Current Drug Delivery - Volume 21, Issue 1, 2024

To target brain cancer, various therapeutic options are present to fight against cancer cells. But the existing therapies are not showing a proper curation of cancer patients. Henceforth, activating the immune cells and targeting oncogenes/proteins might be an emerging therapeutic approach to target and destroy malignant brain tumor. Stem cells (SCs) are considered potential immunomodulators that trigger the highly suppressed immune system in the tumor microenvironment. Also, engineered SCs can repress the aberrantly expressed oncoproteins that cause tumor cell proliferation and growth. SCs have an excellent migration capability to reach the infected site and support the regeneration of damaged blood vessels and tissues. Likewise, oncolytic virotherapy (OVT) is a promising novel therapeutic molecule in which genetically modified viruses can selectively replicate and destroy cancer cells without harming healthy cells. Same as SCs, oncolytic viruses (OVs) tend to stimulate the host's innate and adaptive immune response to battle against the advanced brain tumor. In clinical studies, various OVs have shown good immunogenic responses with a high safety profile and tolerability against cancer patients with reduced morbidity and mortality rate. SCs act as an attractive cargo for OVs which helps to influence the tumor site and destroy the tumor volume. SCs protect the OVs from systemic degradation and promote therapeutic efficacy against cancer cells. SCs carried OVs might be a potential therapeutic way to bring an effective treatment option for brain tumors.

Amongst different routes of drug delivery systems, ophthalmic drug delivery still requires a careful investigation and strict parameter measurements because the eyes are one of the most sensitive parts of the body and require special attention. The conventional systems for eyes lead to rapid elimination of formulation and hence very small contact time on the ocular epithelium. The current review article covers various types of polymers used in ocular drug delivery along with their applications/ limitations. Polymers are widely used by researchers in prodrug techniques and as a penetration enhancer in ocular delivery. This article covers the role and use of different polymeric systems which makes the final formulation a promising candidate for ophthalmic drug delivery. The researchers are still facing multiple challenges in order to maintain the therapeutic concentration of the drug in the eyes because of its complex structure. There are several barriers that further restrict the intraocular entry of the drug. In order to remove/reduce such challenges, these days various types of polymers are used for ocular delivery in order to develop different drug carrier systems for better efficacy and stability. The polymers used are highly helpful in increasing residence time by increasing the viscosity at the ocular epithelium layer. Such preparations also get easily permeated in ocular cells. The combination of different polymeric properties makes the final formulation stable with prolonged retention, high viscosity, high permeability, and better bioavailability, making the final formulation a promising candidate for ocular drug delivery.

Topical ocular delivery of drugs is most commonly preferred route by the patient and physician for the treatment of ocular diseases. The topical route is always followed with the disadvantages like tear turnover, nasolacrimal drainage, reduction in precorneal residence time, etc. To overcome these hindrances associated with topical ocular route, a novel drug delivery system is used for targeting the drug at a specific site. In the Novel Drug delivery System, protein-based nanoparticles are an attractive class of nanoparticles designed to deliver the drug at targeted site in slow and sustained release manner. They have a size in the range of 1-100 nm. Protein nanoparticles are leading, particularly for the topical ocular delivery like reduction in intra ocular pressure, providing sustained release and targeted drug delivery at the site of its action. Various methods are used for formulation of protein nanoparticles like desolvation, emulsification, complex coacervation, electrospray techniques. The characterization parameters include particle size, surface morphology, drug loading and entrapment efficiency. Protein nanoparticles can also be loaded in to the in situgel forming polymers for increasing precorneal residence time of nanoparticles. The characterization parameters of in situgelling systems are gelling time, rheological properties, gel strength. The review mainly describes the use of various proteins in preparation of protein nanoparticles, methods for preparation of protein nanoparticles, polymers used in in situ gelling system and evaluation as well as characterization parameters of protein nanoparticles, in situ gelling systems & patented information related to protein nanoparticles and in situgelling system for ocular drug delivery.

Erythrocytes are responsible for delivering oxygen throughout the body. They have become suitable drug carriers due to outstanding advantages, such as a long lifespan in circulation, high biosafety, and low immunogenicity. Although erythrocyte-based drug delivery has good application prospects and has become a research hotspot in related fields, the application of erythrocyte-based drug delivery systems is rare in the clinic now. In this review, we discuss the characteristics of erythrocytes, diverse drug-loading approaches, and research progress of erythrocyte-based drug delivery systems. Finally, we explore the challenges of erythrocyte-based drug delivery in clinical application.

The brain is a delicate organ and targeting neurological diseases with conventional approaches is still a daunting task. This is due to the presence of necessary physiological barriers, mainly the blood-brain barrier, that blocks the entry of dangerous and poisonous substances from the bloodstream, thus helping in maintaining homeostasis. Furthermore, the presence of multidrug resistance transporters which act by prohibiting the entry of drugs across the cell membrane and by channelizing them to the outside environment is another defense mechanism. Despite the advancements in the understanding of disease pathology, only a restricted number of drugs and drug therapies can treat and target neurological diseases. To overcome this shortcoming, the therapeutic approach using amphiphilic block copolymers - using polymeric micelles has gained momentum because of its wide applications like drug targeting, delivery, and imaging. Polymeric micelles are nanocarriers that arise when amphiphilic block copolymers spontaneously assemble in aqueous solutions. The hydrophobic core–hydrophilic shell configuration of these nanoparticles makes it easier to load hydrophobic drugs into the core and as a result, the solubility of these medications is improved. Micelle-based drug delivery carriers can target the brain with reticuloendothelial system uptake and produce a long-circulating effect. PMs can also be combined with targeting ligands that increase their uptake by specific cells and thus decreasing off-target effects. In the present review, we primarily focused on polymeric micelles for brain delivery along with the method of preparation, mechanism of micelle formulation, and the ongoing formulations under clinical trials for brain delivery.

Background: Molecular targeted therapies are the most important type of medical treatment for GIST, but the development of GIST drugs and their targets have not been summarized. Methods: Drugs in the field of GIST were analyzed and collated through Pharmaprojects, ClinicalTrials. gov and PharmaGO databases. Results: As of 2021, there are 75 drugs that have appeared in the GIST clinical trials. The six most frequent targets in GIST clinical trials, in descending order of frequency, were KIT, PDGFRA, KDR (VEGFR2), FLT3, FLT1 (VEGFR1), and FLT4/VEGFR3. Only 8 drugs are in preclinical research. There are challenges in the development of new drugs for GIST. Conclusion: This article analyzes and summarizes the general situation of GIST drugs, the target distribution of GIST drugs, and the trends in GIST drug-related clinical trials.

Background: Reactive oxygen species (ROS) production and oxidative stress may be responsible for the onset of several chronic diseases. Usnic acid (UA) is a natural secondary metabolite of lichens with several healthful bioactivities, including antioxidant properties. However, UA is a hydrophobic compound known for its hepatic toxicity. These aspects limit its therapeutic applications. To overcome these drawbacks and improve the pharmacological use of hydrophobic compounds, nanotechnology is widely used. Therefore, the incorporation of UA into appropriate nanocarriers could enhance the bioactivity of UA by increasing its solubility. Objective: The aim of this work was to improve the solubility of UA and its bioactivity in the absence of cytotoxicity. Methods: In this study, UA loaded liposomes (UA-LP) were developed. The formulations were chemically and physically characterized, and an in vitro release study was performed. Free UA and UA-LP were tested on RAW 264.7 murine macrophages in terms of cytotoxicity, intracellular ROS production, and NO release in the absence or presence of pro-oxidant LPS stimulus. Results: UA-LP showed excellent physical and chemical stability during storage and improved solubility of UA. UA-LP showed an antioxidant effect in the absence of cytotoxicity compared with free UA on LPS-exposed macrophages. Conclusion: For the first time, liposomal formulation improved the beneficial action of UA in terms of solubility and antioxidant activity.

Background: As episodes of acute migraine for migraineurs, a self-treatment that promptly relieves headaches and eliminates the associated symptoms would be optimal. Based on the consideration, a rapidly dissolving double-layer microneedles derived from natural acacia was developed. Methods: Under the optimized reaction conditions that was screened out through orthogonal designing test, acacia (GA) was conducted on the ionic crosslinking, a prescribed amount of cross-linking composites was applied to fabricate the double-layer microneedles loaded with sumatriptan at the tip. The mechanical strength and dissolving capability of penetrating pigskin along with in vitro release were measured. The component and content of the resulting compound were determined with FT-IR and thermal analysis, and the bonding state of cross-linker was characterized using X-ray photoelectron spectroscopy. Results: Each needle from the constructed microneedles with the maximal drug loading consisted of the crosslinking acacia of around 10.89 μg and the encapsulated sumatriptan of around 1.821 μg. Apart from the excellent solubility, the formed microneedles possessed enough mechanical stiffness to penetrate the multilayer parafilm. The histological section of the pigskin confirmed the insertion depth of the microneedles could reach 300 ± 28 μm, and the needle bulk in the isolated pigskin could be totally dissolved within 240 s. Franz diffusion study displayed that an almost entire release of the encapsulated drug might be realized within 40 min. The coagulum created from crosslinking was composed of -COOof glucuronic acid in the component of acacia and the added crosslinker to form a double coordination bond, and the crosslinking percentage reached about 13%. Conclusion: The release amount of drug from 12 patches made of the prepared microneedles was comparable to that of subcutaneous injection, providing a new possibility for migraine treatment.

Background: Besides systemic drug delivery, the intranasal route of administration has shown potential for direct nose-to-brain drug delivery, which has gained popularity because it bypasses the blood-brain barrier. Objective: The region in the nose from which the epithelial tissue membrane is excised to conduct ex vivo permeation studies for nasal drug delivery studies may be of importance, but the permeability of the epithelium from the different nasal regions has not yet been investigated in the sheep model. Methods: The permeation of five selected model compounds (i.e., atenolol, caffeine, Rhodamine 123, FITC-dextran, and Lucifer Yellow) was measured across epithelial tissues that were excised from two different areas of the sheep nasal cavity, namely the ventral nasal concha (representing respiratory epithelium) and the ethmoid nasal concha (representing olfactory epithelium). Results: Although the selected compounds' permeation was generally slightly higher across the olfactory epithelial tissues than across the respiratory epithelial tissues, it was not statistically significant except in the case of atenolol. Conclusion: The presence of olfactory nerves and supporting cells and the gaps between them in the olfactory epithelial tissues may have contributed to the higher permeation of atenolol, but this needs to be further investigated to elucidate the precise mechanism.

Background: Poor solubility and dissolution rate of drugs are largely responsible for erratic drug absorption and limited oral bioavailability. Etodolac (ETO) is a non-steroidal anti-inflammatory drug (NSAID) that is classified as BCS class II (dissolution rate-dependent absorption). ETO has high safety and efficacy in pain relief and control of inflammation. ETO is commercially available as (400- 600 mg) tablets; poor solubility and dissolution rate of ETO could result in variable oral absorption and inconsistent analgesic responses. The aim of this study was to improve solubility and dissolution rates of ETO by complexation with cyclodextrins (CDs). Methods: Four different CDs namely β-, γ-, HP β-CDs, and HP γ-CDs were prepared using three different methods; solvent evaporation (CO), freeze-drying (FD), and physical mixing (PM). The prepared drug: excipient mixtures were investigated for aqueous solubility, as well as viaDSC, XRD, FTIR, SEM, dissolution, and docking. Results: The results revealed a solubility phase diagram of the AL type, indicating a 1:1 complexation of ETO: CD. These results agreed with our molecular docking calculations. DSC, FTIR, XRD, and SEM results confirmed the formation of an inclusion complex. The complexation efficiency, solubility, and dissolution enhancement were in the order of HPγ-CD > γ -CD > HPβ-CD > β-CD. FD method was superior to both CO and PM. Conclusion: Superior dissolution enhancements of ETO were recorded for the FD mixture (up to 90% dissolved in less than 10 min). In conclusion, γ- and hydroxypropyl γ-derivative of cyclodextrins can be considered a promising excipient for enhancement of dissolution rates concerned for ETO.