Drug Delivery Research Articles

Organelle Targeted Drug Delivery: Key Challenges, Recent Advancements and Therapeutic Implications.

Organelle-specific targeted drug delivery has emerged as a promising approach in the field of drug delivery and therapeutics. This innovative strategy involves the precise delivery of therapeutic agents to specific organelles within cells, such as the nucleus, mitochondria, endoplasmic reticulum, or lysosomes, with the aim of enhancing drug efficacy while minimizing offtarget effects. Despite its tremendous potential, organelle-specific drug delivery faces several key challenges. One major challenge is the development of delivery systems that can accurately navigate the complex intracellular environment and deliver drugs exclusively to the desired organelles. Achieving this level of precision demands advanced nanotechnology and biomaterials engineering. Furthermore, ensuring the safety and biocompatibility of these delivery systems is paramount. Recent advancements in this field include the development of nanocarriers, such as liposomes, nanoparticles, and dendrimers, designed to target specific organelles through ligandreceptor interactions or pH-responsive mechanisms. Additionally, advancements in molecular biology and genetic engineering have enabled the design of genetically encoded organellespecific drug delivery systems. The therapeutic implications of organelle-specific drug delivery are vast. This approach has the potential to revolutionize the treatment of diseases with organelle- specific pathologies, such as neurodegenerative disorders, cancer, and mitochondrial diseases. By precisely targeting the organelles involved in disease progression, the efficacy of therapies can be significantly improved while minimizing collateral damage to healthy tissues.

Dysprosium-containing Cobalt Sulfide Nanoparticles as Anticancer Drug Carriers.

Among various materials designed for anticancer drug transport, sulfide nanoparticles are uniquely intriguing owing to their spectral characteristics. Exploration of newer nanoscale copper sulfide particles with dysprosium doping is reported herein. It leads to a change in the physicochemical properties of the sulfide nanoparticles and hence the difference in drug release and cytotoxicity. We intend to purport the suitably engineered cobalt sulfide and dysprosium-doped cobalt sulfide nanoparticles that are magnetic and NIR-absorbing, as drug delivery vehicles. The drug loading and release are based on the supramolecular drug complex formation on the surface of the nanoparticles. The nanomaterials are synthesized employing hydrothermal procedures, coated with a biocompatible poly-β-cyclodextrin, and characterized using the methods of diffractometry, microscopy, spectroscopy, thermogravimetry and magnetometry. The sustained drug release is investigated in vitro. 5-Fluorouracil is loaded in the nanocarriers. The empty and 5-fluorouracil-loaded nanocarriers are screened for their anti-breast cancer activity in vitro on MCF-7 cells. The size of the nanoparticles is below 10 nm. They show soft ferromagnetic characteristics. Further, they show broad NIR absorption bands extending up to 1200 nm, with the dysprosium-doped material displaying greater absorbance. The drug 5-fluorouracil is encapsulated in the nanocarriers and released sustainably, with the expulsion duration extending over 10 days. The IC50 of the blank and the drug-loaded cobalt sulfide are 16.24 ± 3.6 and 12.2 ± 2.6 μg mL-1, respectively. For the drug-loaded, dysprosium-doped nanocarrier, the IC50 value is 9.7 ± 0.3 μg mL-1. The ultrasmall nanoparticles possess a size suitable for drug delivery and are dispersed well in the aqueous medium. The release of the loaded 5-fluorouracil is slow and sustained. The anticancer activity of the drug-loaded nanocarrier shows an increase in efficacy, and the cytotoxicity is appreciable due to the controlled release. The nanocarriers show multi-functional characteristics, i.e., magnetic and NIR-absorbing, and are promising drug delivery agents.

Advancements in the Transdermal Drug Delivery Systems Utilizing Microemulsion-based Gels.

Microemulsion gel, as a promising transdermal nanoparticle delivery system, addresses the limitations of microemulsions and enhances their performance in drug delivery and release. This article aims to discuss the advantages of microemulsion gel, including improved drug bioavailability, reduced drug irritation, enhanced drug penetration and skin adhesion, and increased antimicrobial properties. It explores the methods for selecting microemulsion formulations and the general processes of microemulsion preparation, as well as commonly used oil phases, surfactants, and co-surfactants. Additionally, the biomedical applications of microemulsion gel in treating conditions, such as acne and psoriasis, are also discussed. Overall, this article elucidates the significant potential of microemulsion gel in topical drug delivery, providing insights into future development and clinical applications.

Magnetosomes as Potential Nanocarriers for Cancer Treatment.

Magnetotactic bacteria (MTBs) and their organelles, magnetosomes, are intriguing options that might fulfill the criteria of using bacterial magnetosomes (BMs). The ferromagnetic crystals contained in BMs can condition the magnetotaxis of MTBs, which is common in water storage facilities. This review provides an overview of the feasibility of using MTBs and BMs as nanocarriers in cancer treatment. More evidence suggests that MTBs and BMs can be used as natural nanocarriers for conventional anticancer medicines, antibodies, vaccine DNA, and siRNA. In addition to improving the stability of chemotherapeutics, their usage as transporters opens the possibilities for the targeted delivery of single ligands or combinations of ligands to malignant tumors. Magnetosome magnetite crystals are different from chemically made magnetite nanoparticles (NPs) because they are strong single-magnetic domains that stay magnetized even at room temperature. They also have a narrow size range and a uniform crystal morphology. These chemical and physical properties are essential for their usage in biotechnology and nanomedicine. Bioremediation, cell separation, DNA or antigen regeneration, therapeutic agents, enzyme immobilization, magnetic hyperthermia, and contrast enhancement of magnetic resonance are just a few examples of the many uses for magnetite-producing MTB, magnetite magnetosomes, and magnetosome magnetite crystals. From 2004 to 2022, data mining of the Scopus and Web of Science databases showed that most research using magnetite from MTB was carried out for biological reasons, such as in magnetic hyperthermia and drug delivery.

Novel Biomaterials Based Strategies for Neurodegeneration: Recent Advancements and Future Prospects.

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, pose significant challenges for effective treatment due to the complex nature of the central nervous system and the limited delivery of therapeutic agents to the brain. Biomaterial-based drug delivery systems offer promising strategies to overcome these challenges and improve therapeutic outcomes. These systems utilize various biomaterials, such as nanoparticles, hydrogels, and implants, to deliver drugs, genes, or cells to the affected regions of the brain. They provide advantages such as targeted delivery, controlled release, and protection of therapeutic agents. This review examines the role of biomaterials in drug delivery for neurodegeneration, discussing different biomaterialbased approaches, including surface modification, encapsulation, and functionalization techniques. Furthermore, it explores the challenges, future perspectives, and potential impact of biomaterialbased drug delivery systems in the field of neurodegenerative diseases.

Key Challenges, Influencing Factors, and Future Perspectives of Nanosuspensions in Enhancing Brain Drug Delivery.

Many brain diseases pose serious challenges to human life. Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common neurodegenerative diseases that seriously threaten human health. Glioma is a common malignant tumor. However, drugs cannot cross physiological and pathological barriers and most therapeutic drugs cannot enter the brain because of the presence of the Blood-brain Barrier (BBB) and Blood- -brain Tumor Barrier (BBTB). How to enable drugs to penetrate the BBB to enter the brain, reduce systemic toxicity, and penetrate BBTB to exert therapeutic effects has become a challenge. Nanosuspension can successfully formulate drugs that are difficult to dissolve in water and oil by using surfactants as stabilizers, which is suitable for the brain target delivery of class II and IV drugs in the Biopharmaceutical Classification System (BCS). In nanosuspension drug delivery systems, the physical properties of nanostructures have a great impact on the accumulation of drugs at the target site, such as the brain. Optimizing the physical parameters of the nanosuspension can improve the efficiency of brain drug delivery and disease treatment. Therefore, the key challenges, influencing factors, and future perspectives of nanosuspension in enhancing brain drug delivery are summarized and reviewed here. This article aims to provide a better understanding of nanosuspension formulation technology used for brain delivery and strategies used to overcome various physiological barriers.

Application of Nanocomposites and Nanoparticles in Treating Neurodegenerative Disorders.

Neurodegenerative diseases represent a formidable global health challenge, affecting millions and imposing substantial burdens on healthcare systems worldwide. Conditions, like Alzheimer's, Parkinson's, and Huntington's diseases, among others, share common characteristics, such as neuronal loss, misfolded protein aggregation, and nervous system dysfunction. One of the major obstacles in treating these diseases is the presence of the blood-brain barrier, limiting the delivery of therapeutic agents to the central nervous system. Nanotechnology offers promising solutions to overcome these challenges. In Alzheimer's disease, NPs loaded with various compounds have shown remarkable promise in preventing amyloid-beta (Aβ) aggregation and reducing neurotoxicity. Parkinson's disease benefits from improved dopamine delivery and neuroprotection. Huntington's disease poses its own set of challenges, but nanotechnology continues to offer innovative solutions. The promising developments in nanoparticle-based interventions for neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), have offered new avenues for effective treatment. Nanotechnology represents a promising frontier in biomedical research, offering tailored solutions to the complex challenges posed by neurodegenerative diseases. While much progress has been made, ongoing research is essential to optimize nanomaterial designs, improve targeting, and ensure biocompatibility and safety. Nanomaterials possess unique properties that make them excellent candidates for targeted drug delivery and neuroprotection. They can effectively bypass the blood-brain barrier, opening doors to precise drug delivery strategies. This review explores the extensive research on nanoparticles (NPs) and nanocomposites in diagnosing and treating neurodegenerative disorders. These nanomaterials exhibit exceptional abilities to target neurodegenerative processes and halt disease progression.

Platelet membrane-coated oncolytic vaccinia virus with indocyanine green for the second near-infrared imaging guided multi-modal therapy of colorectal cancer

Colorectal cancer (CRC) is a prevalent malignancy with insidious onset and diagnostic challenges, highlighting the need for therapeutic approaches to enhance theranostic outcomes. In this study, we elucidated the unique temperature-resistant properties of the oncolytic vaccinia virus (OVV), which can synergistically target tumors under photothermal conditions. To capitalize on this characteristic, we harnessed the potential of the OVV by surface-loading it with indocyanine green (ICG) and encapsulating it within a platelet membrane (PLTM), resulting in the creation of PLTM-ICG-OVV (PIOVV). This complex seamlessly integrates virotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT). The morphology, size, dispersion stability, optical properties, and cellular uptake of PIOVV were evaluated using transmission electron microscopy (TEM). In vitro and in vivo experiments revealed specificity of PIOVV for cancer cells; it effectively induced apoptosis and suppressed CT26 cell proliferation. In mouse models, PIOVV exhibits enhanced fluorescence at tumor sites, accompanied by prolonged blood circulation. Under 808 nm laser irradiation, PIOVV significantly inhibited tumor growth. This strategy holds the potential for advancing phototherapy, oncolytic virology, drug delivery, and tumor-specific targeting, particularly in the context of CRC theranostics.

Alginate-based bio-nanocomposite reinforced with poly(2-hydroxypropyl methacrylamide) and magnetite graphene oxide for delivery of etoposide and photothermal therapy

Recently, bio-nanocomposite nanogels/hydrogels composed of natural polymers and carbon-based nanomaterials are attracting increasing attention in the fields of nanomedicine and bioengineering due to their unique properties. In this study, we propose the creation of an innovative multifunctional bio-nanocomposite based on alginate graft copolymer with poly(2-hydroxypropyl methacrylamide) (SA-g-PHPM) and magnetite graphene oxide (mGO) loaded with etoposide (EPS) for drug delivery and photothermal therapy (PTT). The SA-g-PHPM/mGO bio-nanocomposite was synthesized using an emulsion method and exhibited favorable physicochemical properties. The structural functionalities and surface morphology of the SA-g-PHPM/mGO bio-nanocomposite were comprehensively characterized using spectroscopic techniques, including FT-IR, XRD, UV, DLS, TEM/FE-SEM, and AFM analyses. Under near-infrared (NIR) irradiation (808 nm, 1 Wcm-2, 10 min), the SA-g-PHPM/mGO bio-nanocomposite demonstrated the ability to effectively induce a temperature increase exceeding 29 °C. Additionally, exposure to NIR light and magnetic field led to an increased release of EPS whereas an increment in percentage of mGO caused a decreased EPS release. Notably, the synergistic effects of chemotherapy, light-triggered drug release, and PTT collectively contributed to a significant enhancement in lung cancer (H1299) cell death. In conclusion, our findings suggest that the developed SA-g-PHPM/mGO/EPS bio-nanocomposite serves as an efficient vehicle for multimodal therapy in lung cancer.

Exploring Applications of Flexible Vesicular Systems as Transdermal Drug Delivery.

Deformable lipidic-nano carriers are a category of advanced liposomal formulations. Deformable lipidic-nano carriers have a specific character to transform by rearranging the lipidic backbone to squeeze themself through a pore opening ten times smaller than their diameter when exposed to a variable condition like hydration gradient as these have potentially been used as a non-invasive delivery system to transdermally migrate various therapeutic agents for over three decades. Despite their vast application in transdermal drug delivery system, non-uniformity to express their chemical nature still exist and authors use various terms synonymously and interchangeably with each other. The present study delineates the terminologies used to express different derived deformable vesicular carriers to harmonize the terminological use. It also includes the effectiveness of deformable nanocarriers like Transferosomes, Ethosomes, Menthosomes, Invasomes, and Glycerosomes in skin conditions like basal cell carcinoma, fungal and viral infections, and hyperpigmentation disorders, along with others. Various review and research articles were selected from the 'Pubmed' database. The keywords like Transferosomes, Flexi-vesicular system, ultra-deformable vesicles, and nano-vesicular systems were used to extract the data. The data was reviewed and compiled to categorically classify different flexible vesicular systems. The composition of the different vesicular systems is identified and a report of various pathological conditions where the use of flexible lipid nanocarrier systems was implemented is compiled. The review also offers suggestive approaches where the applicability of these systems can be explored further.

Designing and Formulation of Nanocarriers for "Alzheimer's and Parkinson's" Early Detection and Therapy.

The potential of nanotechnology in advancing the diagnosis and treatment of neurodegenerative diseases is explored in this comprehensive literature review. The findings of these studies suggest that nanotechnology has the capacity to improve existing therapeutic approaches, create novel and safe compounds, and develop more precise imaging techniques and diagnostic methods for neurodegenerative diseases. With the emergence of the nanomedicine era, a new and innovative approach of diagnosing and treating these conditions has been introduced. Notably, the researchers' development of a nanocarrier drug delivery tool demonstrates immense potential compared to conventional therapy, as it maximizes therapeutic efficacy and minimizes undesirable as side effects.

Biological Activities and Nanoparticle Synthesis of Dioscorea bulbifera and its Mechanistic Action - An Extensive Review.

Dioscorea bulbifera is commonly known as air potato present in the tropical and subtropical regions. It is a perennial climber traditionally used for various therapeutic purposes by traditional healers. This review explores various medicinal uses of D. bulbifera and its active ingredients, as well as describes its nanoparticle synthesis for medical applications. The Google Scholar search engine was used to conduct this comprehensive review along with the databases of the following publishers: Elsevier, Springer, Taylor and Francis, Bentham, and PubMed. D. bulbifera contains several bioactive compounds that are responsible for its pharmacological properties, such as antioxidant, anti-inflammatory, neuroprotective, anticancer, and antidiabetic properties. It is also used as a nutritive functional food. D. bulbifera-mediated nanoparticle synthesis has been established by the scientific communities for various medicinal applications. D. bulbifera contains numerous active ingredients, including diosbulbins, bafoudiosbulbin, β-sitosterol, diosgenin, dioscin, pennogenin, myricetin, quercetin, and stigmasterols with numerous biological activities. In addition, it has a vital role in synthesizing nanoparticles with good pharmacological applications, especially in drug delivery systems. However, its potential characteristic features and functional properties of the active molecules present in this tuber need to be further explored in clinical trials. We suggest that using this edible tuber, we may formulate the valueadded food with good medicinal applications.

Scope and Application of Hot Melt Extrusion in the Development of Controlled and Sustained Release Drug Delivery Systems.

Controlled-release drug delivery systems (CRDDS) are more beneficial than conventional immediate release (IRDDS) for reduced intake, prolonged duration of action, lesser adverse effects, higher bioavailability, etc. The preparation of CRDDS is more complex than IRDDS. The hot melt extrusion (HME) technique is used for developing amorphous solid dispersion of poorly water soluble drugs to improve their dissolution rate and oral bioavailability. HME can be employed to develop CRDDS. Sustained release delivery systems (SRDDS), usually given orally, can also be developed using HME. This technique has the advantages of using no organic solvent, converting crystalline drugs to amorphous, improving bioavailability, etc. However, the heat sensitivity of drugs, miscibility between drug-polymer, and the availability of a few polymers are some of the challenges HME faces in developing CRDDS and SRDDS. The selection of a suitable polymer and the optimization of the process with the help of the QbD principle are two important aspects of the successful application of HME. In this review, strategies to prepare SRDDS and CRDDS using HME are discussed with its applications in research.

Physicochemical Stimulus-Responsive Systems Targeted with Antibody Derivatives.

The application of monoclonal antibodies and antibody fragments with the advent of recombinant antibody technology has made notable progress in clinical trials to provide a regulated drug release and extra targeting to the special conditions in the function site. Modification of antibodies has facilitated using mAbs and antibody fragments in numerous models of therapeutic and detection utilizations, such as stimuli-responsive systems. Antibodies and antibody derivatives conjugated with diverse stimuli-responsive materials have been constructed for drug delivery in response to a wide range of endogenous (electric, magnetic, light, radiation, ultrasound) and exogenous (temperature, pH, redox potential, enzymes) stimuli. In this report, we highlighted the recent progress on antibody-conjugated stimuli-responsive and dual/multi-responsive systems that affect modern medicine by improving a multitude of diagnostic and treatment strategies.

Non-Invasive Blood-Brain Barrier Disruption Using Acoustic Holography With a Clinical Focused Ultrasound System.

Holographic methods can be used with phased array transducers to shape an ultrasound field. We tested a simple method to create holograms with a hemispherical 1024-element phased array transducer and explored how it could benefit ultrasound-mediated blood-brain barrier (BBB) disruption. With this method, individual acoustic simulations for each element of the transducer were simultaneously loaded into computer memory. Each element's phase was systematically modulated until the combined field matched a desired pattern. The method was evaluated with a 220 kHz transducer being tested clinically to enhance drug delivery via BBB disruption. The holograms were evaluated in a tissue-mimicking phantom and in vivo in experiments disrupting the BBB in rats and in a macaque. We also explored whether this approach could mitigate secondary reflections from the skull using simulations of transcranial focusing in clinical treatments of transcranial sonication for BBB disruption. This approach can enlarge the focal volume in a patient-specific manner and could reduce the number of sonication targets needed to disrupt large volumes, improve the homogeneity of the disruption, and improve our ability to detect microbubble activity in tissues with low vascular density. Simulations suggest that the method could also mitigate secondary reflections during transcranial sonication.

Aloe-emodin: Progress in Pharmacological Activity, Safety, and Pharmaceutical Formulation Applications.

Aloe-emodin (AE) is an anthraquinone derivative and a biologically active component sourced from various plants, including Rheum palmatum L. and Aloe vera. Known chemically as 1,8-dihydroxy-3-hydroxymethyl-anthraquinone, AE has a rich history in traditional medicine and is esteemed for its accessibility, safety, affordability, and effectiveness. AE boasts multiple biochemical and pharmacological properties, such as strong antibacterial, antioxidant, and antitumor effects. Despite its array of benefits, AE's identity as an anthraquinone derivative raises concerns about its potential for liver and kidney toxicity. Nevertheless, AE is considered a promising drug candidate due to its significant bioactivities and cost efficiency. Recent research has highlighted that nanoformulated AE may enhance drug delivery, biocompatibility, and pharmacological benefits, offering a novel approach to drug design. This review delves into AE's pharmacological impacts, mechanisms, pharmacokinetics, and safety profile, incorporating insights from studies on its nanoformulations. The goal is to outline the burgeoning research in this area and to support the ongoing development and utilization of AE-based therapies.

Delivery of Extracellular Vesicles Loaded with Immune Checkpoint Inhibitors for Immunotherapeutic Management of Glioma

Glioma is a common primary malignant brain tumor with low survival rate. Immunotherapy with immune checkpoints inhibitors (ICI) can be a choice for glioma management, and extracellular vesicles (EVs) are recognized as a potential drug delivery system for various disease management due to their enhanced barrier permeation ability and immunomodulatory effect. The aim of this study is to develop ICI-loaded EVs (ICI/EV) that have sufficient efficacy in managing glioma. Calcium phosphate particles (CaP) were used to stimulate the secretion of EVs from murine macrophage cells. CaP conditioning of cells showed an enhanced amount of EVs secretion and macrophage polarization toward a proinflammatory phenotype. The CaP-induced EVs were shown to polarize macrophages into proinflammatory phenotype in vitro, as correlated with the conditioning method. ICI/EVs were successfully prepared with high loading efficiency using the sonication method. The EVs can be distributed throughout the entire brain upon intranasal administration and facilitate ICIs distribution into glioma lesion. Combinatory treatment with ICI/EVs showed benefit in glioma-bearing mice by reducing their tumor volume and prolonging their survival. Cytotoxic T cell infiltration, polarization of tumor-associated macrophage, and lower tumor proliferation were observed in ICI/EVs-treated mice. The developed ICI/EVs showed promise in immunotherapeutic management of glioma.

Box–Behnken design for the development of fluconazole-loaded classical ethosomes

Introduction: Ethosomes are soft and flexible vesicles mainly composed of phospholipids, ethanol and water. The presence of a high amount of ethanol ensure deeper drug penetration; however, an optimal formulation is necessary. This study aims to develop and characterize Fluconazole loaded classical ethosomes using Box-Behken design, in order to achieve to an optimal formulation having a minimal vesicle size, low polydispersity index, high zeta potential and good entrapment efficiency (% EE). Methods: Fluconazole ethosomes were prepared using cold method and tested for vesicle size, polydispersity index, zeta potential and EE%. Box-Behken design was created using Design Expert® Software, where the impact of sonication time and amount of ethanol and soybean lecithin on resulting formulation were investigated. Results: It was determined that increasing the concentration of ethanol up to an optimized limit reduces vesicle size and improves % EE. It was also observed that soybean lecithin concentrations affected positively vesicle size but negatively % EE. Whereas sonication time had an inverse effect both on, vesicle size and EE%. All prepared formulations showed a low polydispersity index and a good zeta potential indicating homogeneity and high stability. Therefore, the optimal formulation had % EE of 80.05±0.306 % and vesicular size of 226.501±5.34 nm with polydispersity index of 0.487±0.0078. Conclusion: In summary, using Box-Behnken design can enhance the understanding of the correlations between the variables involved in ethosome formation and their effects on vesicle size, polydispersity index and % EE. The optimal formulation obtained can be incorporated into drug delivery systems to enhance skin permeation and antifungal activity.

Chitosan‐based spray‐dried solid dispersions of apigenin in a 3D printable drug delivery system

Chitosan‐based spray‐dried solid dispersions of apigenin in a <scp>3D</scp> printable drug delivery system

Abstract C027: Nanoscale-metal organic frameworks as drug delivery vehicles for novel hepatocellular carcinoma therapy

Abstract C027: Nanoscale-metal organic frameworks as drug delivery vehicles for novel hepatocellular carcinoma therapy