Nanocarriers Research Articles

Intranasal delivery of metformin using metal–organic framework (MOF)-74-Mg nanocarriers

Dosage tolerance is one of the translational challenges of using metformin (Met) in brain therapeutics. This paper presents metal–organic framework (MOF)-74-Mg nanocarriers (NCs) for intranasal (IN) delivery of brain-specific agents with a prolonged release time. We confirmed their excellent biocompatibility (5 mg/mL) and intrinsic fluorescence properties (370/500 nm excitation/emission peak) in Neuro-2A cells. This NC exhibited a high Met loading rate (10% wt/wt) and a sustained and prolonged release pattern of Met (90% release in 16 h) in Dulbecco’s Modified Eagle Medium. We observed an optimal brain accumulation of Met-MOF (9% of the injected dosage) 8 h after IN injection. This percentage is at least 82 times higher than oral administration. Confocal imaging demonstrated significantly higher uptake of Met-MOF, 45 min after IN injection, by 79–85% neurons and 93–97% microglia than astrocytes and oligodendrocytes across 5xFAD mouse brain regions, including hippocampus and striatum. These results suggest MOF-74-Mg is a potential NC for high brain Met accumulation, real-time imaging, and prolonged and sustained release of Met and other neurotherapeutic agents that are challenging to deliver using traditional carriers and administration routes.

Toward Resolving Heterogeneous Mixtures of Nanocarriers in Drug Delivery Systems through Light Scattering and Machine Learning.

Nanocarriers (NCs) have emerged as a revolutionary approach in targeted drug delivery, promising to enhance drug efficacy and reduce toxicity through precise targeting and controlled release mechanisms. Despite their potential, the clinical adoption of NCs is hindered by challenges in their physicochemical characterization, essential for ensuring drug safety, efficacy, and quality control. Traditional characterization methods, such as dynamic light scattering and nanoparticle tracking analysis, offer limited insights, primarily focusing on particle size and concentration, while techniques like high-performance liquid chromatography and mass spectrometry are hampered by extensive sample preparation, high costs, and potential sample degradation. Addressing these limitations, this work presents a cost-effective methodology leveraging light scattering and optical forces, combined with machine learning algorithms, to characterize polydisperse nanoparticle mixtures, including lipid-based NCs. We prove that our approach provides quantification of the relative concentration of complex nanoparticle suspensions by detecting changes in refractive index and polydispersity without extensive sample preparation or destruction, offering a high-throughput solution for NC characterization in drug delivery systems. Experimental validation demonstrates the method's efficacy in characterizing commercially available synthetic nanoparticles and Doxoves, a liposomal formulation of Doxorubicin used in cancer treatment, marking a significant advancement toward reliable, noninvasive characterization techniques that can accelerate the clinical translation of nanocarrier-based therapeutics.

Exosomes as nature's nano carriers: Promising drug delivery tools and targeted therapy for glioma.

Exosomes, minute vesicles originating from diverse cell types, exhibit considerable potential as carriers for drug delivery in glioma therapy. These naturally occurring nanocarriers facilitate the transfer of proteins, RNAs, and lipids between cells, offering advantages such as biocompatibility, efficient cellular absorption, and the capability to traverse the blood-brain barrier (BBB). In the realm of cancer, particularly gliomas, exosomes play pivotal roles in modulating tumor growth, regulating immunity, and combating drug resistance. Moreover, exosomes serve as valuable biomarkers for diagnosing diseases and assessing prognosis. This review aims to elucidate the therapeutic and diagnostic promise of exosomes in glioma treatment, highlighting the innovative advances in exosome engineering that enable precise drug loading and targeting. By circumventing challenges associated with current glioma treatments, exosome-mediated drug delivery strategies can enhance the efficacy of chemotherapy drugs like temozolomide and overcome drug resistance mechanisms. This review underscores the multifaceted roles of exosomes in glioma pathogenesis and therapy, underscoring their potential as natural nanocarriers for targeted therapy and heralding a new era of hope for glioma treatment.

The investigation of the interaction of warangalone with transferrin as a therapeutic biological macromolecule and the formation of a protein-ligand nanocomplex with superior anticancer activity against lung cancer cells.

Though warangalone has shown anticancer properties against breast cancer cells, its colloidal stability and therapeutic index ought to be improved using a potential strategy, especially via protein-based (nano)carriers. In this research, transferrin was used as a plasma protein for the development of the warangalone-transferrin NPs. To investigate the mechanism underlying the formation of this complex, the interaction between warangalone and transferrin, as well as transferrin NPs, was analyzed using spectroscopic methods. The anticancer properties of warangalone and warangalone-transferrin NPs in lung cancer were subsequently evaluated. The findings showed that the hydrodynamic size, PDI, and zeta potential values of transferrin NPs were 122.4 ± 12.38 nm, 0.210, and -23.40 ± 3.28 mV, respectively. The association between warangalone and transferrin NP showed a strong binding strength (log Kb = 5.44 ± 0.07), while this affinity was reduced for the warangalone and the transferrin protein (log Kb = 4.88 ± 0.04). Theoretical research indicated that hydrophobic interactions serve as the main driving forces for the interaction of warangalone and transferrin. Cellular assays showed that the warangalone-transferrin NPs significantly affected cell death in lung cancer cells. This research, by offering promising data, could be highly beneficial for advancing warangalone-transferrin NPs as a promising anticancer platform.

Potential of Nanoparticle Based Antimicrobial Drug Repurposing to Efficiently Target Alzheimer's: A Concise Update on Evidence-based Research and Challenges Ahead.

Repurposing of drugs through nanocarriers (NCs) based platforms has been a recent trend in drug delivery research. Various routine drugs are now being repurposed to treat challenging neurodegenerative disorders including Alzheimer disease (AD). AD, at present is one of the challenging neurodegenerative disorders characterized by extracellular accumulation of amyloid-β and intracellular accumulations of neurofibrillary tangles. In spite of catchy progress in drug development, effective treatment outcome in AD patients is far-fetched dream. Out of several proposed hypothesis in the development and progression of AD, potential role of microorganisms causing dementia and AD cannot be ruled out. Several recent researches have been documented a clear correlation in between microbial infection and neuronal damage leading to progression of AD. Thus, antimicrobial drugs repurposing has been emerged as alternate, potential, cost-effective strategy to check progression of AD. Further, for efficient delivery of antimicrobial drugs to brain tissue, novel NCs based platforms are the preferred option to bypass blood-brain barrier. Several polymeric and lipid NCs have been extensively studied over the past years to improve antimicrobial drug delivery to brain. The present review encompasses various repurposing strategy of antimicrobial drugs delivered through various NCs to target AD. Evidence-based research outcome compiled from authentic database like Scopus, PubMed, Web of science have been pooled to provide an updated review. Side by side some light has been thrown on the practical problems faced by nanodrug carriers during technology transfer.

Development of amphiphilic self-assembled nucleolipid as BBB targeting probe based on SPECT

Several approaches have been utilised to deliver therapeutic nanoparticles inside the brain but rendered by certain limitation such as active efflux, non-stability, toxicity of the nanocarrier, transport, physicochemical properties and many more. In this context use of biocompatible nano carriers is currently investigated. We herein present the hypothesis that the nucleoside-lipid based conjugates (nucleolipids) which are biocompatible in nature and have molecular recognition can be tuned for improved permeation across blood–brain barrier (BBB). In this work, a di-C15-palmitoyl-ketal nucleolipid nanoparticle bearing an acyclic chelator has been formulated, radiolabeled with 99mTc and evaluated for in vivo fate using SPECT imaging. The mean particle size of particles was 113 nm and found to be nontoxic as depticted through haemolytic assay (2.33% erythrocyte destruction) and 75 ± 0.3% HEK(Human Embryonic Kidney) cells survived at 72 h as depicted in SRB (Sulforhodamine B) toxicity assay. The encapsulation efficiency (68 ± 2.75%) and drug loading capacity (22 ± 1.8%.) was calculated for nanoparticles using Methotrexate as model anti-cancer drug. The mathematical models indicate fickian release with a release constant KH = 20.70. With 98 ± 0.75% radiolabelling efficiency and established in vitro stability, nanoparticles showed brain uptake in normal mice as 0.91 times in comparison to BBB compromised mice (1.6% ± 0.03 ID/g)indicating higher brain uptake with rapid clearance as depicted through blood kinetics.Graphical absract

Formulation of Morus Alba extract loaded solid lipid nanoparticles: in silico, characterizations, and In vitro cytotoxicity study

Objective This study aimed to formulate Morus alba leaf extract (MAE) loaded solid lipid nanoparticles (SLNs) and investigate its cytotoxic potential using MDA-MB231 cell line. Significance SLNs can protect MAE from degradation, enhance cytotoxicity potential, and making them suitable for various therapeutic areas. Methods SLNs were developed using high-pressure homogenization method, and the formulations were optimized based on particle size, zeta potential, % entrapment efficiency (EE), and % cumulative drug release (CDR). The in vitro cytotoxic efficacy of MAE-loaded SLNs was evaluated through apoptosis assays and compared to that of free MAE. Results The particle size, zeta potential, % EE, and % CDR of optimized SLNs were found 116.3 nm, −26.18 mV, 89.30%, and 79.4%, respectively. MAE-loaded SLNs demonstrated significantly greater cytotoxic effects than the MAE (p < 0.05). SLNs induced less inhibition in the G0/G1 phase but showed marked inhibition in the S phase (9.7 ± 1.7%) and G2/M phase (2.2 ± 0.6%), indicating effective disruption of DNA replication and cell division, with significant cytotoxicity compared to control cells. The percentage of total apoptosis was 72.49 ± 2.7% for MAE alone and 81.46 ± 2.9% for MAE loaded SLNs, demonstrating a notably higher apoptosis rate for the SLNs formulation (p < 0.05). These findings indicated that MAE loaded SLNs significantly enhance the apoptotic and cytotoxic impact compared to MAE. Conclusion These results proved that MAE loaded SLNs as a promising nano carrier system to improve the therapeutic performance of MAE

Isoform-Specific vs Isoform-Universal Drug Targeting: A New Targeting Paradigm Illustrated by New Anti-ICAM-1 Antibodies

ABSTRACT Drug targeting can be achieved by coupling drugs or their carriers to affinity molecules, mostly antibodies (Abs), which recognize specific protein targets. However, most proteins are not expressed in an exclusive configuration but as various isoforms. Hence, selected targeting molecules may fail to target with enough efficiency in clinical trials, which is overlooked. We illustrate this by targeting ICAM-1, a cell-surface protein overexpressed in many pathologies. Most ICAM-1 targeting studies used Ab R6.5, which binds ICAM-1 domain 2 (D2). Yet, literature and our data show that D2 is frequently absent among ICAM-1 isoforms. We thus produced a battery of five new Abs (B4, B6, B11, C12, G2) and tested their ability to recognize both full-length and -D2 ICAM-1. In solution, all Abs recognized both ICAM-1 forms (from 5.3x1011 to 4.2x1012 sum intensity/well). Coating them on nanocarriers (NCs) rendered G2 specific against -D2 ICAM-1 (4.2x106 NCs/well) while other Abs kept their dual recognition (from 6.4x106 to 2.2x107 NCs/well). All Abs induced NC intracellular uptake in respective cells (from 42% to 85%) and displayed good cross-species reactivity (from 4.4x1011 to 2.6x1012 sum intensity/well). These Abs represent valuable tools to target ICAM-1 and illustrate a new targeting paradigm that may improve classical strategies.

Targeted drug delivery via nanoparticles for cancer treatment

This review paper addresses the latest techniques for treating cancer as well as the numerous recent studies conducted on nanoparticles as delivery vehicles for anticancer medication. Numerous chemical and structural formulations of nanoparticles have been investigated for their ability to selectively bind to certain targets and to function as a drug delivery system. The surface characteristics and size of nanoparticles are key factors that impact the bio distribution of chemotherapy medications in the body as well as the efficiency of Nano carriers. For targeting cancerous cells and transporting anticarcinogenic drugs in a controlled way, numerous scientific researchers have been led to investigate the usage of magnetic nanoparticles in the cure of oncogenic breast cancer and brain tumor cells. Other drug delivery systems that have been tested include liposomes, magnetic nanoparticles, polymeric micelles, ceramic nanoparticles, and colloidal gold nanoparticles. The application of ceramic nanoparticles in photodynamic therapy for the cure of cancer is also covered in this article. Thus, the article provides a brief overview of the topic with suitable references to review articles and original research articles that describe previous and ongoing research findings related to different types of nanoparticles for drug delivery in cancer treatment.

PLA/PLGA nanocarriers fabricated by microfluidics-assisted nanoprecipitation and loaded with Rhodamine or gold can be efficiently used to track their cellular uptake and distribution

This study represents a pioneering investigation into using microfluidic technology for manufacturing PLA and PLGA nanocarriers (NCs) loaded with tracer molecules or metals through a co-precipitation protocol that involves saturating the water phase. The effects of total flow rate (TFR), flow rate ratio (FRR), surfactant amount, and polymer concentration on particle sizes and distributions were examined. The average size of PLA-NCs varied from 349 ± 175 nm to 170 ± 64 nm, with surface charges ranging from −13 to −6 mV. In contrast, PLGA-NCs had an average size between 192 ± 46 nm and 100 ± 34 nm, with surface charges from –23 mV to −53 mV. Increasing the TFR from 6 to 10 mL/min with a fixed FRR of 1:1 and reducing polymer concentrations in the organic phase from 20 to 5 mg/mL generally resulted in smaller NC sizes and distributions (monodispersed), with PLGA-NCs consistently exhibiting smaller dimensions. Under these specific conditions, Rhodamine B (Rhod) and gold (Au) were successfully loaded, achieving encapsulation efficiencies exceeding 50 %. Electron microscopy analysis confirmed that the nanocarriers exhibited a consistent spherical shape with smooth surface morphology. X-ray energy-dispersive spectroscopy (EDX) revealed a uniform distribution of gold within the polymer matrix. PLA-NCs were effectively internalized by various cell types, including human Peripheral Blood Mononuclear Cells (PBMCs), HT-29 colon cancer cells, and C6 glioma cells. Uptake occurred in a dose-dependent manner for PLA-NCs sized at 260 ± 51 nm, with only 30 % internalization at 2 mg/mL concentration after 24 to 48 h. Notably, smaller PLA-NCs with a mean size of 170 ± 64 nm achieved nearly 100 % uptake across all tested cell types after 48 h, indicating that particle size significantly influenced cellular uptake.

Liver Regeneration Following Thermal Ablation Using Nanocarrier Mediated Targeted Mesenchymal Stem Cell Therapy

Abstract Purpose To test the efficacy of nanocarrier (NC) mediated mesenchymal stem cell (MSC) therapy for liver regeneration following thermal ablation of porcine livers. Materials and Methods Liver radiofrequency ablation was performed in 18 swines divided into MSC, MSC + NC and control groups. The test groups received infusion of MSC or MSC + NC labeled with enhanced green fluorescent protein (eGFP) via hepatic artery. MSC + NC group had MSCs coated with dendrimer nanocarrier complexed with I-Domain of lymphocyte function-associated antigen-1 (LFA-1). Nanocarriers direct homing of MSCs by binding to its counterpart protein, intercellular adhesion molecule-1 (ICAM-1), which is overexpressed at the periablation margins from inflammation. Ablation cavity reduction by CT volumetry was used as surrogate marker for liver regeneration. Cell proliferation was assessed with Ki67 and HepPar-1 stains. GFP identified MSC derived cells. Results Total number of ablations in control animals were 13 across 4 animals. In the MSC group, there were 23 ablations across 6 animals, and in MSC + NC group there were 21 ablations across 6 animals. Ablation cavity volume reduction from day 0 to 30 were 64.4 ± 15.0%, 61.5 ± 12.9% and 80.3 ± 9.4% for control, MSC and MSC + NC groups, respectively (MSC + NC vs MSC: p &lt; 0.001, MSC + NC vs. control: p = 0.001). GFP+ cell count at margins was 426.8 ± 193.2 for MSC group and 498.6 ± 235.2 for MSC + NC group (p = 0.01). The mean Ki67 and HepPar-1 staining at margins were 9.81 ± 4.5% and 6.12 ± 4.2% for MSC + NC group versus 7.59 ± 3.7% and 5.09 ± 3.7% for MSC group, respectively (P &lt; 0.001 and P = 0.09, respectively). Conclusion Nanocarrier-mediated MSC therapy promotes liver regeneration by engrafting MSCs at ablation margins, potentially making liver-directed therapy viable for patients with severe liver dysfunction. This technology may also benefit other solid organs. Graphical Abstract

Nanostructured lipid carriers decorated with polyphosphate coated linear and loop cell-penetrating peptides

AimThis study aimed to evaluate the cellular uptake of nanostructured lipid carriers (NLCs) decorated with polyphosphate coated linear and loop cell-penetrating peptides (CPPs). MethodsLinear-CPPs and loop-CPPs were synthesized via ring-opening polymerization and anchored on the surface NLCs, followed by coating with polyphosphate (PP). These nanocarriers (NCs) were characterized in terms of particle size, polydispersity index (PDI), and zeta potential. Cell viability and hemolysis, as well as enzyme-induced charge conversion via phosphate cleavage by free and membrane-bound intestinal alkaline phosphatase (IAP) were investigated. Cellular uptake studies by Caco-2 and HEK cells were quantitatively analyzed by flow cytometry and visualized by confocal microscopy. ResultsA shift in charge from positive to negative was obtained for both linear- and loop-CPPs-NLCs by coating with PP. PP-linear-CPPs-NLCs and PP-loop-CPPs-NLCs exhibited a particle size < 270 nm and a PDI of approximately 0.3. They had a minor effect on cell viability and caused in a concentration of 0.1 % (m/v) around 10 % hemolysis within 24 h. IAP triggered the cleavage and release of monophosphate from the surface of NLCs causing charge conversion from –22.2 mV to + 5.3 mV (Δ27.5 mV) for PP-linear-CPPs-NLCs and from −19.2 mV to + 11.9 mV (Δ31.1 mV) for PP-loop-CPPs-NLCs. Inhibition of alkaline phosphatase activity on Caco-2 and HEK cells confirmed the involvement of this enzyme in charge conversion. PP-linear-CPPs-NLCs showed on Caco-2 cells a higher uptake than PP-loop-CPPs-NLCs, whereas on HEK cells uptake of both types of NLCs was on the same level. The results of cellular uptake were confirmed visually by confocal microscopy. ConclusionCPPs-NLCs coated with polyphosphate are a promising approach to overcome the polycationic dilemma and to enhance cellular uptake.

Targeted delivery of quercetin using gelatin/starch/Fe3O4 nanocarrier to suppress the growth of liver cancer HepG2 cells

To suppress HepG2 liver cancer cells, a nanocarrier (NC) consisting of Fe3O4, Gelatin (G), and Starch (S) was synthesized and characterized for targeted delivery of Quercetin (QC) drug. The spectra obtained from X-ray diffraction (XRD) and Fourier transform infrared (FTIR) demonstrated that the nanoparticles (NP) in the NC are well-interconnected to each other and have formed a regular structure. Also, field emission scanning electron microscopy (FE-SEM) indicates a smooth and homogeneous surface of the synthesized NC. The results of the vibrating sample magnetometer (VSM) also corroborated the correctness of the synthesis of Fe3O4 NPs and Gelatin/Starch/Fe3O4@Quercetin NC (G/S/Fe3O4@QC) because the magnetic properties of Fe3O4 decreased with the addition of G/S@QC. Stability and particle size were determined by zeta potential and Dynamic light scattering (DLS). The percentage of drug loading and encapsulation efficiency of QC in the NC was 46.25 % and 87 %, respectively. QC profile release in acidic and natural environments showed controlled release and pH sensitivity of the NC. Cytotoxicity of L929 and HepG2 treated cells with the G/S/Fe3O4@QC was investigated by MTT staining, which agreed with the flow cytometry result. The results of Flowcytometry and MTT showed 43.5 % apoptosis and 42 % cytotoxicity in treated HepG2 cells by G/S/Fe3O4@QC, while it was not toxic to L929 normal cells. According to the results, G/S/Fe3O4@QC is a suitable NC for the targeted delivery of QC as a drug against HepG2 cancer cells.

Charge-converting nanocarriers: Phosphorylated polysaccharide coatings for overcoming intestinal barriers

For the design of charge-converting nanocarriers (NCs), cationic lipid-based NCs containing curcumin as model drug were coated with phosphorylated starch (NC-SP) and phosphorylated dextran (NC-DP). NCs showed a drug encapsulation efficiency of 94 % and had a mean size of 175 to 180 nm. The recorded zeta potential of the core NC (cNC) was +8.3 mV, whereas it reversed to −10.6 mV and −7.4 mV after decorating with SP and DP, respectively. Furthermore, a 3-fold higher amount of curcumin having been incorporated in these NCs remained stable within 2 h of UV exposure indicating a photoprotective effect of this delivery system. Charge-converting properties were confirmed by cleavage with intestinal alkaline phosphatase (IAP) and resulted in a zeta potential shift of Δ15.4 mV for NC-SP and Δ11.2 mV for NC-DP. NC-SP and NC-DP showed enhanced mucus permeating properties compared to cNC, that were additionally confirmed by an up to 2.2-fold improved cellular uptake on mucus secreting Caco-2/HT29-MTX cells. According to these results, NC-SP and NC-DP coatings hold promise as a viable and efficient strategy for charge-converting NCs.

New cellular models to support preclinical studies on ICAM-1-targeted drug delivery

Intercellular adhesion molecule 1 (ICAM-1) is a cell-surface protein actively explored for targeted drug delivery. Anti-ICAM-1 nanocarriers (NCs) target ICAM-1-positive sites after intravenous injection in animal models, but quantitative mechanistic examination of cellular-level transport in vivo is not possible. Prior studies in human cell cultures indicated efficient uptake of these formulations via cell adhesion molecule-(CAM)-mediated endocytosis. However, ICAM-1 sequence differs among species; thus, whether anti-ICAM-1 NCs induce similar behavior in animal cells, key for intracellular drug delivery, is unknown. To begin bridging this gap, we first qualitatively verified intracellular transport of anti-ICAM-1 NCs in vivo and then developed new cellular models expressing ICAM-1 from mouse, dog, pig, and monkey, species relevant to pharmaceutical translation and veterinary medicine. ICAM-1 expression was verified by flow cytometry and confocal microscopy. These cells showed specific targeting compared to IgG NCs or cells treated with anti-ICAM-1 blocker. Anti-ICAM-1 NCs entered cells in a time- and temperature-dependent manner, with kinetics and pathway compatible with CAM-mediated endocytosis. All parameters tested were strikingly similar to those from human cells expressing ICAM-1 endogenously. Therefore, this new cellular platform represents a valuable tool that can be used in parallel to support in vivo studies on ICAM-1-targeted NCs during pharmaceutical translation.

Toward the Integration of Machine Learning and Molecular Modeling for Designing Drug Delivery Nanocarriers.

The pioneering work on liposomes in the 1960s and subsequent research in controlled drug release systems significantly advances the development of nanocarriers (NCs) for drug delivery. This field is evolved to include a diverse array of nanocarriers such as liposomes, polymeric nanoparticles, dendrimers, and more, each tailored to specific therapeutic applications. Despite significant achievements, the clinical translation of nanocarriers is limited, primarily due to the low efficiency of drug delivery and an incomplete understanding of nanocarrier interactions with biological systems. Addressing these challenges requires interdisciplinary collaboration and a deep understanding of the nano-bio interface. To enhance nanocarrier design, scientists employ both physics-based and data-driven models. Physics-based models provide detailed insights into chemical reactions and interactions at atomic and molecular scales, while data-driven models leverage machine learning to analyze large datasets and uncover hidden mechanisms. The integration of these models presents challenges such as harmonizing different modeling approaches and ensuring model validation and generalization across biological systems. However, this integration is crucial for developing effective and targeted nanocarrier systems. By integrating these approaches with enhanced data infrastructure, explainable AI, computational advances, and machine learning potentials, researchers can develop innovative nanomedicine solutions, ultimately improving therapeutic outcomes.

Bioconjugated clicked chitosan/alginate nanocarriers with trastuzumab: Unlocking curcumin's potential in targeting breast cancer

Curcumin (Cur) has shown potential anticancer effects against various cancers, including colorectal and breast cancers. The aim of this study was to develop nanocarriers (NCs) bioconjugated with trastuzumab (Tras) using click reactions. Chitosan-maleimide (CHI-Mal) and thiolated alginate (SH-ALG) were synthesized to prepare CS-Mal/SH-ALG NCs, which were then conjugated with Tras as a receptor-targeting ligand via click chemistry. The characteristics of the NCs, including Cur loading and release profiles, were examined. Biocompatibility, anticancer effects, targetability, and cell death analysis were conducted on HER2-positive breast cancer cell line (SK-BR-3). The developed NCs exhibited a nano-scaled size, relatively spherical shape, and positive surface charge. The 7-day release of Cur from the Cur-loaded CHI-Mal/SH-ALG NCs (Cur-NCs) was significantly higher in the cancer environment (pH 5.5; 98%) compared to body fluid (pH 7.4; 57%). Tras-conjugated Cur-NCs (Tras-Cur-NCs) demonstrated superior anticancer effects, receptor-targeting efficiency, and cellular uptake compared to free Cur and non-targeted Cur-NCs. Additionally, Tras-Cur-NCs enhanced apoptotic cell death, indicating a non-inflammatory cell death with strong anticancer effect against HER2-positive SK-BR-3 cells. The spontaneous click reaction successfully formed pH-responsive Tras-conjugated NCs for targeted Cur delivery to HER2-positive breast cancer cells.

Ferrocene-functionalized magnetic core-shell nanoparticles based on hydrosilylation reaction for pH-responsive doxorubicin delivery system

This study describes the development of an innovative pH-sensitive drug delivery system (DDS) utilizing ferrocene (Fc) and magnetic nanoparticles (MNPs) for cancer therapy. One potential method for generating a diverse range of functional NPs involves attaching functional substances to MNPs. In this investigation, we display the successful modification of Fe3O4 NPs by an Fc derivative (4-Ferrocenylbutyl)dimethylsilane through a hydrosilylation reaction toward the synthesis of the Fe3O4@SiO2@VTES@Fc nanocarrier (NC). The doxorubicin (DOX) drug was loaded onto Fe3O4@SiO2@VTES@Fc NC with a drug loading capacity of about 80 % via π-π stacking interactions. Also, the prepared materials were thoroughly characterized using FT-IR, XRD, FE-SEM, EDX-MAP, VSM, DAPI, MTT, antioxidants, and CV techniques. In vitro studies on the release of DOX from Fe3O4@SiO2@VTES@Fc NC indicated a pH-responsive behavior with a lower release rate (< 10 %) at pH 7.4 compared to pH 5 (approximately 70 %) over a period of 96 h. Moreover, cytotoxicity assessments demonstrated notable cytotoxic effects of DOX-loaded Fe3O4@SiO2@VTES@Fc on MCF-7 cells (IC50 value: ∼8 µg/mL). The study findings suggest that the fabricated magnetic core-shell NC (Fe3O4@SiO2@VTES@Fc/DOX) exhibits stimulus-responsive behavior and holds promise as a sophisticated approach to specifically transport therapeutic agents into tumor sites while minimizing exposure to healthy tissues.

Biomimetic Oil-in-Water Nanoemulsions as a Suitable Drug Delivery System to Target Inflamed Endothelial Cells.

Currently, the biomimetic approach of drawing inspiration from nature has frequently been employed in designing drug nanocarriers (NCs) of actively target various diseases, ranging from cancer to neuronal and inflammation pathologies. The cell-membrane coating can confer upon the inner nanomaterials a biological identity and the functions exhibited by the cells from which the membrane is derived. Monocyte- and macrophage-membrane-coated nanomaterials have emerged as an ideal delivery system to target inflamed vasculature. Herein, we developed two biomimetic NCs using a human-derived leukaemia monocytic cell line (THP-1), either undifferentiated or differentiated by phorbol 12-myristate 13-acetate (PMA) into adherent macrophage-like cells as membrane sources for NC coating. We employed a secondary oil-in-water nano-emulsion (SNE) as the inner core, which served as an optimal NC for high payloads of lipophilic compounds. Two different biomimetic systems were produced, combining the biomimetic features of biological membranes with the physicochemical and nano-sized characteristics of SNEs. These systems were named Monocyte NEsoSome (M-NEsoSome) and Macrophage NEsoSome (M0-NEsoSome). Their uptake ability was investigated in tumour necrosis factor alfa (TNFα)-treated human umbilical vein endothelial cells (HUVECs), selected as a model of inflamed endothelial cells. The M0 membrane coating demonstrated accelerated internalisation compared with the monocyte coating and notably surpassed the uptake rate of bare NCs. In conclusion, M0-NEsoSome NCs could be a therapeutic system for targeting inflamed endothelial cells and potentially delivering anti-inflammatory drugs in vascular inflammation.

Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation.

Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.