GENERATION DEPENDENT TARGETING POTENTIAL OF DONEPEZIL LOADED POLY (PROPYLENEIMINE) DENDRIMER THROUGH GOAT NASAL MUCOSA

Objective: In the domain of nano drug delivery, dendrimers are the most explored bioactive polymeric carrier system. The present work was aimed to study the diffusion potential of different generations of Poly (propyleneimine) (PPI) dendrimers on goat nasal mucosa in an ex vivo study and synthesize a stable dendrimer for olfactory drug delivery.Methods: The generations (3.0G, 4.0G, and 5.0G) of PPI dendrimer were synthesized, and PEGylated by MPEG 5000 and then loaded with donepezil. A comparative study was carried out among all generations in term of their drug loading capacity, stability, sustained release behaviour as well as for targeting efficacy. An ex-vivo study was carried out on Franz Diffusion Cell with goat nasal mucosa.Results: The developed G3, G4, and G5 dendrimerformulations had entrapment efficiency of 24.33±0.56%, 40.12±0.62%, and 60.4±0.6%, respectively. The nasal diffusion study revealed that 5.0G PPI dendrimer increased diffusion of donepezil up to 47% as compared to the pure solution of donepezil while 10% improvement in diffusion was seen as compared to 4.0 G PPI dendrimer. Thus obtained results claimed that the drug loading as well as targeting potential of PPI dendrimers increased with the increase in the number of generation. The investigation outcome indicated promising results of 5.0G PPI dendrimer over the 3.0G and 4.0G PPI dendrimer generations for their drug loading capacity, stability, and sustained release action.Conclusion: The 5.0G PPI dendrimer proved its superior candidature over the other lower generations of PPI dendrimers for drug delivery and drug targeting

ACUTE TOXICOLOGICAL INVESTIGATION OF POLYETHYLENE GLYCOL DERIVATIZED FOURTH AND FIFTH GENERATION POLY (PROPYLENEIMINE) DENDRIMERS

Objective: The aim of the present study leads a comparative assessment of the toxicological profile of PEGylated fourth and fifth-generation poly (propylene imine) dendrimers (PPI). Methods: 4.0G and 5.0G generations of PPI dendrimer were synthesized and PEGylated with Mono polyethylene glycol 5000 (MPEG-5000). Each PEGylated 4.0G and 5.0G dendrimeric generation were administered in three different doses: 2.5 mg/kg, 25 mg/kg and 250 mg/kg (i.e., low, intermediate and high dose) to wister rats. After the dose administration, the blood and tissue samples of wister rats were collected after 24 h and 15 d after. All the collected samples were proceeded for hematological, biochemical and histopathological studies. Results: After 24 h of (250 mg/kg) dose administration PEGylated 5.0G PPI dendrimer the RBC count, hemoglobin content and WBC count were found 7.873±0.129 mill/cmm, 13.833±0.491g/dl and 9033.33±2384.906 mill/cmm, while PEGylated 4.0G PPI dendrimer indicated RBC count, hemoglobin content and WBC count 8.733±0.239 mill/cmm, 14.033±0.12 g/dl and 9666.667±2567.316 mill/cmm, in blood samples as compare to RBC count 9.346±0.037 mill/cmm, hemoglobin content 15.35±0.15 g/dl and WBC count 8500±286.675 mill/cmm of the animals of normal control group. Thus there are no remarkable changes (p>0.05) in RBC count, hemoglobin content and other hematological profile after 24 h in comparison of normal control group of animals. Similarily insignificant changes (p>0.05) in serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), lactate dehydrogenase (LDH) and sections of different organs indicate inoffensive nature of both generations of PEGylated 4.0G and 5.0 G PPI dendrimers. Conclusion: It can be concluded that fifth-generation PPI dendrimers are more suitable as compared to fourth generation of PPI dendrimer, while both dendrimers are not generating any severe toxicity

Comparative outcome assessment of total hip arthroplasty versus bipolar hemiarthroplasty in intracapsular neck of femur fracture in old age

Background: This prospective study aimed to compare the outcomes of total hip replacement (THR) and bipolar hemiarthroplasty for the treatment of displaced femoral neck fractures in elderly patients. Methods: A total of 30 patients aged over 60 years with femoral neck fractures were included in the study, with 15 patients receiving a bipolar prosthesis and patients receiving THR between June 2021 and January 2023. The patients were followed up for 6 months postoperatively, with functional analysis conducted using the modified Harris hip score. Results: The results showed that the modified Harris hip score was significantly higher in the THR group compared to the bipolar prosthesis group at day 1, 3, 6 and 12 months postoperatively. Pain levels were similar between the two groups at all follow-up intervals. Gait and range of motion were significantly higher in the THR group compared to the bipolar prosthesis group at all-time points. Conclusions: Based on the short-term functional outcomes of this study, THR appears to be a preferable option over bipolar prosthesis for managing femoral neck fractures in elderly

PAMAM Dendrimers as Promising Nanocarriers for RNAi Therapeutics

Therapeutics based on RNA interference mechanisms are highly promising for the management of several diseases including multi-drug resistant cancers. However, effective delivery of siRNAs and oligonucleotides still remains challenging. In this regard, hyper-branched, PAMAM dendrimers having unique three-dimensional architecture and nanoscale size, with cationic surface charge can potentially serve as siRNA condensing agents as well as robust nano-vectors for targeted delivery. In addition, their surface functionality permits conjugation of drugs and genes or development of hybrid systems for combination therapy. Thus far, in vitro cellular testing of dendrimer-mediated siRNA delivery has revealed great potential, with reports on their in vivo effectiveness starting to appear. These favorable outcomes portend a promising future for dendrimer mediated RNAi therapeutics

Clathrin-mediated endocytic uptake of PUFA enriched self-nanoemulsifying lipidic systems (SNELS) of an anticancer drug against triple negative cancer and DMBA induced preclinical tumor model

The current studies envisage unravelling the underlying cellular internalisation mechanism of the systematically developed docetaxel (DTH) polyunsaturated fatty acid (PUFA) enriched self-nanoemulsifying lipidic micellar systems (SNELS). The concentration-, time- and cytotoxicity-related effects of DTH-SNELS on triple negative breast cancer (TNBC) MDA-MB-231 and non-TNBC MCF-7 cell lines were assessed through Presto-blue assay. Subsequently, rhodamine-123 (Rh-123) loaded SNELS were employed for evaluating their internalisation through flow cytometry and fluorescence microscopy, establishing it to be “clathrin-mediated” endocytic pathway. Apoptosis assay (65% cell death) and cell cycle distribution (47% inhibition at G2/M phase) further corroborated the cytotoxicity of DTH-SNELS towards cancerous cells. Biodistribution, histopathology and haematology studies indicated insignificant toxicity of the optimized formulation on vital organs. Preclinical anticancer efficacy studies using 7,12-dimethylbenzantracene (DMBA)-induced model construed significant reduction in breast tumor-volume. Overall, extensive in vitro and in vivo studies indicated the intracellular localization and cytotoxicity, suggesting DTH-SNELS as promising delivery systems for breast tumor therapeutics including TNBC

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1 alpha

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC-BSA nanoparticles (NPs). These PIC-BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC-BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC-BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC-BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC-BSA NPs, enhances its therpautice potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possiable human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients