Exosome-mediated delivery and regulation in neurological disease progression.

Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-ß protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.

Freeze-drying revolution: unleashing the potential of lyophilization in advancing drug delivery systems.

Lyophilization also known as freeze-drying is a technique that has been employed to enhance the long-term durability of nanoparticles (NPs) that are utilized for drug delivery applications. This method is used to prevent their instability in suspension. However, this dehydration process can cause stress to the NPs, which can be alleviated by the incorporation of excipients like cryoprotectants and lyoprotectants. Nevertheless, the freeze-drying of NPs is often based on empirical principles without considering the physical-chemical properties of the formulations and the engineering principles of freeze-drying. For this reason, it is crucial to optimize the formulations and the freeze-drying cycle to obtain a good lyophilizate and ensure the preservation of NPs stability. Moreover, proper characterization of the lyophilizate and NPs is of utmost importance in achieving these goals. This review aims to update the recent advancements, including innovative formulations and novel approaches, contributing to the progress in this field, to obtain the maximum stability of formulations. Additionally, we critically analyze the limitations of lyophilization and discuss potential future directions. It addresses the challenges faced by researchers and suggests avenues for further research to overcome these limitations. In conclusion, this review is a valuable contribution to the understanding of the parameters involved in the freeze-drying of NPs. It will definitely aid future studies in obtaining lyophilized NPs with good quality and enhanced drug delivery and therapeutic benefits.

CRISPR/Cas9 assisted stem cell therapy in Parkinson's disease.

Since its discovery in 2012, CRISPR Cas9 has been tried as a direct treatment approach to correct the causative gene mutation and establish animal models in neurodegenerative disorders. Since no strategy developed until now could completely cure Parkinson's disease (PD), neuroscientists aspire to use gene editing technology, especially CRISPR/Cas9, to induce a permanent correction in genetic PD patients expressing mutated genes. Over the years, our understanding of stem cell biology has improved. Scientists have developed personalized cell therapy using CRISPR/Cas9 to edit embryonic and patient-derived stem cells ex-vivo. This review details the importance of CRISPR/Cas9-based stem cell therapy in Parkinson's disease in developing PD disease models and developing therapeutic strategies after elucidating the possible pathophysiological mechanisms.

Nanotechnological Advances for Nose to Brain Delivery of Therapeutics to Improve the Parkinson Therapy.

Blood-Brain Barrier (BBB) acts as a highly impermeable barrier, presenting an impediment to the crossing of most classical drugs targeted for neurodegenerative diseases including Parkinson's disease (PD). About the nature of drugs and other potential molecules, they impose unavoidable doserestricted limitations eventually leading to the failure of therapy. However, many advancements in formulation technology and modification of delivery approaches have been successful in delivering the drug to the brain in the therapeutic window. The nose to the brain (N2B) drug delivery employing the nanoformulation, is one such emerging delivery approach, overcoming both classical drug formulation and delivery-associated limitations. This latter approach offers increased bioavailability, greater patient acceptance, lesser metabolic degradation of drugs, circumvention of BBB, ample drug loading along with the controlled release of the drugs. In N2B delivery, the intranasal (IN) route carries therapeutics firstly into the nasal cavity followed by the brain through olfactory and trigeminal nerve connections linked with nasal mucosa. The N2B delivery approach is being explored for delivering other biologicals like neuropeptides and mitochondria. Meanwhile, this N2B delivery system is associated with critical challenges consisting of mucociliary clearance, degradation by enzymes, and drug translocations by efflux mechanisms. These challenges finally culminated in the development of suitable surfacemodified nano-carriers and Focused- Ultrasound-Assisted IN as FUS-IN technique which has expanded the horizons of N2B drug delivery. Hence, nanotechnology, in collaboration with advances in the IN route of drug administration, has a diversified approach for treating PD. The present review discusses the physiology and limitation of IN delivery along with current advances in nanocarrier and technical development assisting N2B drug delivery.

Freeze drying: exploring potential in development of orodispersible tablets of sumatriptan succinate.

The present investigation is aimed at development and characterization of sumatriptan succinate orodispersible tablets (ODTs) prepared by freeze drying technology. The tablet excipients were screened and the composition was optimized based on parameters which involved general appearance, tablet size and shape, uniformity of weight, mechanical properties, surface pH, moisture analysis, drug content, wetting time, in vitro and in vivo disintegration time. Furthermore, fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron micrograph of cross-section of the tablet and in vitro dissolution studies were performed. Studies revealed that formulation containing gelatin-mannitol (3.75% w/v and 3.5% w/v, respectively) with camphor as a volatile pore forming agent exhibited superior properties with disintegration time of less than 10 s. Furthermore, in vitro release studies revealed 90% release of drug from developed dosage form within 10 min, thus suggesting rapid drug dissolution followed by faster onset of action, which forms a strong rationale for development of ODTs of sumatriptan succinate. The developed technology is simple, which involves few steps and can be easily scaled up. Thus, it holds enormous potential for commercial exploitation.

Stability-indicating HPLC method for arteether and application to nanoparticles of arteether.

A simple, precise, isocratic, reverse-phase high-performance liquid chromatography method was developed for the rapid determination of arteether using an Agilent RP C18, 4.6 × 150 mm, 5 µm XDB column. The runtime was 9 min. The effect of flow rate, injection volume and mobile phase composition on resolution was investigated. The analytical procedures of the method were validated with respect to precision, accuracy and linearity according to the International Conference on Harmonization guidelines. The limit of detection and the limit of quantitation were 3.3 and 10.0 µg/mL, respectively. Linearity range was from 10.00 to 500 µg/mL. Further, the proposed method was found to be reproducible and convenient for stability-indicating analysis of arteether as a bulk drug and from nanoparticulate formulation.

A versatile liquid chromatographic technique for pharmacokinetic estimation of curcumin in human plasma.

A simple, rapid, sensitive and specific liquid chromatographic method was developed and validated for the determination of curcumin in human plasma. Berberine was used as the internal standard. Chromatographic separation was achieved on a Zorbax Eclipse C18 column at 40 °C, with a mobile phase consisting of 1% acetic acid (pH 3 adjusted with 50% triethanolamine): acetonitrile (55:45), at a flow rate of 1.25 mL/min. The method was validated for precision, accuracy, linearity, lower limit of quantification (LLOQ) and extraction efficiency according to the International Conference on Harmonization guidelines. The method was successfully developed with an LLOQ of 10 ng/mL and a runtime of 9 min. Linearity range was from 10 to 1000 ng/mL. Curcumin and Berberine were well separated with retention times of 8.2 ± 0.2 and 1.4 ± 0.1 min, respectively. Further, the method was successfully employed to study the pharmacokinetic parameters of curcumin, following oral administration of curcumin-loaded hydroxy propyl cellulose (HPC) nanoparticles and curcumin suspension in female Wistar rats. Curcumin-loaded HPC nanoparticles (Cmax: 106.01 ± 20.11 ng/mL) showed significant improvement in pharmacokinetic parameters when compared with curcumin suspension (Cmax: 30.13 ± 0.47 ng/mL) indicating 43.73-fold increase in relative bioavailability.

pH-sensitive nanoparticles of curcumin-celecoxib combination: evaluating drug synergy in ulcerative colitis model.

Inflammatory bowel diseases, which largely comprise ulcerative colitis (UC) and Crohn's disease, are increasingly posing as a global threat because of the incompetence of the current therapy in the entire patient population. This necessitates the identification of alternative therapeutic molecules or their combinations, which may serve as effective first-line or maintenance therapeutics. In this quest, celecoxib, a selective cyclooxygenase-2 inhibiting nonsteroidal anti-inflammatory agent and curcumin, a natural antioxidant and anti-inflammatory agent, have both been found to be useful in alleviating UC. Furthermore, studies involving their combination have proved synergistic action of these two agents. In the current investigation, we have formulated pH-sensitive nanoparticles of curcumin-celecoxib combination as a potential therapy for UC. Synergistic action of the drug combination, delivery advantages of nanosized carriers, and pH-sensitive nature of the polymer were collectively hypothesized to reduce the overall toxicity and total dose of celecoxib and provide enhanced efficacy for mitigating UC. The hypothesis was confirmed in a UC model in rats, where pH-sensitive nanoparticles of the drug combination were found to be more efficacious than nanoparticles of either drugs or drug/s suspension. Further, the blank nanoparticles did not exhibit any therapeutic effect, thereby confirming efficacy of the drug combination for treating UC.

Modification of PLGA nanoparticles for improved properties as a 99mTc-labeled agent in sentinel lymph node detection.

We have earlier reported on the possible application of poly [lactide (co-glycolide)] (PLGA) nanoparticles of suitable size to serve as a (99m)Tc-labeled diagnostic tracer in sentinel lymph node detection (SLND). Additional efforts have now been made to improve both the radiolabeling yield and the biological efficacy by modifying the PLGA particles. Two approaches were taken, one based on in situ loading of mebrofenin inside PLGA nanoparticles and the second one based on functionalization of existing terminal carboxylic acid groups on the nanoparticle surface with p-aminobenzyl diethylenetriamine pentaacetic acid (p-NH2-Bz-DTPA) for enhanced availability of functional groups suitable for (99m)Tc complexation. The modified PLGA derivatives were purified and characterized. Radiolabeling of the modified PLGA nanoparticles was carried out with (99m)Tc using stannous chloride as the reducing agent. Mebrofenin encapsulated PLGA nanoparticles (mebrofenin-PLGA) did not show any significant improvement in the radiolabeling yield in comparison to the earlier reported "plain" PLGA nanoparticles, probably due to inaccessibility of the mebrofenin moiety to (99m)Tc upon encapsulation. DTPA-conjugated PLGA nanoparticles (DTPA-PLGA) showed appreciable improvement in radiolabeling yield under more moderate reaction conditions and better stability. In the biological evaluation performed in Wistar rat model, (99m)Tc-DTPA-PLGA nanoparticles showed a considerable increase in uptake in the sentinel node and the percentage popliteal extraction of the preparation was also higher. (99m)Tc-mebrofenin-PLGA did not show any improvement in SLN uptake over plain PLGA nanoparticles. The above results suggest that surface modification of PLGA by covalently coupling DTPA to PLGA nanoparticles prior to (99m)Tc labeling appears to be a superior approach to achieve a suitable (99m)Tc-labeled PLGA nanoparticle preparation for SLND.

Self-microemulsifiyng suppository formulation of ß-artemether.

Parasitic diseases are of immense global significance as around 30% of world's population experiences parasitic infections. Among these, malaria is the most life-threatening disease. Various routes of administration have been explored for delivering antimalarial actives. The present investigation aims at formulating self-microemulsifying suppositories of ß-artemether with faster onset of action and prolonged effect to be administered by rectal route. These were compared with conventional polyethylene glycol suppositories with respect to melting range, rheology, texture analysis, disintegration time, self microemulsification time, particle size, and drug content. In vitro drug release was studied by using USP apparatus II. Further, the suppositories were evaluated in murine model against virulent rodent malaria parasite Plasmodium berghei wherein the developed self-microemulsifying suppositories could sustain the activity (94%) for 20 days post infection. The survival of animals was also better as compared to the conventional formulation.