a pedicled preputial tube (PPT) was needed. The success rate was 69.2% in Step 4, 74.4% in the abdominoperineal approach, and 86.4% in PPT; however, recurrence-free survival was not significantly different between groups (p = 0.22). Step 4 perineal anastomotic urethroplasty represents a surgical option in the armamentarium of PFUI treatment. Indications should be carefully reviewed to improve patient selection and avoid surgical failure, stopping at the step which first gives a tension-free anastomosis.

Advances in urethroplasty.

There has been rapid evolution in management of urethral strictures in the last 3 decades. From the era of dilatation, we have moved to urethral reconstruction. Reinvention of buccal grafts changed the outcomes of urethroplasty. Barbaglis dorsal onlay popularised stricture management across the globe. Kulkarni described a single stage surgery for panurethral stricture. Advances have taken place, and we have moved from transecting to the non-transecting approaches. We describe the various advances in urethral reconstruction in the last decade.

Honoring the gift: The transformative potential of transplant-declined human organs.

For decades, transplantation has been a life-saving treatment for those fortunate enough to gain access. Nevertheless, many patients die waiting for an organ and countless more never make it onto the waitlist because of a shortage of donor organs. Concurrently, thousands of donated organs are declined for transplant each year because of concerns about poor outcomes post-transplant. The decline of any donated organ-even if medically justified-is tragic for both the donor family and potential recipients. In this Personal Viewpoint, we discuss the need for a new mindset in how we honor the gift of organ donation. We believe that the use of transplant-declined human organs in translational research has the potential to hasten breakthrough discoveries in a multitude of scientific and medical areas. More importantly, such breakthroughs will allow us to properly value every donated organ. We further discuss the many practical challenges that such research presents and offer some possible solutions based on experiences in our own research laboratories. Finally, we share our perspective on what we believe are the necessary next steps to ensure a future where every donated organ realizes its full potential to impact the lives of current and future patients.

The impact of surgical volume on perioperative safety after urethroplasty: a population-based study.

BACKGROUND: The aim of the study was to assess whether the risk of perioperative complications after urethroplasty was affected by hospital annual surgical volume (ASV). METHODS: In the Nationwide Inpatient Sample, we searched for patients who underwent urethroplasty between 2001 and 2015. Hospitals were categorized into empirically determined tertiles, according to ASV of performed urethroplasties and divided into low (<3) (LVC), intermediate (3-19) (IVC) and high (>20) volume centers (HVC). Multivariable logistic regression (MLR) analyses examined the effect of ASV on perioperative complications and on four specific sub-types of post-operative complications. RESULTS: A weighted estimate of 39 912 patients underwent urethroplasty in the US. 34.9% were operated in HVC, while the rate of performed urethroplasties increased in LVC and decreased in HVC. Overall, 1.1%, 18.8% and 2.1% patients respectively experienced intraoperative, post-operative, and transfusions complications. At MLR, IVC and LVC were associated with higher risk of both intraoperative (IVC: OR 2.65, P=0.0008; LVC: OR 4.98, P<0.0001), post-operative (IVC: OR 1.14, P=0.01; LVC: OR 1.26, P=0.001) and transfusions complications (IVC: OR 1.85, P<0.001; LVC: OR 3.03, P=0.01). LVC was also associated with higher risk of hematuria (OR 3.77), urinary infections (OR 1.60) and sepsis (OR 2.83) complications. CONCLUSIONS: Approximately 65% of patients were operated in IVC and LVC, and patients treated in IVC or LVC had higher risk of developing both intra and post-operative complications. These data provide important indicators for policy makers to categorize institution based on urethroplasty outcomes.

How to do a penile urethroplasty using a novel self-retaining penile retractor.

Effective retraction and clear exposure of urethral tissue is essential in reconstructive penile surgery. The Joshi-Kulkarni retractor provides stable, bloodless operative exposure via non-traumatic tissue compression at the base of penis. The self-retaining design of this retractor also improves ergonomics thereby reducing surgeon fatigue. In this article, we describe how to do a penile urethroplasty by using the Joshi-Kulkarni penile retractor.

Ethical analysis examining the prioritisation of living donor transplantation in times of healthcare rationing.

The transplant community has faced unprecedented challenges balancing risks of performing living donor transplants during the COVID-19 pandemic with harms of temporarily suspending these procedures. Decisions regarding postponement of living donation stem from its designation as an elective procedure, this despite that the Centers for Medicare and Medicaid Services categorise transplant procedures as tier 3b (high medical urgency-do not postpone). In times of severe resource constraints, health systems may be operating under crisis or contingency standards of care. In this manuscript, the United Network for Organ Sharing Ethics Workgroup explores prioritisation of living donation where health systems operate under contingency standards of care and provide a framework with recommendations to the transplant community on how to approach living donation in these circumstances.To guide the transplant community in future decisions, this analysis suggests that: (1) living donor transplants represent an important option for individuals with end-stage liver and kidney disease and should not be suspended uniformly under contingency standards, (2) exposure risk to SARS-CoV-2 should be balanced with other risks, such as exposure risks at dialysis centres. Because many of these risks are not quantifiable, donors and recipients should be included in discussions on what constitutes acceptable risk, (3) transplant hospitals should strive to maintain a critical transplant workforce and avoid diverting expertise, which could negatively impact patient preparedness for transplant, (4) transplant hospitals should consider implementing protocols to ensure early detection of SARS-CoV-2 infections and discuss these measures with donors and recipients in a process of shared decision-making.

Co-rotating twin screw process for continuous manufacturing of solid crystal suspension: A promising strategy to enhance the solubility, permeation and oral bioavailability of Carvedilol.

Background: In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier. Methods: In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months. Results: Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content. Conclusions: TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.

2D Hetero-Nanoconstructs of Black Phosphorus for Breast Cancer Theragnosis: Technological Advancements.

As per global cancer statistics of 2020, female breast cancer is the most commonly diagnosed cancer and also the foremost cause of cancer death in women. Traditional treatments include a number of negative effects, making it necessary to investigate novel smart drug delivery methods and identify new therapeutic approaches. Efforts for developing novel strategies for breast cancer therapy are being devised worldwide by various research groups. Currently, two-dimensional black phosphorus nanosheets (BPNSs) have attracted considerable attention and are best suited for theranostic nanomedicine. Particularly, their characteristics, including drug loading efficacy, biocompatibility, optical, thermal, electrical, and phototherapeutic characteristics, support their growing demand as a potential substitute for graphene-based nanomaterials in biomedical applications. In this review, we have explained different platforms of BP nanomaterials for breast cancer management, their structures, functionalization approaches, and general methods of synthesis. Various characteristics of BP nanomaterials that make them suitable for cancer therapy and diagnosis, such as large surface area, nontoxicity, solubility, biodegradability, and excellent near-infrared (NIR) absorption capability, are discussed in the later sections. Next, we summarize targeting approaches using various strategies for effective therapy with BP nanoplatforms. Then, we describe applications of BP nanomaterials for breast cancer treatment, which include drug delivery, codelivery of drugs, photodynamic therapy, photothermal therapy, combined therapy, gene therapy, immunotherapy, and multidrug resistance reversal strategy. Finally, the present challenges and future aspects of BP nanomaterials are discussed.

Blood Transcriptomes of SARS-CoV-2-Infected Kidney Transplant Recipients Associated with Immune Insufficiency Proportionate to Severity.

BACKGROUND: Among patients with COVID-19, kidney transplant recipients (KTRs) have poor outcomes compared with non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort. METHODS: We ascertained clinical data by chart review. A single sample of blood was collected for transcriptome analysis. Total RNA was poly-A selected and RNA was sequenced to evaluate transcriptome changes. We also measured cytokines and chemokines of serum samples collected during acute infection. RESULTS: A total of 64 patients with COVID-19 in KTRs were enrolled, including 31 with acute COVID-19 (<4 weeks from diagnosis) and 33 with post-acute COVID-19 (>4 weeks postdiagnosis). In the blood transcriptome of acute cases, we identified genes in positive or negative association with COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways but downregulation of T cell and adaptive immune activation pathways. This finding was independent of lymphocyte count, despite reduced immunosuppressant use in most KTRs. Compared with acute cases, post-acute cases showed "normalization" of these enriched pathways after 4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of immunosuppression. Analysis of the non-KTR cohort with COVID-19 showed significant overlap with KTRs in these functions. Serum inflammatory cytokines followed an opposite trend (i.e., increased with disease severity), indicating that blood lymphocytes are not the primary source. CONCLUSIONS: The blood transcriptome of KTRs affected by COVID-19 shows decreases in T cell and adaptive immune activation pathways during acute disease that, despite reduced immunosuppressant use, associate with severity. These pathways show recovery after acute illness.