Current Drug Delivery - Online First

Plant-derived extracellular vesicles (PDEVs) are vital for intercellular material exchange and information transfer. They significantly regulate cellular functions, tissue repair, and self-defense mechanisms.

This review summarizes the formation pathways, composition, and potential applications of PDEVs in anti-tumor research and drug delivery systems.

We conducted a literature search using keywords such as “plant-derived extracellular vesicles,” “exosomes,” “drug delivery,” “isolation and purification,” “stability,” “anti-tumor,” and “tumor therapy” in databases including PubMed, Web of Science, and Scopus. We examined studies on the formation pathways of PDEVs, including fusion of multivesicular bodies with the plasma membrane, exosome-positive organelles, and vacuole release. We also reviewed isolation and purification techniques critical for studying their biological functions. Furthermore, we analyzed research on the application of PDEVs in cancer therapy, focusing on their inhibitory effects in various cancer models and their role as carriers in drug delivery systems.

PDEVs have demonstrated potential in anti-tumor research, particularly with vesicles from plants like tea, garlic, and Artemisia annua showing inhibitory effects in breast, lung, and gastric cancer models. Additionally, PDEVs serve as effective carriers in drug delivery systems, offering possibilities for developing ideal therapeutic solutions.

While PDEVs show promise in cancer treatment and drug delivery, challenges such as standardization, storage stability, and elucidation of action mechanisms remain. Further research is needed to overcome these challenges and advance the clinical translation of PDEVs.

Influenza, a seasonal infectious disease, has consistently posed a formidable challenge to global health in recent years. Favipiravir, an RNA-dependent RNA polymerase inhibitor, serves as an anti-influenza medication, currently administered solely in oral form for clinical use. However, achieving an effective therapeutic outcome often necessitates high oral doses, which can be accompanied by adverse effects and suboptimal patient adherence.

To enhance favipiravir delivery efficiency and potentially mitigate dosage-related side effects, this study aimed to formulate favipiravir as a dry powder for pulmonary inhalation, facilitating direct targeting of lung tissue.

Employing L-leucine as a carrier, favipiravir was prepared as an inhalable dry powder through the spray-drying technique. A 3x3 full-factorial design approach was adopted to optimize the formulation. The optimized spray-dried powder underwent comprehensive characterization, including assessments of its morphology, crystallinity, flowability, and aerodynamic particle size distribution. The therapeutic efficacy of the powder was evaluated in a mouse model infected with the H1N1 influenza virus.

The formulated powder demonstrated good aerosol properties, rendering it suitable for inhalation delivery. Its therapeutic efficacy was demonstrated in the mouse model, where it exhibited marked protective effects against the virus in vivo after 5 days of treatment. Notably, the inhalation dose required (15 mg/kg/day) was significantly lower than the oral gavage dose (150 mg/kg/day), indicating that substantially reduced doses, when administered via inhalation, were sufficient to confer protection against mortality in mice.

The findings underscore the potential of inhalation therapy using spray-dried favipiravir powder as an effective and efficient treatment option for influenza, offering the promise of reduced dosing requirements and associated adverse effects.

In traditional Chinese medicine, the decoction turns into a complex multiphase system following exposure to high temperatures and a complex chemical environment. However, the effective dispersion system of the decoction of Kushen Huaihua (DKH) for the treatment of ulcerative colitis (UC) has yet to be elucidated.

DKH was separated into precipitated phase (DKH-P), nanophase (DKH-N), and solution phase (DKH-S) according to the particle size by ultracentrifugation dialysis, and the physicochemical properties of each phase group, such as particle size, morphology, chemical composition, and content, were analysed by TEM and HPLC. The anti-UC effects of the different phases were evaluated by ELISA and HE staining. Furthermore, the composition of the effective dispersion system and release characteristics were investigated by UV and HPLC.

The fingerprint analysis of DKH recognized 11 key components, namely Ru, Qu, Ka, Fo, Iso, Kur, SFG, OMT, OSC, MT, and SC. The content of these components in DKH-N was found to be 69.51%, 88.30%, 84.60%, 82.92%, 73.35%, 77.03%, 74.02%, 89.95%, 85.99%, 79.53%, and 85.24% of the corresponding levels in DKH, respectively. Pharmacodynamic results demonstrated that DKH-N exerted the same anti-UC effect as DKH, decreased DAI and CMDI scores, increased IL-4 and IL-10 activities, and reduced expression of IL-6, TNF-α, and MPO, which were significantly different from those of the model group (**P<0.01). Additionally, DKH-N was found to comprise 30.30% polysaccharides and 24.93% protein components. Furthermore, 11 components in DKH-N demonstrated more than 80% release in enzyme-containing simulated colonic fluid in 24 h.

DKH-N may be an effective dispersion system for DKH treatment of UC.

Superparamagnetic iron oxide nanoparticles (SPIONs) with a specific size range of 15-70 nm are usually considered nontoxic substances with superior antibacterial activity, making them strong candidates for wound dressing applications. Although SPIONs have significant antibacterial activity, their ability to treat infected wounds still needs to be explored.

The objective of the present study was to synthesize antibacterial SPIONs (G-SPIONs) using aqueous garlic extract as a bioreducing agent and evaluate the synthesized G-SPIONs-incorporated nanohydrogel for wound healing potential.

Synthesized G-SPIONs were characterized by SEM, zeta potential, VSM, FTIR, etc. The antibacterial effects of G-SPIONs were evaluated against S. epidermidis, S. aureus, and E. coli, as compared to garlic extract. The synthesized G-SPIONs were further incorporated into the chitosan-based hydrogel (ChiG-SPIONs) to assess their wound healing potential using the in vivo rat model.

The synthesized G-SPIONs had a positive surface charge of +3.82 mV and were spherical, with sizes ranging between 20-80 nm. Additionally, their hemo-biocompatible nature was confirmed by hemolysis assay. The magnetic nature of synthesized G-SPIONs was investigated using a vibrating sample magnetometer, and the saturation magnetization (Ms) was found to be 53.793emu/g. The in vivo wound healing study involving rats revealed a wound contraction rate of around 95% with improved skin regeneration. The histopathological examination demonstrated a faster rate of re-epithelialization with regeneration of blood vessels and hair follicles.

The results demonstrated that the developed ChiG-SPIONs could be a novel and efficient nanohydrogel dressing material for the effective management of wound infections.

Overcoming the poor aqueous solubility of small-molecule drugs is a major challenge in developing clinical pharmaceuticals. Felodipine (FLDP), an L-type calcium calcium channel blocker, is a poorly water-soluble drug.

The study aimed to explore the potential applications of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) stabilized amorphous dispersions for augmenting the oral delivery of poorly water-soluble drugs.

Soluplus-stabilized amorphous FLDP (FLDP-SSAs) was prepared using a two-phase mixing method. The samples were analyzed for their microscopic and macroscopic behavior using polarized light microscopy (PLM), differential scanning calorimetry (DSC), molecular simulation, and in vitro dissolution studies. Subsequently, the pharmacokinetics of FLDP-SSAs were evaluated.

The maximum drug-to-Soluplus mass ratio of FLDP-SSAs was 50:50, with a drug concentration of 8.0 mg/mL. They exhibited an amorphous nature, as confirmed by PLM and DSC. FLDP-SSAs generated nanoparticles with a particle size of approximately 50 nm during in vitro dissolution. Compared to FLDP oral solution, FLDP-SSAs exhibited higher solubility due to their amorphous nature and the generation of nanoparticles. The area under the curve (AUC) for oral FLDP-SSAs was 16.7-fold larger than that of the FLDP suspension.

FLDP-SSAs could stabilize FLDP in an amorphous state and serve as drug carriers to enhance oral absorption.

Poly(methyl vinyl ether co-maleic acid) (PMVE/MA) hydrogel microneedles (HMN) are investigated for transdermal delivery of macromolecular drugs owing to their biocompatibility and super-swelling properties. However, the drug delivery efficacy reduces with increasing molecular weight due to the entrapment within the HMN matrices. Furthermore, integrating external drug reservoirs extends the drug diffusion path and reduces the efficiency of drug permeation.

A direct drug loading approach in the HMN matrix was introduced in this work following a pH modification step. The effect of pH modification on the physicochemical properties of HMN was studied. Then, bovine serum albumin (BSA), a model protein, was loaded into the pH-modified HMN, and the morphological changes in HMN and protein stability were also assessed. Finally, the efficacy of BSA-loaded HMN in the transdermal delivery was evaluated ex vivo.

A significant increase in swelling was recorded following the pH modification of HMN (p < 0.001). The structure of pH-modified hydrogel was highly porous, and ATR-FTIR spectra indicated a shift in the carboxylic peak. The secondary structure of BSA loaded in the pH-modified HMN was also preserved. The BSA-loaded HMN mediated a sustained ex-vivo drug release with a cumulative release of 64.70% (3.88 mg) in 24 h.

Hence, the model drug-incorporated PMVE/MA HMN system shows potential for sustainable transdermal delivery of proteins.

Rheumatoid arthritis is a chronic autoimmune disease, progressively distinctive via cartilage destruction, auto-antibody production, severe joint pain, and synovial inflammation. Nanotechnology represents one of the utmost promising scientific technologies of the 21^st century. Nanocarriers could be the key to unlocking its potential by encapsulating Rutin in targeted drug delivery systems, potentially for targeted Rheumatoid arthritis therapy.

The rationale of current research is to prepare liposomes loaded with a bioflavonoid drug rutin for effective management of rheumatoid arthritis.

This study investigated the formulation of rutin liposomes using the thin-film hydration technique, also known as the Bangham method. A Box-Behnken design was employed to optimize the formulation parameters. The LP2 batch was then characterized for its mean particle size, zeta potential, shape, diffraction pattern, and thermal properties. Finally, the in-vitro anti-oxidant and anti-inflammatory potential of the rutin liposomes were evaluated using appropriate assays.

Out of thirteen batches, LP2 was found to be an optimized batch with a mean particle size of 167.1 nm, zeta potential -13.50 mV, and entrapment efficiency of 61.22%. The above results showed higher stability of rutin liposomes. Further characterization of LP2 for morphological assessment, XRD analysis, and DSC revealed its spherical shape less than 1 µm, polycrystalline nature, and thermographic peak at 139°C, respectively. Evaluation of the antioxidant properties and anti-inflammatory potential of LP2 revealed its maximum therapeutic potential in the reduction of inflammation and protein denaturation when evaluated via in-vitro assays.

Rutin liposomal formulation has tremendous potential for the management of Rheumatoid arthritis due to its enhanced bioavailability, anti-oxidant, and anti-inflammatory properties when compared to free rutin.

Assessing the cytotoxicity of gold nanoparticles (GNPs) has gained importance due to their development in the biomedical field.

In this study, we systematically synthesized gold nanorods (GNRs), gold nanobipyramids (GNBPs), and gold nanocups (GNCs) using a seed-mediated method, with an average length of 32.53 ± 4.67 nm, 72.90 ± 7.54 nm and 118.01 ± 11.02 nm, respectively.

Furthermore, using the cell counting kit-8 (CCK-8) assay, we assessed the cellular cytotoxicity of three different types of GNPs with various different surface coatings, such as organic cetyltrimethylammonium bromide (CTAB) and polyethylene glycol (PEG). The results showed that the cytotoxic behavior of GNPs was shape-dependent in the concentration range of 3.125 -100 μg/mL. The types of GNPs and their surface coating had a significant impact on how the GNPs behaved in cells. Compared to PEG-coated GNPs, which do not induce cell injury, CTAB-coated GNPs show more noticeable cytotoxicity.

Furthermore, compared to GNCs, the toxicity of GNRs and GNBPs against GES-1 cells, RAW 264.7 cells and LX-2 cells was greater. Our research provides an important new understanding of the effects of surface modification on the biocompatibility and the shape of GNPs in the biomedical field.

Tetrandrine (TET) has multiple pharmacological activities, but its water solubility is poor, which is the main reason for its low bioavailability.

The purpose of this study was to prepare TET nanocrystals (TET-NCs) using a grinding method to enhance the dissolution rate and ultimately improve the bioavailability of TET.

TET-NCs were synthesized via media milling, employing Poloxam 407 (P407) as surface stabilizers and mannitol as a cryoprotectant during freeze-drying. The crystal structure, particle diameter, and zeta potential were characterized using differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The in vitro release behavior and pharmacokinetics of TET-NCs were assessed. The cytotoxicity of TET and TET-NCS on RAW264.7 cells was determined by the CCK-8 method.

The particle size of TET-NCs was 360.0±7.03 nm, PDI was 0.26±0.03, and zeta potential was 6.64±0.22 mV. The cumulative dissolution within 60 minutes was 96.40±2.31%. The pharmacokinetic study showed that AUC0-72 h and Cmax of TET-NCs were significantly enhanced by 3.07 and 2.57 times, respectively, compared with TET (p<0.01). TET-NCs significantly increased the cell inhibition on RAW264.7 cells compared to the TET (P<0.01).

The preparation of TET-NCs enhanced dissolution rate and bioavailability significantly, and it also improved the inhibition effect of RAW264.7 cells.