Treatment-induced ototoxicity and accompanying hearing loss are a great concern associated with chemotherapeutic or antibiotic drug regimens. Thus, prophylactic cure or early treatment is desirable by local delivery to the inner ear. In this study, we examined a novel way of intratympanically delivered sustained nanoformulation by using crosslinked hybrid nanoparticle (cHy-NPs) in a thermoresponsive hydrogel i.e. thermogel that can potentially provide a safe and effective treatment towards the treatment-induced or drug-induced ototoxicity. The prophylactic treatment of the ototoxicity can be achieved by using two therapeutic molecules, Flunarizine (FL: T-type calcium channel blocker) and Honokiol (HK: antioxidant) co-encapsulated in the same delivery system. Here we investigated, FL and HK as cytoprotective molecules against cisplatin-induced toxic effects in the House Ear Institute - Organ of Corti 1 (HEI-OC1) cells and in vivo assessments on the neuromast hair cell protection in the zebrafish lateral line. We observed that cytotoxic protective effect can be enhanced by using FL and HK in combination and developing a robust drug delivery formulation. Therefore, FL-and HK-loaded crosslinked hybrid nanoparticles (FL-cHy-NPs and HK-cHy-NPs) were synthesized using a quality-by-design approach (QbD) in which design of experiment-central composite design (DoE-CCD) following the standard least-square model was used for nanoformulation optimization. The physicochemical characterization of FL and HK loaded-NPs suggested the successful synthesis of spherical NPs with polydispersity index < 0.3, drugs encapsulation (> 75%), drugs loading (~ 10%), stability (> 2 months) in the neutral solution, and appropriate cryoprotectant selection. We assessed caspase 3/7 apopototic pathway in vitro that showed significantly reduced signals of caspase 3/7 activation after the FL-cHy-NPs and HK-cHy-NPs (alone or in combination) compared to the CisPt. The final formulation i.e. crosslinked-hybrid-nanoparticle-embedded-in-thermogel was developed by incorporating drug-loaded cHy-NPs in poloxamer-407, poloxamer-188, and carbomer-940-based hydrogel. A combination of artificial intelligence (AI)-based qualitative and quantitative image analysis determined the particle size and distribution throughout the visible segment. The developed formulation was able to release the FL and HK for at least a month. Overall, a highly stable nanoformulation was successfully developed for combating treatment-induced or drug-induced ototoxicity via local administration to the inner ear.

Hydrogel-based injectable drug delivery systems provide temporally and spatially controlled drug release with reduced adverse effects on healthy tissues. Therefore, they represent a promising therapeutic option for unresectable solid tumor entities. In this study, a peptide-starPEG/hyaluronic acid-based physical hydrogel is modified with ferrocene to provide a programmable drug release orchestrated by matrix-drug interaction and local reactive oxygen species (ROS). The injectable ROS-responsive hydrogel (hiROSponse) exhibits adequate biocompatibility and biodegradability, which are important for clinical applications. HiROSponse is loaded with the two cytostatic drugs (hiROSponsedox/ptx) doxorubicin (dox) and paclitaxel (ptx). Dox is a hydrophilic compound and its release is mainly controlled by Fickian diffusion, while the hydrophobic interactions between ptx and ferrocene can control its release and thus be regulated by the oxidation of ferrocene to the more hydrophilic state of ferrocenium. In a syngeneic malignant melanoma-bearing mouse model, hiROSponsedox/ptx slows tumor growth without causing adverse side effects and doubles the relative survival probability. Programmable release is further demonstrated in a tumor model with a low physiological ROS level, where dox release, low dose local irradiation, and the resulting ROS-triggered ptx release lead to tumor growth inhibition and increased survival.

Pancreatic cancer (PC) remains the predominant type of upper gastrointestinal tract cancer, associated with heightened morbidity and a survival rate below 12%. While immunotherapy has brought about transformative changes in the standards of care for most solid tumors, its application in PC is hindered by the \'\'cold tumor\'\' microenvironment, marked by the presence of immunosuppressive cells. Modest response rates in PC are attributed, in part to, the fibrotic stroma that obstructs the delivery of systemic immunotherapy. Furthermore, the occurrence of immune-related adverse events (iRAEs) often necessitates the use of sub-therapeutic doses or treatment discontinuation. In the pursuit of innovative approaches to enhance the effectiveness of immunotherapy for PC, implantable drug delivery devices and scaffolds emerge as promising strategies. These technologies offer the potential for sustained drug delivery directly to the tumor site, overcoming stromal barriers, immunosuppression, T cell exclusion, immunotherapy resistance, optimizing drug dosage, and mitigating systemic toxicity. This review offers a comprehensive exploration of pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of PC, accompanied by a critical analysis of the challenges the microenvironment presents to the development of successful combinational immunotherapy approaches. Despite efforts, these approaches have thus far fallen short in enhancing treatment outcomes for PDAC. The review will subsequently delve into the imperative need for refining delivery strategies, providing an examination of past and ongoing studies in the field of localized immunotherapy for PDAC. Addressing these issues will lay the groundwork for the development of effective new therapies, thereby enhancing treatment response, patient survival, and overall quality of life for individuals diagnosed with PDAC.

The conventional treatment of osteomyelitis with antibiotic-loaded nondegradable polymethylmethacrylate (ATB-PMMA) beads has certain limitations, including impeded bone reconstruction and the need for secondary surgery. To overcome this challenge, this study aimed to develop and characterize an injectable vancomycin-loaded silk fibroin/methylcellulose containing calcium phosphate-based in situ thermosensitive hydrogel (VC-SF/MC-CAPs). The VC-SF/MC-CAPs solution can be easily administered at room temperature with a low injectability force of ≤30 N and a high vancomycin (VC) content of ~96%. Additionally, at physiological temperature (37 °C), the solution could transform into a rigid hydrogel within 7 minutes. In vitro drug release performed under both physiological (pH 7.4) and infection conditions (pH 4.5) revealed a prolonged release pattern of VC-SF/MC-CAPs following the Peppas-Sahlin kinetic model. In addition, the released VC from VC-SF/MC-CAPs hydrogels exhibited antibacterial activity against Staphylococcus aureus for a period exceeding 35 days, as characterized by the disk diffusion assay. Furthermore, at pH 7.4, the VC-SF/MC-CAPs demonstrated >60% degradation within 35 days. Importantly, when exposed to physiological pH conditions, CAPs are transformed into bioactive hydroxyapatite, which benefits bone formation. Therefore, VC-SF/MC-CAPs showed significant potential as a local drug delivery system for treating osteomyelitis.

Background Chronic localized periodontitis is a prevalent and persistent inflammatory condition in which there is the gradual degradation of the gingiva, periodontal ligament fibers, and alveolar bone loss. The objectives of periodontal therapy encompass not solely the elimination of local factors from the periodontal pocket but also the eradication of the dysbiotic microbial milieu to restore periodontal health. The present study aimed to compare the efficacy of scaling and root planing (SRP) with and without the placement of placental extract gel in the therapeutic management of chronic localized periodontitis under magnification. Materials and methods The present investigation encompassed 40 sites in 20 systemically healthy patients with chronic localized periodontitis. The allocation of the sites was done randomly, resulting in two distinct groups: group I (test site) and group II (control site). Group I was subjected to SRP, followed by the placement of placental extract gel, while group II solely received SRP. Clinical evaluations of pocket probing depth, plaque index, relative attachment level (RAL), gingival index (GI), and bleeding on probing (BoP) were performed at each site at baseline, six weeks, and three months. Results Placental extract gel as an accompaniment to SRP showed significant improvement in clinical parameters like pocket probing depth, RAL, GI, and BoP. Conclusion Placental extract gel may significantly act as a local drug delivery agent in the treatment of localized periodontal pockets.

OBJECTIVE: We have previously reported that protracted Cyclooxygenase-2 (COX-2) activity in bone marrow-derived cells (BMDCs) infiltrating into biopsy wounds adjacent to the biopsy cavity of breast tumors in mice promotes M2-shift of macrophages and pro-metastatic changes in cancer cells, effects which were suppressed by oral administration of COX-2 inhibitors. Thus, local control of COX-2 activity in the biopsy wound may mitigate biopsy-induced pro-metastatic changes.
METHODS: A combinatorial delivery system-thermosensitive biodegradable poly(lactic acid) hydrogel (PLA-gel) incorporating celecoxib-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Cx-NP/PLA-gel)-was injected into the biopsy cavity of Py230 murine breast tumors to achieve local control of COX-2 activity in the wound stroma.
RESULTS: A single intra-biopsy cavity injection of PLA-gel loaded with rhodamine-encapsulated nanoparticles (NPs) showed sustained local delivery of rhodamine preferentially to infiltrating BMDCs with minimal to no rhodamine uptake by the reticuloendothelial organs in mice. Moreover, significant reductions in M2-like macrophage density, cancer cell epithelial-to-mesenchymal transition, and blood vessel density were observed in response to a single intra-biopsy cavity injection of Cx-NP/PLA-gel compared to PLA-gel loaded with NPs containing no payload. Accordingly, intra-biopsy cavity injection of Cx-NP/PLA-gel led to significantly fewer metastatic cells in the lungs than control-treated mice.
CONCLUSIONS: This study provides evidence for the feasibility of sustained, local delivery of payload preferential to BMDCs in the wound stroma adjacent to the biopsy cavity using a combinatorial delivery system to reduce localized inflammation and effectively mitigate breast cancer cell dissemination.

Local drug delivery to the esophagus is hampered by rapid transit time and poor permeability of the mucosa. If some strategies aimed to improve the residence time have been proposed, non-invasive approaches to increase the drug penetration in the mucosa have not been described so far. Herein, we designed mucosa-penetrating liposomes to favor the penetration and retention of curcumin (CURC) in the esophagus. A novel mucosa penetrating peptide (MPP), SLENKGP, was selected by Phage Display and conjugated to pegylated liposomes at different PEG and MPP\'s surface densities. Pegylation assured a long residence time of liposomes (at least 30 min) in the esophagus in vivo, but it did not favor the penetration of CURC in the mucosa. MPP-decorated liposomes instead delivered a significant higher amount of CURC in the mucosa compared to naked pegylated liposomes. Confocal microscopy studies showed that naked pegylated liposomes remain confined in the superficial layers of the mucosa whereas MPP-decorated liposomes penetrate the whole epithelium. In vitro, MPP reduced the interaction of PEG with mucin, meanwhile favoring the paracellular penetration of liposomes across epithelial cell multilayers. In conclusion, pegylated liposomes represent a valid approach to target the esophagus and the surface functionalization with MPP enhances their penetration in the mucosa.

Background Periodontitis, characterized by chronic inflammation and tissue destruction, remains a significant public health concern. Conventional treatment like scaling and root planing (SRP) is effective but often augmented with adjunctive therapies to improve outcomes. Local drug delivery (LDD) systems containing pharmacological agents offer targeted treatment with reduced systemic side effects. Rosuvastatin (RSV), known for its anti-inflammatory and tissue regenerative properties, has shown promise in periodontal therapy. This prospective clinical trial assessed the effectiveness of 1.2% RSV hydrogel as an adjunct to SRP in managing generalized chronic periodontitis. Methods Thirty patients were grouped into Group A (SRP alone) and Group B (SRP + 1.2% RSV hydrogel). Clinical measurements, such as the modified sulcular bleeding index (mSBI), probing pocket depth (PPD), and clinical attachment level (CAL), were documented both at the beginning of the study and after three months. Statistical analysis was performed using SPSS software. A p-value of less than 0.05 was considered statistically significant. Results Participants in Group B showed significant improvements in mSBI (from 2.34 ± 0.59 to 1.01 ± 0.29), PPD (from 7.36 ± 1.12 mm to 4.63 ± 0.88 mm), and CAL (from 8.56 ± 1.22 mm to 5.90 ± 1.24 mm) compared to Group A at the three-month follow-up. The mean values of these parameters decreased significantly in both groups from baseline to three months. However, the reductions were more substantial in Group B, indicating the beneficial effect of RSV hydrogel adjunctive therapy. Conclusion The study demonstrates the efficacy of 1.2% RSV hydrogel employed as a localized drug in enhancing the outcomes of SRP for generalized chronic periodontitis. The adjunctive use of RSV hydrogel led to noteworthy enhancements in clinical parameters, highlighting its potential in periodontal therapy.

Introduction Periodontitis, a persistent inflammatory condition, impacts the tissues supporting teeth. Beyond mechanically eradicating the biofilm, additional host-modulating agents can aid in the treatment of periodontitis. Among these, gels are a very popular choice for use in the field of dentistry as these systems boast high biocompatibility and bioadhesiveness. These qualities make them easily administered and fabricated. They are typically placed into the periodontal site via wide-port needle syringes. Many investigations have demonstrated that hydrogels possess the ability for controlled drug release and aid in periodontal wound healing. Hence, this study aimed to develop a ferulic acid hydrogel and assess its effectiveness for managing periodontitis. Materials and methods Ferulic acid hydrogel was prepared followed by haemolysis assay and biocompatibility assay. After the in vitro analysis, a clinical trial was conducted: 20 patients were divided into Group A (comprising patients in whom scaling and root planing (SRP) was done) and Group B (comprising patients in whom SRP along with hydrogel application was done). Each patient\'s pocket depth (PD), clinical attachment loss (CAL), gingival index (GI), and plaque index (PI) were recorded at baseline and at three months. Intergroup and intragroup comparisons of the parameters were made. Results Ferulic acid hydrogels exhibit a minimal ratio of red blood cell destruction, indicating their low haemolytic activity. Beyond 94 hours, ferulic acid hydrogel demonstrates minimal toxicity towards human fibroblasts, suggesting it has good biocompatibility. When clinical parameters were compared after three months of treatment with SRP alone, significant reductions were observed in all parameters. However, when hydrogel application was done along with SRP, greater reduction was seen in terms of all clinical parameters indicating the efficacy of the ferulic acid hydrogel as an adjunct.  Conclusion Ferulic acid has distinct haemolytic activity as well as good biocompatibility. Its use also led to a considerable reduction in all clinical parameters, necessitating its role as a local drug delivery agent in the treatment of periodontitis.

UNASSIGNED: To compare and evaluate the clinical efficacy of \"ofloxacin incorporated L-PRF\" and \"L-PRF alone\" when used as an adjuvant to non-surgical periodontal therapy.
UNASSIGNED: A split-mouth study was conducted in 50 patients diagnosed as chronic periodontitis with pocket depth ≥6 with at least one site in each quadrant. All patients underwent scaling and root planning. Test site received with ofloxacin incorporated L-PRF and control site received L-PRF alone. Clinical parameters pocket depth (PD), plaque index (PI), and gingival bleeding index (GBI) were recorded at baseline and 1 month after scaling and root planning.
UNASSIGNED: In total, 100 sites were treated (50 test group and 50 control group) with no uneventful healing effects. Statistically significant decreases in PD (P = .0001 for both test and control groups), PI (P = .001), GBI (P = .001 for both groups), between pre-treatment and 1 month post-treatment were noted in both test and control groups. For intergroup comparisons, there was a statistically significant difference in all clinical indices (P > .005).
UNASSIGNED: Use of L-PRF with ofloxacin as an adjuvant to non-surgical periodontal therapy showed better improvements in clinical parameters.