Nanoparticulate Drug Delivery Systems Research Articles

Nanoparticle drug delivery to target breast cancer brain metastasis: Current and future trends.

Breast cancer brain metastasis (BCBM) is rapidly becoming an impediment to continuing survival gains seen in breast cancer patients. Drug delivery across the blood-brain barrier is the main issue hindering systemic therapy against BCBM. This review details recent advances in nanoparticle (NP) drug delivery systems to target BCBM. Their primary benefits are: enhanced circulating and intra-BCBM drug biodistribution, BCBM targeting through NP functionalization, opportunities for gene manipulation and their theragnostic applications. Multiple NPs have been synthesized to deliver therapeutic HER2 blockade, which is particularly important given HER2-positive breast cancer's tendency to form BCBM. Finally, we review the clinical context in which NP-based therapeutics have been investigated in BCBM patients. While a breakthrough in improving patient outcomes remain awaited, these clinical trials represent positive steps in the changing attitude towards BCBM as a treatable illness. Although multiple challenges remain in the clinical translation of BCBM-directed NP therapies, ongoing research in the field offers promising avenues for novel targeting of this devastating disease.

Situation analysis on the regulation of nanomedicines in Southern Africa.

Medical products incorporating nanoparticle drug delivery systems (nanomedicines) are therapeutic or imaging agents, which comprise a delivery system within the nanometer size range (1 - 1000 nm). As medical products, nanomedicines meet definitions of medicines according to various national legislations for regulation of medicines. However, for the regulation of nanomedicines, additional assessments including toxicological issues have to be considered. These complexities require extra regulatory effort. In the resource-limited context of low- and middle-income countries, many National Medicines Regulatory Authorities (NMRAs) lack resources and capacities to effectively assure the quality of medicinal products in their countries. With emerging trends in innovative technologies, including nanotechnology, this burden is worsened. The need to overcome regulatory challenges drove the formation of a work sharing initiative in the Southern African Development Community (SADC), ZaZiBoNA in 2013. Regulatory agencies participating in this initiative cooperate in the assessment of applications for registration of medicines. A cross-sectional exploratory study design with qualitative techniques was used to investigate the status of the regulation of nanomedicines in Southern African countries in particular those participating in the ZaZiBoNA initiative. The study found that in general, NMRAs are aware of the existence of nanomedicines and they apply legislation applicable to other medical products. The NMRAs however neither have specific definition for nanomedicines and technical guidance documents, nor technical committees specific for consideration of nanomedicines. Collaboration with external experts or organisations in the regulation of nanomedicines was also found to be lacking. Capacity building and collaboration in the area of regulation of nanomedicines is strongly encouraged.

Abstract 2703: Evaluation of the effect of tumor-targeted and immunomodulating nanoparticles on the activity of cytotoxic T cells using CAR T cells as an in vitro model

Abstract In solid tumors, there are multiple barriers that prevent anticancer agents and T cells from being able to be delivered into and reach tumor cells. For effective antitumor activity, it is necessary to have direct interactions between cytotoxic T cells and tumor cells. Hyaluronic acid and Iron oxide both have distinctive properties that are advantageous for the development of biocompatible and biodegradable nanoparticle drug delivery systems for cancer. We have developed several targeting and immunomodulatory ligands that can be conjugated to the nanoparticles while carrying chemotherapy or molecular targeted agents for targeted cancer therapy as shown in Table 1. Although the therapeutic efficacy of those targeted nanoparticles has been demonstrated in mouse tumor models, the effect of nanoparticles and their payload drugs on the activities of tumor specific cytotoxic T cells is still unclear. To determine the effect of those nanoparticles on T cell immune responses, CAR T cells provided a well-suited in vitro cellular model. In this study, anti-mesothelin CAR T cells generated from lentiviral CAR T vector transduced T cells were incubated with nanoparticle/drugs and free drugs. The effect of various nanoparticles on CAR T cell viability, and in vitro cytotoxicity on pancreatic cancer cells was evaluated by live/dead, Alamarblue and SRB proliferation Assays. Our results showed that the incubation of CAR T cells with targeted nanoparticles/drugs did not reduce CAR T cells' viability and did not inhibit T cells' activity in killing tumor cells. The ATFmmp14-HANP/SN38 nanoparticle showed an enhanced effect of CAR T cells. Thus, this nanoparticle/drug has the potential for the development of combination therapy with CAR T cells to improve the CAR T cell delivery while synergizing anti-tumor effect by targeted drug delivery, stroma modulation, and tumor cell killing by drug and CAR T cells. Table 1. Nanoparticle formulations overview Nanoparticle Types Target Payload Mechanism of action Observed Results (in vivo) Observed Results (in vitro) ATFmmp14-HANP/SN38:ATFmmp14 conjugated HANP uPAR CD44 SN38 (an active metabolite of irinotecan) Inhibits DNA topoiso-merase I, causing DNA single strand breaks and DNA damage. Significant tumor growth inhibition in human pancreatic and breast cancer PDX models. HANP more effective towards pancreatic cell line and less toxic against CAR T cells: Greater anti-tumor with combination HANP/GKT831: HANP CD44 Setanaxib (GKT831:an inhibitor of NOX1 and NOX4 Reduce the level of reactive oxygen species (ROS): DNA repair downregulation, increases DNA damage Efficient delivery into mouse breast PDX tumors and sensitizing tumor cells to radiotherapy and DNA damaging agents. Nontoxic towards CAR T cells: limited additional therapeutic effects PDY1-HANP/Avasimibe: PD-L1 blocking PDY1 peptide conjugated HANP PD-L1 CD44 Avasimibe (Ava), an inhibitor of acyl-Coenzyme A:cholesterolacyltransferase Decreases intracellular cholesterol.Inhibit tumor cell growth, Activate cytotoxic T cells Efficient delivery into mouse colon tumors, Inhibition of tumor growth: Increased levels of CD8+ T cells and CD68+ Macrophages in tumors Nontoxic towards pancreatic cell lines and CAR T cells: limited additional therapeutic effects ATFmmp14-IONP-DOX: ATFmmp14 conjugated IONP uPAR Doxorubicin Direct DNA damage and inhibits DNA repair by inhibiting topoisomerase Significantly inhibited tumor growth in human pancreatic and breast cancer PDX model ATFmmp14-IONP/DOX more effective towards pancreatic cancer cell lines and less toxic against CAR T cells: slightly increased killing of tumor cells with combination ATFmmp14: Amino terminal fragment (ATF) of uPA fused with MMP14 catalytic domain; PD1Y: PD1 peptide mimetic that binds to and inhibit PD-L1 HANP: Hyaluronic acid nanoparticle; IONP: Iron oxide nanoparticle Citation Format: Kory Wells, Tongrui Lui, Lei Zhu, Chrystal Paulos, Lily Yang. Evaluation of the effect of tumor-targeted and immunomodulating nanoparticles on the activity of cytotoxic T cells using CAR T cells as an in vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2703.

Treg-targeted efficient-inducible platform for collagen-induced arthritis treatment.

Regulatory T cells (Tregs) display great promise in rheumatoid arthritis (RA) therapy. However, their low number and differentiation rate limit their further application in the clinics. In the present study, we first optimized a combination of IL-2, TGF-β and cyclin dependent kinase inhibitor AS2863619 (IL-2/TGF-β/AS), which could induce Tregs with high efficiency in vitro. After the induced Tregs (iTregs) were confirmed to suppress lymphocyte proliferation and pro-inflammatory T help cells (Th1 and Th17) activation, a chitosan-stabilized nanoparticle drug delivery system (NDDS) was developed according to the optimized formula of IL-2/TGF-β/AS. In vivo study, the NDDS was injected into the knees of mice with collagen-induced arthritis (CIA). As a result, the NDDS remarkably reduced the pathological score of the CIA, alleviated the inflammatory cell infiltration and synovial hyperplasia, and minimized cartilage tissue damage in the knee joint of the CIA mice. Mechanically, the NDDS administration promoted Treg differentiation and decreased Th17 production, consequently reversing the ratio of Treg/Th17, and reducing the secretion of TNF-α in the sera, which facilitated to relieve the severity and progression of arthritis. In sum, NDDS capable of efficiently inducing Tregs were constructed successfully and provided a potential platform for treating RA by restoring the equilibrium of Treg/Th17 destroyed in RA.

Eradicating the tumor "seeds": nanomedicines-based therapies against cancer stem cells.

Cancer stem cells (CSCs), a small subpopulation of cells with high tumorigenesis and strong intrinsic drug resistance, exhibit self-renewal and differentiation abilities. CSCs play a crucial role in tumor progression, drug resistance, recurrence and metastasis,and conventional therapy is not enough to eradicate them. Therefore, developing novel therapies targeting CSCs to increase drug sensitivity and preventing relapse is essential. The objective of this review is to present nanotherapies that target and eradicate the tumor "seeds". Evidence was collected and sorted from the literature ranging from 2000 to 2022, using appropriate keywords and key phrases as search terms within scientific databases such as Web of Science, PubMed and Google Scholar. Nanoparticle drug delivery systems have been successfully applied to gain longer circulation time, more precise targeting capability and better stability during cancer treatment. Nanotechnology-based strategies that have been used to target CSCs, include (1) encapsulating small molecular drugs and genes by nanotechnology, (2) targeting CSC signaling pathways, (3) utilizing nanocarriers targeting for specific markers of CSCs, (4) improving photothermal/ photodynamic therapy (PTT/PDT), 5)targeting the metabolism of CSCs and 6) enhancing nanomedicine-aided immunotherapy. This review summarizes the biological hallmarks and markers of CSCs, and the nanotechnology-based therapies to kill them. Nanoparticle drug delivery systems are appropriate means for delivering drugs to tumors through enhanced permeability and retention (EPR) effect. Furthermore, surface modification with special ligands or antibodies improves the recognition and uptake of tumor cells or CSCs. It is expected that this review can offer insights into features of CSCs and the exploration of targeting nanodrug delivery systems.

Medicinal plant-based drug delivery system for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic recurrent intestinal disease. The incidence rate of IBD is increasing year by year, which seriously endangers human health worldwide. More and more studies have shown that medicinal plants or their main phytochemicals have great potential in the treatment of intestinal diseases. However, the disadvantages of low oral absorption rate, low biological distribution and low systemic bioavailability limit their clinical application to a certain extent. In recent years, the application of nanotechnology has made it possible to treat IBD. Nanoparticles (NPs) drug delivery system has attracted special attention in the treatment of IBD due to its small size, low immunogenicity, surface modification diversity, targeting and other advantages. Synthetic nanoparticles and extracellular vehicles (EVs) can deliver drug components to colon, and play a role in anti-inflammation, regulation of oxidative stress, improvement of intestinal flora, etc. In addition, some medicinal plants can secrete EVs by themselves, and carry biological molecules with therapeutic effects to act on the intestine. Some clinical trials to evaluate the safety, tolerance, toxicity and effectiveness of EVs-loaded drugs in IBD are also progressing steadily. This review introduces that synthetic nanoparticles and medicinal plants derived EVs can play an important role in the treatment of IBD by carrying the effective active phytochemicals of medicinal plants, and discuss the limitations of current research and future research needs, providing a scientific and reliable basis and perspective for further clinical application and promotion.

Tuning Targeted Liposome Avidity to Cells via Lipid Phase Separation.

The addition of both cell-targeting moieties and polyethylene glycol (PEG) to nanoparticle (NP) drug delivery systems is a standard approach to improve the biodistribution, specificity, and uptake of therapeutic cargo. The spatial presentation of these molecules affects avidity of the NP to target cells in part through an interplay between the local ligand concentration and the steric hindrance imposed by PEG molecules. Here, we show that lipid phase separation in nanoparticles can modulate liposome avidity by changing the proximity of PEG and targeting protein molecules on a nanoparticle surface. Using lipid-anchored nickel-nitrilotriacetic acid (Ni-NTA) as a model ligand, we demonstrate that the attachment of lipid anchored Ni-NTA and PEG molecules to distinct lipid domains in nanoparticles can enhance liposome binding to cancer cells by increasing ligand clustering and reducing steric hindrance. We then use this technique to enhance the binding of RGD-modified liposomes, which can bind to integrins overexpressed on many cancer cells. These results demonstrate the potential of lipid phase separation to modulate the spatial presentation of targeting and shielding molecules on lipid nanocarriers, offering a powerful tool to enhance the efficacy of NP drug delivery systems.

Perspectives on cutting-edge nanoparticulate drug delivery technologies based on lipids and their applications.

Numerous nanotech arenas in therapeutic biology have recently provided a scientific platform to manufacture a considerable swath of unique chemical entities focusing on drugs. Recently, nanoparticulate drug delivery systems have emerged to deliver a specific drug to a specified site. Among all other carriers, lipids possess features exclusive to nanostructured dosage forms. The bioavailability of orally administered drugs is typically negatively affected by their poor water solubility, resulting from the unique chemical moieties introduced. Because of their unique advantages, lipid nanoparticles must become increasingly predictable as a robust delivery mechanism. The enhanced biopharmaceutical properties and significance of lipid-based targeting technologies such as liposomes, niosomes, solid lipid nanoparticles and micelles are highlighted in this review. Pharmaceutical implications of lipid nanocarriers for the transport and distribution of various therapeutic agents, such as biotechnological products and small pharmaceutical molecules, is a booming topic. Lipid nanoparticles as drug delivery systems have many appealing properties, including high biocompatibility, ease of preparation, tissue specificity, avoidance of reticuloendothelial systems, delayed drug release, scale-up feasibility, nontoxicity and targeted delivery. The use of lipid nanoparticles to enhance the transport of biopharmaceuticals is currently considered state-of-the-art. Similarly, we critically examine the upcoming guidelines that therapeutic scientists should handle.

Impact of Nanoparticle Physicochemical Properties on Protein Corona and Macrophage Polarization.

Macrophages, the major component of the mononuclear phagocyte system, uptake and clear systemically administered nanoparticles (NPs). Therefore, leveraging macrophages as a druggable target may be advantageous to enhance NP-mediated drug delivery. Despite many studies focused on NP-cell interactions, NP-mediated macrophage polarization mechanisms are still poorly understood. This work aimed to explore the effect of NP physicochemical parameters (size and charge) on macrophage polarization. Upon exposure to biological fluids, proteins rapidly adsorb to NPs and form protein coronas. To this end, we hypothesized that NP protein coronas govern NP-macrophage interactions, uptake, and subsequent macrophage polarization. To test this hypothesis, model polystyrene NPs with various charges and sizes, as well as NPs relevant to drug delivery, were utilized. Data suggest that cationic NPs potentiate both M1 and M2 macrophage markers, while anionic NPs promote M1-to-M2 polarization. Additionally, anionic polystyrene nanoparticles (APNs) of 50 nm exhibit the greatest influence on M2 polarization. Proteomics was pursued to further understand the effect of NPs physicochemical parameters on protein corona, which revealed unique protein patterns based on NP charge and size. Several proteins impacting M1 and M2 macrophage polarization were identified within cationic polystyrene nanoparticles (CPNs) corona, while APNs corona included fewer M1 but more M2-promoting proteins. Nevertheless, size impacts protein corona abundance but not identities. Altogether, protein corona identities varied based on NP surface charge and correlated to dramatic differences in macrophage polarization. In contrast, NP size differentially impacts macrophage polarization, which is dominated by NP uptake level rather than protein corona. In this work, specific corona proteins were identified as a function of NP physicochemical properties. These proteins are correlated to specific macrophage polarization programs and may provide design principles for developing macrophage-mediated NP drug delivery systems.

Chemical Sensors Based on Molecularly Imprinted Polymers Can Determine Drug Release Kinetics from Nanocarriers without Filtration, Centrifugation, and Dialysis Steps.

With the development of drug delivery systems, the use of nanomaterials for slow, targeted, and effective drug release has grown significantly. To ensure the quality of performance, it is essential to obtain drug release profiles from therapeutic nanoparticles prior to in vivo testing. Typically, the methods of monitoring the drug release profile from nanoparticle drug delivery systems include one or more filtration, separation, and sampling steps, with or without membrane, which cause several systematic errors and make the process time-consuming. Here, the release rate of doxorubicin as a model drug from liposome as a nanocarrier was determined via highly selective binding of released doxorubicin to the doxorubicin-imprinted electropolymerized polypyrrole as a molecularly imprinted polymer (MIP). Incubation of the MIP-modified substrate with imprinted cavities complementary to doxorubicin molecules in the releasing medium leads to the binding of released doxorubicin molecules to cavities. The drug trapped in the cavities is determined by one of the analytical methods depending on its signaling properties. In this work, due to the favorable electrochemical properties of doxorubicin, the voltammetry method was used for quantitative analysis of released doxorubicin. The voltammetric oxidation peak current intensity of doxorubicin on the surface of the electrode was enhanced by increasing the release time. This membranelle platform allows fast, reliable, and simple monitoring of drug release profiles without any sample preparation, filtration, and centrifugation in buffer and blood serum samples.

Cell Membrane Biomimetic Nanoparticles with Potential in Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is to blame for about 60% of dementia cases worldwide. The blood-brain barrier (BBB) prevents many medications for AD from having clinical therapeutic effects that can be used to treat the affected area. Many researchers have turned their attention to cell membrane biomimetic nanoparticles (NPs) to solve this situation. Among them, NPs can extend the half-life of drugs in the body as the "core" of the wrapped drug, and the cell membrane acts as the "shell" of the wrapped NPs to functionalize the NPs, which can further improve the delivery efficiency of nano-drug delivery systems. Researchers are learning that cell membrane biomimetic NPs can circumvent the BBB's restriction, prevent harm to the body's immune system, extend the period that NPs spend in circulation, and have good biocompatibility and cytotoxicity, which increases efficacy of drug release. This review summarized the detailed production process and features of core NPs and further introduced the extraction methods of cell membrane and fusion methods of cell membrane biomimetic NPs. In addition, the targeting peptides for modifying biomimetic NPs to target the BBB to demonstrate the broad prospects of cell membrane biomimetic NPs drug delivery systems were summarized.

Nanoparticulate drug delivery systems for the treatment of rheumatoid arthritis: A comprehensive review

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects 1% of the world's population. It is a progressive condition that causes joint inflammation, polyarticular synovitis, bone and cartilage destruction, bone erosion, and deformation, resulting in impairments, morbidity, and a lower quality of life. There is no curative therapy for rheumatoid arthritis because the complete pathogenesis is unknown. The treatment aim is to give symptomatic relief while preventing irreversible joint injury. The standard treatment involves glucocorticoids alone or in combination with nonbiologic and biologic disease-modifying anti-rheumatoid drugs (DMARDs). Treatment of RA with conventional dosage forms has limitations such as non-specificity, dose-escalation, increased frequency of administration, toleration, and systemic side effects. Through its application to medicine, nanotechnology has been able to address the drawbacks of conventional treatment and the complexity of the disease, thus offering new possibilities for the treatment of RA by achieving specificity to joints through active and passive targeting strategies, overcoming dose escalation, increased frequency of administration, and the adverse effects associated with it. This review entails a thorough understanding of various Nanoparticulate drug delivery systems, including polymeric nanoparticles such as polymeric micelles, nanocapsules, and dendrimers; lipid-based nanoparticles such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, Transferosomes, exosomes, nanoemulsions, ethosomes; and metallic nanoparticles such as gold and silver nanoparticles, quantum dots, siRNA, and peptide-based nanoparticulate delivery systems. A comprehensive review of the merits and drawbacks of nanoparticulate drug delivery systems is provided, as well as an update on their application on the pharmacotherapy, toxicity, clinical trial of Nanoparticles on rheumatoid arthritis and patents granted in this field.

A State-of-the-art Review on Keratin Biomaterial as Eminent Nanocarriers for Drug Delivery Applications

Abstract: The utilization of biomaterials in the human body was first practiced several years ago to restore normal functional activities by replacing the impaired organs with bio-inspired materials without devastating the cells and tissues. Today, many advanced technologies are reported to be worthwhile to effectively prepare different categories of biomaterials with amplified properties and characteristics for therapeutic applications. When considering the prosperous aspects of biomaterials, keratin has proved to be a fascinating material and has allured many researchers in various novel scientific studies, especially in drug delivery systems. Keratin is a naturally derived fibrous protein with cysteine, proline, serine, and glycine as the main amino acid constituents and has been found to have remarkable properties. Although keratin exhibits excellence and loss of distinction, it is utilized effectively in drug delivery for treating various diseases. Certainly, keratin nanoparticles (KNPs) showed remarkable features, such as optimistic surface area, good encapsulation efficiency, and controlled release of drugs. However, there is a need for more research to know about the cell interaction with keratin nanoparticles in novel drug delivery management. Indeed, certain biological and mechanical factors in alpha and beta keratins are still ambiguous, and higher attentiveness is required. The major purpose of this review is to assess the prospective utility and outstanding features of keratin nanoparticles in drug delivery systems. Keratin types, source of extraction, and properties are reviewed in this article. The characteristics and development of KNP are highlighted. Furthermore, the importance of nanoparticles in drug delivery, drug release mechanisms, challenges, and the need for future research are discussed.

Corrigendum to “Dual drug delivery system of PLGA nanoparticles to reverse drug resistance by altering BAX/Bcl-2” [J. Drug Deliv. Sci. Technol. 47 (2018) 291–298

Corrigendum to “Dual drug delivery system of PLGA nanoparticles to reverse drug resistance by altering BAX/Bcl-2” [J. Drug Deliv. Sci. Technol. 47 (2018) 291–298

Advances in Antiviral Delivery Systems and Chitosan-Based Polymeric and Nanoparticulate Antivirals and Antiviral Carriers.

Current antiviral therapy research is focused on developing dosage forms that enable highly effective drug delivery, providing a selective effect in the organism, lower risk of adverse effects, a lower dose of active pharmaceutical ingredients, and minimal toxicity. In this article, antiviral drugs and the mechanisms of their action are summarized at the beginning as a prerequisite background to develop relevant drug delivery/carrier systems for them, classified and briefly discussed subsequently. Many of the recent studies aim at different types of synthetic, semisynthetic, and natural polymers serving as a favorable matrix for the antiviral drug carrier. Besides a wider view of different antiviral delivery systems, this review focuses on advances in antiviral drug delivery systems based on chitosan (CS) and derivatized CS carriers. CS and its derivatives are evaluated concerning methods of their preparation, their basic characteristics and properties, approaches to the incorporation of an antiviral drug in the CS polymer as well as CS nanoparticulate systems, and their recent biomedical applications in the context of actual antiviral therapy. The degree of development (i.e., research study, in vitro/ex vivo/in vivo preclinical testing), as well as benefits and limitations of CS polymer and CS nanoparticulate drug delivery systems, are reported for particular viral diseases and corresponding antivirotics.

Recent Progress in Chitosan-Based Nanomedicine for Its Ocular Application in Glaucoma.

Glaucoma is a degenerative, chronic ocular disease that causes irreversible vision loss. The major symptom of glaucoma is high intraocular pressure, which happens when the flow of aqueous humor between the front and back of the eye is blocked. Glaucoma therapy is challenging because of the low bioavailability of drugs from conventional ocular drug delivery systems such as eye drops, ointments, and gels. The low bioavailability of antiglaucoma agents could be due to the precorneal and corneal barriers as well as the low biopharmaceutical attributes of the drugs. These limitations can be overcome by employing nanoparticulate drug delivery systems. Over the last decade, there has been a lot of interest in chitosan-based nanoparticulate systems to overcome the limitations (such as poor residence time, low corneal permeability, etc.) associated with conventional ocular pharmaceutical products. Therefore, the main aim of the present manuscript is to review the recent research work involving the chitosan-based nanoparticulate system to treat glaucoma. It discusses the significance of the chitosan-based nanoparticulate system, which provides mucoadhesion to improve the residence time of drugs and their ocular bioavailability. Furthermore, different types of chitosan-based nanoparticulate systems are also discussed, namely nanoparticles of chitosan core only, nanoparticles coated with chitosan, and hybrid nanoparticles of chitosan. The manuscript also provides a critical analysis of contemporary research related to the impact of this chitosan-based nanomedicine on the corneal permeability, ocular bioavailability, and therapeutic performance of loaded antiglaucoma agents.

Nanoparticle drug delivery systems for synergistic delivery of tumor therapy.

Nanoparticle drug delivery systems have proved anti-tumor effects; however, they are not widely used in tumor therapy due to insufficient ability to target specific sites, multidrug resistance to anti-tumor drugs, and the high toxicity of the drugs. With the development of RNAi technology, nucleic acids have been delivered to target sites to replace or correct defective genes or knock down specific genes. Also, synergistic therapeutic effects can be achieved for combined drug delivery, which is more effective for overcoming multidrug resistance of cancer cells. These combination therapies achieve better therapeutic effects than delivering nucleic acids or chemotherapeutic drugs alone, so the scope of combined drug delivery has also been expanded to three aspects: drug-drug, drug-gene, and gene-gene. This review summarizes the recent advances of nanocarriers to co-delivery agents, including i) the characterization and preparation of nanocarriers, such as lipid-based nanocarriers, polymer nanocarriers, and inorganic delivery carriers; ii) the advantages and disadvantages of synergistic delivery approaches; iii) the effectual delivery cases that are applied in the synergistic delivery systems; and iv) future perspectives in the design of nanoparticle drug delivery systems to co-deliver therapeutic agents.

Contemporary Review on Solubility Enhancement Techniques

The limited water solubility of pharmacoactive molecules hinders their ability to be used as pharmacological agents, yet the indispensability of a certain solubility parameter precludes any compromises. To overcome this challenge, various methods are employed in order to increase their bioavailability. Pharmaceutical molecules with lower solubility present an elevated risk of failure for drug development and innovation. Their solubility affects important processes such as pharmacokinetics, pharmacodynamics, distribution, protein binding, and absorption. As a result these parameters are greatly impacted by the dissolution rate of a particular molecule. Out of all pharmaceutical dosage forms, more than half are oral. For the drug molecule to reach its target site and be effective therapeutically, solubility and bioavailability must be taken into consideration. Unfortunately, during screening programs conducted by the pharmaceutical industry it became evident that nearly 40% of new chemical entities (NCEs) face various roadblocks when transitioning from formulation to development due to their poor solubility and bioavailability. The pharmaceutical industry is constantly confronted with the difficulty of improving drug bioavailability and solubility in formulations. This article covers a range of technological advancements to boost the solubility of insoluble drugs, such as complexation, emulsions and micelles production, microemulsion generation with cosolvents, polymeric micelle preparation methods, particle size decrease techniques, pharmaceutical salts application, prodrugs usage, solid-state alteration practices, soft gel technology implementation crystal engineering approaches and nanomorphology. Through this review, we will discuss a variety of more complex methods for improving solubility and bioavailability such as crystal engineering, micronization, solid dispersions, nano sizing, and use of cyclodextrins, solid lipid nanoparticles (SLNPs), colloidal drug delivery systems and drug conjugates. We'll also provide references to studies that have been conducted in connection with these topics.
 Keywords: Solubility, permeability, bioavailability, nano particles drug delivery systems, microemulsions, low water solubility

Tracking of Human Parvovirus B19 Virus-Like Particles Using Short Peptide Tags Reveals a Membrane-Associated Extracellular Release of These Particles.

B19 virus (B19V) is a pathogenic human parvovirus that infects erythroid progenitor cells. Because there are limited in vitro culture systems to propagate this virus, little is known about the molecular mechanisms by which it propagates in cells. In this study, we introduced a HiBiT peptide tag into various loops of VP2 located on the surface of B19V particles and evaluated their ability to form virus-like particles (VLPs). Three independent sites were identified as permissive sites for peptide tag insertion without affecting VLP formation. When the HiBiT tag was introduced into B19V clones (pB19-M20) and transfected into a semipermissive erythroleukemia cell line (UT7/Epo-S1), HiBiT-dependent luciferase activities (HiBiT activities) increased depending on helicase activity of viral NS1. Furthermore, we used a GFP11 tag-split system to visualize VLPs in the GFP1-10-expressing live cells. Time-lapse imaging of green fluorescent protein (GFP)-labeled VLPs revealed that nuclear VLPs were translocated into the cytoplasm only after cell division, suggesting that the breakdown of the nuclear envelope during mitosis contributes to VLP nuclear export. Moreover, HiBiT activities of culture supernatants were dependent on the presence of a detergent, and the released VLPs were associated with extracellular vesicles, as observed under electron microscopy. Treatment with an antimitotic agent (nocodazole) enhanced the release of VLPs. These results suggest that the virions accumulated in the cytoplasm are constitutively released from the cell as membrane-coated vesicles. These properties are likely responsible for viral escape from host immune responses and enhance membrane fusion-mediated transmission. IMPORTANCE Parvovirus particles are expected to be applied as nanoparticles in drug delivery systems. However, little is known about how nuclear-assembled B19 virus (B19V) virions are released from host cells. This study provides evidence of mitosis-dependent nuclear export of B19V and extracellular vesicle-mediated virion release. Moreover, this study provides methods for modifying particle surfaces with various exogenous factors and contributes to the development of fine nanoparticles with novel valuable functions. The pB19-M20 plasmid expressing HiBiT-tagged VP2 is a novel tool to easily quantify VP2 expression. Furthermore, this system can be applied in high-throughput screening of reagents that affect VP2 expression, which might be associated with viral propagation.

AN UPDATE ON RECENT ADVANCES IN NANOEMULSION BASED HYDROGELS: NANOEMULGELS

The newly developed lipophilic drug molecules encounter problems like availability of less amount of drug at the site of action, unpredictable absorption, etc. To overcome these disadvantages, enhancement of solubility and development of novel formulation is a continuous process. Recent advances in technology had helped in developing novel nanoparticulate topical delivery systems. Their characteristic properties such as nano droplet size i.e. 20-200nm, high interfacial area, transparent, translucent appearance, capability to freely solublise in water, high kinetic stability, sedimentation, flocculation and coalescence created a new era in the development nanoparticulate topical drug delivery systems with increased applications. The most advantageous thing about topical nanoemulsion is that it can penetrate and permeate the skin membrane without incorporation of a permeation enhancer. Various studies revealed that the activity of anti inflammatory and anti fungal drugs have been increased as topical nano preparations i.e. nanoemulsions and nanoemulgels with compared to conventional emulsions and emulgels. Nanoemulgels are nanoemulsion based hydrogels prepared by adding nanoemulsion to the hydrogel matrix. The inability of hydrogels led to the development of nanoemugels which solublises the lipophilic drug in the oily phase of the emulsion followed by the addition of this mixture into a gel base.