Current Drug Delivery - Volume 21, Issue 2, 2024

Currently, the main cause of cancer chemotherapy failure is multi-drug resistance (MDR), which involves a variety of complex mechanisms. Compared with traditional small-molecule chemotherapy, targeted nanomedicines offer promising alternative strategies as an emerging form of therapy, especially active targeted nanomedicines. However, although single-targeted nanomedicines have made some progress in tumor therapy, the complexity of tumor microenvironment and tumor heterogeneity limits their efficacy. Dual-targeted nanomedicines can simultaneously target two tumor-specific factors that cause tumor MDR, which have the potential in overcoming tumor MDR superior to single-targeted nanomedicines by further enhancing cell uptake and cytotoxicity in new forms, as well as the effectiveness of tumor-targeted delivery. This review discusses tumor MDR mechanisms and the latest achievements applied to dual-targeted nanomedicines in tumor MDR.

In the current era, the Transdermal delivery of bioactive molecules has become an area of research interest. The transdermal route of administration enables direct entry of bioactive molecules into the systemic circulation with better and easy accessibility, bypassing the hepatic metabolism and improving patient compliance. Permeation through the skin has always been a barrier. To overcome this challenge, an efficient route by the vesicular system has been adopted so as to have better skin permeation of the bioactive molecules. A novel vesicular and non-invasive drug delivery system called Nanoethosomes was developed. Nanoethosomes are lipid-based vesicular carriers that are used for deeper permeation of the bioactive agents into the skin. The main components of Nanoethosomes are Phospholipids, water, and ethanol. High ethanol concentration in Nanoethosomes distinguishes them from other nano-formulation and results in deeper permeation and smaller vesicular size. This review article gives detailed information on the formulation techniques, and characterization parameters of nanoethosomes along with the research work done by various researchers in the same field. The compiled manuscript gives detailed elaboration about the various drugs used to treat different diseases which when incorporated in nanoethosomes resulted in better permeability and enhanced bioavailability.

Cancer is a disease with a high mortality rate; therefore, research on new treatment strategies is essential. There has been increased interest in novel drug delivery systems (DDS) in recent years, such as calixarene, one of the most important principal molecules in supramolecular chemistry. Calixarene is a cyclic oligomer of phenolic units linked by methylene bridges that belongs to the third generation of supramolecular compounds. By modifying the phenolic hydroxyl end (lower edge) or the para-position, a wide range of calixarene derivatives can be obtained (upper edge). Drugs are combined with calixarenes to modify and have new properties, such as strong water solubility, the ability to bond with guest molecules, and excellent biocompatibility. In this review, we summarize the applications of calixarene in the construction of anticancer drug delivery systems and its application in clinical treatment and diagnosis. It provides theoretical support for the diagnosis and treatment of cancer in the future.

Cancer is a broad term for a set of disorders marked by the development of physically and functionally changed cells that proliferate uncontrollably, infect neighboring tissues, and result in malignant tumours, 'neoplasm'. Cancer remains a difficult disease to treat because of the significant adverse effects and poor pharmacokinetic profile of antineoplastic drugs, despite advancements in our understanding of the features and behavior of tumor cells in recent decades. In this series, the role of natural polymers is prominent as a component of a novel delivery system of anticancer drugs. These natural polymeric drug delivery systems (NPDDS) have many advantages over synthetic polymers like controlled delivery, biodegradability, inexpensive, low toxicity profile, and easily obtainable. These polymers further modify for the targeting of tumour cells. This review discusses and critically analyses the different natural polymers, such as chitosan, cellulose, starch, albumin, dextran, fucoidan, gelatin, etc., in terms of natural ingredient-based polymeric nanocarriers specifically for cancer therapy. It also describes benefits, drawbacks, and opinions and provides insights about the efficacy of NPDDS as well as its future perspectives and tabulated recent patents and cases under clinical trials exploited for cancer treatment.

Therapeutic proteins and peptides (PPTs) have become one of the most important biological molecules for the management of many common and complex diseases due to their high specificity and high bioactivity. However, these biomolecules are mainly given by the hypodermic injection, which often leads to poor patient compliance due to the invasive nature of this route of administration. The oral route has been considered the most convenient and patient-friendly route for drug delivery relative to hypodermic injections. Despite the ease and simplicity conferred by oral administration, this drug delivery route suffers rapid peptide degradation in gastric fluid and low intestinal uptake. In order to circumvent these issues, several strategies, such as enzyme inhibitors, permeation enhancers, chemical modification, mucoadhesive and stimuli-responsive polymers, and specialised particulate formulation have been developed. Such strategies are designed with the aim of protecting PPTs from the harsh gastrointestinal environment as well as providing a strategy to enhance the uptake of the therapeutic across the gastrointestinal tract. This review aims to provide an overview of the current development in enteral drug delivery strategies for PPTs. The design of these drug delivery systems in overcoming physical and chemical barriers along the gastrointestinal tract while improving oral bioavailability will be highlighted and discussed.

Background: Realgar, a Chinese herbal decoction, has been used to treat various types of tumors with positive outcomes; however, there is a lack of convincing evidence on its use for the treatment of esophageal cancer (EC). In this study, the role of the p62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the regulation of EC cell proliferation, migration, and ferroptosis in response to realgar was assessed. Methods: Different concentrations of realgar (0, 10, 20, 40, 60, 80, and 100 μmol/L) were applied to the EC cell lines Eca109 and KYSE150. The inhibition rate and half-inhibitory concentration (IC50) were determined using the Cell Counting Kit-8 (CCK-8) method. Subsequently, the cells were treated with realgar (1/2IC50, IC50, 2IC50). Cell migration was measured using the scratch assay, and cell invasion was measured using the transwell assay. The mRNA expression of p62, Keap1, and Nrf2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the protein expression of p62, Keap1, Nrf2, matrix metalloproteinase (MMP)-2, MMP-9, E-cadherin, Slug, N-cadherin, and vimentin was measured by Western blot. The control, 2IC50, shRNA-NC, shRNA-p62, 2IC50 + shRNA-NC, 2IC50 + shRNA-p62, shRNA-Keap1, 2IC50 + shRNA-Keap1, and 2IC50 + shRNA-p62 + shRNA-Keap1 groups were defined. The CCK-8 method was used to measure the cell inhibition rate, and the clone formation assay was used to measure the clone formation ability. Moreover, the scratch assay was used to detect the cell migration ability, and the transwell assay was used to detect the cell invasion ability. Transmission electron microscopy was used to observe the mitochondrial morphology, Prussian blue staining was used to observe the intracellular iron particle distribution, and flow cytometry was used to detect changes in intracellular reactive oxygen species. In addition, qRT-PCR was performed to detect p62, Keap1, Nrf2, and glutathione peroxidase 4 (GPX4) mRNA expression, and Western blot was performed to detect p62, Keap1, Nrf2, E-cadherin, Slug, N-cadherin, and GPX4 protein expression. Results: Realgar inhibited Eca109 and KYSE150 cell proliferation in a time- and concentrationdependent manner. It also significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and affected the mRNA and protein expression of p62, Keap1, and Nrf2. In response to realgar, low p62 expression inhibited the proliferation, migration, and invasion of Eca109 and KYSE150 cells, as well as ferroptosis induction. Conclusion: The findings demonstrate that inhibiting the p62-Keap1-Nrf2 signaling pathway promotes the inhibitory effects of realgar on EC cells.

Background: Nicotine is a fat-soluble substance that is easily absorbed through the skin and mucosal tissues of the human body. However, its properties, such as light exposure, heat decomposition, and volatilization, restrict its development and application in external preparations. Objective: This study focused on the preparation of stable nicotine-encapsulated ethosomes. Methods: During their preparation, two water-phase miscible osmotic promoters, ethanol and propylene glycol (PG), were added to obtain a stable transdermal delivery system. Skin nicotine delivery was enhanced through the synergistic action of osmotic promoters and phosphatidylcholine in binary ethosomes. Various characteristics of the binary ethosomes were measured, including the vesicle size, particle size distribution, and zeta potential. In order to optimize the ratio of ethanol and PG, the skin permeability test was performed on mice in vitro in a Franz diffusion cell to compare cumulative skin permeabilities. The penetration depth and fluorescence intensity of rhodamine-B-entrapped vesicles in isolated mouse skin samples were observed using laser confocal scanning microscopy. Results: When ethanol:PG was used in a ratio of 5:5 (w/w), binary ethosomes were found to be the most stable, had the highest encapsulation rate (86.13 ± 1.40), smallest particle size (106.0 ± 11.0) nm, maximum transdermal depth (180 μm), and maximum fluorescence intensity (160 AU). Nicotineencapsulated ethosomes (ethanol: PG = 5:5, w/w) were an efficient and stable transdermal delivery system. Conclusion: The nicotine-encapsulated ethosomes containing ethanol and PG are considered to be safe and reliable as a transdermal administration agent, which does not irritate the skin.

Background: Formononetin (FNT), a methoxy isoflavone, is a potential phytoconstituent utilized for refurbishing fractures in bone tissue. Conceding to its involvement in first-pass metabolism followed by glucuronidation, its absorption efficacy is limited. Hence, it belongs to the BCS class II classification. Objective: We designed the present work to enhance FNT oral bioavailability by using Phospholipids (PL) as a promising carrier. Formononetin Phospholipid Complex (FNT-PC) was prepared by the solvent evaporation method and characterized. Methods: FNT-PC was prepared by solvent evaporation method and characterization (FNT-PC) was performed using aqueous/n-octanol solubility and partition coefficient, FTIR, NMR, SEM, and in vivo pharmacokinetic study in female SD rats at 50 mg/kg. Results: Physicochemical properties like aqueous/n-octanol solubility and partition coefficient were enhanced in FNT-PC. The FTIR spectrum confirmed there was no involvement of functional groups in the preparation of FNT-PC. Whereas, the NMR study resulted in the attachment of carbon (C-8) position of FNT by replacing the quaternary amine of PL to form FNT-PC. When scrutinized for its surface morphology, the FNT-PC exhibited the amorphous geometry that remarkably enhanced the dissolution of FNT (p<0.05) from its pure form. This dissolution effect was also affirmed by the per-oral administration of FNT-PC in female Sprague Dawley (SD) rats at 50 mg/kg dose. The pharmacokinetic profile showed the free FNT levels were markedly increased, correspondingly decreasing the conjugated FNT levels in rat plasma. Conclusion: To summarize, FNT-PC could substantially reduce the first-pass metabolism with enhanced free concentration, improving oral bioavailability for therapeutic use.

Aim: The aim of this study is to improve the water solubility and stability of cannabidiol (CBD) utilizing micelle technology. Materials and Methods: Mixing of rubusoside (RUB) with Poloxamer 407 (P407) was explored as the wall material for the preparation of CBD micelles. In this study, CBD-loaded mixed micelles (CBD-M) composed of P407 and RUB was successfully formed by self-assembly then solid were prepared by solvent evaporation. The saturated solubility of CBD-loaded micelles in water increased to 15.60 mg/mL, 1560-fold compared with its intrinsic solubility (0.01 mg/mL). The average size of CBD-M was 103 ± 2.66 nm and the encapsulation efficiency for CBD was 92.8 + 4.7 %, and 18.6 + 0.94% for drug-loading. Results: The morphology and encapsulation of CBD-M were characterized by TEM, FI-IR, DSC and TG. The CBD-M solution was stable and CBD-M did not precipitate or leak after being diluted and centrifugated. Besides, CBD-M solution was stable for 6 months at 4°C and room temperature. In vitro antioxidant studies found that the antioxidant activity of CBD remained at the same level after micellization. Conclusion: These results suggest that CBD-M may be a promising and competitive formulation for the delivery of CBD, laying a foundation for improving the bioavailability in the future.

Background: Biocompatible MIL-100 (Fe), a metal organic framework material, has recently attracted increasing attention in biomedical engineering. The high surface area, pore volume, and accessible Lewis acid sites make MIL-100 (Fe) a proper candidate for hydrophobic anticancer drug loading and storage. In this study, a novel investigation of cyclophosphamide (CP) -loaded MIL-100(Fe) (MIL- 100(Fe)/CP) and a simulation of drug loading at a molecular level is presented. Methods: This research used a facile synthesis method to prepare MIL-100(Fe), which addresses the high temperature and pressure challenges of synthesis methods. MIL-100(Fe) and MIL-100(Fe)/CP were characterized using x-ray diffraction (XRD), Brunauer–Emmett–Teller (BET), Fourier transform infrared (FTIR), and field emission scanning electron microscopy (FESEM). Results: The carriers' drug loading and release behavior are determined by using UV-visible spectrophotometry. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay is applied to examine the biocompatibility and the anticancer effect of MIL-100(Fe)/CP on the human breast cancer cell line (MCF-7). Conclusion: In vivoantitumor experiments and histological observation reveal inhibition properties of MIL-100(Fe)/CP on the tumor cells. MIL-100(Fe)/CP, with 37.41% drug payload, represents impressive antitumor activity.

Introduction: Anti-inflammatory medications, in particular aspirin, have chemopreventive and anticancer adjuvant effects on specific types of cancers, according to ongoing anti-tumor research. Additionally, efforts have been made to transform Poly(salicylic acid) (PSA) into delivery-related nanocarriers. to transport anticancer medications into nanocarriers. However, tumor cell targeting and tumor selectivity were lacking in the salicylic acid polymer-based nanocarriers, preventing them from performing to their full potential. Objective: The objective of this study is to prepare targeting and reduction-responsive poly pre-drug nanocarriers (HA-ss-PSA NPs) and to investigate the feasibility of delivering adriamycin (DOX) as nanocarriers. Methods: The structures of the polymers were confirmed by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR) and infrared spectroscopy (IR); the encapsulation rate and drug loading of DOX-loaded nanoparticles were determined by HPLC; and the anti-tumor effects of the carriers were evaluated by MTT experiments and in vivoexperiments. Results: The prepared nanocarriers had uniform particle size distribution. The drug release rate was up to 80% within 48 h in the tumor environment. DOX/HA-ss-PSA NPs showed significant cytostatic effects. In addition, HA-ss-PSA NPs showed significant targeting and inhibition of cell migration in cell uptake and scratch assays. In vivoexperiments showed that the prepared carriers had high tumor inhibition rates, good targeting effects on the liver and tumor, and significantly reduced toxicity to other tissues. Conclusion: The prepared HA-ss-PSA NPs could effectively inhibit the growth of HepG2 cells and tumors in vivo, indicating that PSA could be used as a backbone component of a safe and reliable drug delivery system, providing a new strategy for the treatment of liver cancer.