Active Targeting Of Nanoparticles Research Articles

Hyaluronic acid/lactoferrin–coated polydatin/PLGA nanoparticles for active targeting of CD44 receptors in lung cancer

Traditional chemotherapeutic drugs lack optimal efficacy and invoke severe adverse effects in cancer patients. Polydatin (PD), a phytomedicine, has gradually gained attention due to its antitumor activity. However, its low solubility and poor bioavailability are still cornerstone issues. The present study aimed to fabricate and develop hyaluronic acid/lactoferrin–double coated PD/PLGA nanoparticles via a layer-by-layer self-assembly technique for active targeting of CD44 receptors in lung cancer. Different molecular weights (M.wt.) of HA (32 and 110 kDa) were exploited to study the relationship between the HA M.wt. and the NPs targeting efficacy. The optimized formulations were fully characterized. Their cytotoxicity and cellular uptake were investigated against A549 cell line by CCK-8 kit and fluorescence imaging, respectively. Finally, HA110/Lf-coated PD/PLGA NPs (F9) were subjected to a competitive inhibition study to prove internalization through CD44 overexpressed receptors. The results verified the fabrication of F9 with a particle size of 174.87 ± 3.97 nm and a zeta potential of −24.37 ± 1.19 mV as well as spherical NPs architecture. Importantly, it provoked enhanced cytotoxicity (IC50 = 0.57 ± 0.02 µg/mL) and superior cellular uptake efficacy. To conclude, the current investigation lays the foundation for the prospective therapeutic avenue of F9 for active targeting of CD44 receptors in lung cancer.

Long-term residence and efficacy of adenovirus-mimetic nanoparticles in renal target tissue

A major shortcoming in the treatment of mesangial cell-associated diseases such as IgA nephropathy, diabetic nephropathy, or lupus nephritis, which frequently progress to end-stage renal disease, is poor drug availability in the glomerular mesangium. Drug delivery via active targeting of nanoparticles, using ligands attached to the particle surface for target cell recognition to increase the biodistribution to the mesangium, is a promising strategy to overcome this hurdle. However, although several glomerular tissue targeting approaches have been described, so far no study has demonstrated the particles’ ability to deliver sufficient drug amounts combined with an appropriate nanoparticle target retention time to trigger relevant biological effects in the mesangium. In our study, we encapsulated erastin, a ferroptosis-inducing model compound, into adenovirus-mimetic, mesangial cell-targeting nanoparticles, enabling the direct visualisation of biological effects through ferroptosis-dependent histological changes. By intravital microscopy and analysis of histological sections, we were not only able to localise the injected particles over 10 days within the target cells but also to demonstrate biological activity in the renal glomeruli. In conclusion, we have characterised adenovirus-mimetic nanoparticles as a highly suitable drug delivery platform for the treatment of mesangial cell-associated diseases and additionally provided the basis for a potential renal disease model.

Targeted Nanocarrier-Based Drug Delivery Strategies for Improving the Therapeutic Efficacy of PARP Inhibitors against Ovarian Cancer.

The current focus of ovarian cancer (OC) research is the improvement of treatment options through maximising drug effectiveness. OC remains the fifth leading cause of cancer-induced mortality in women worldwide. In recent years, nanotechnology has revolutionised drug delivery systems. Nanoparticles may be utilised as carriers in gene therapy or to overcome the problem of drug resistance in tumours by limiting the number of free drugs in circulation and thereby minimising undesired adverse effects. Cell surface receptors, such as human epidermal growth factor 2 (HER2), folic acid (FA) receptors, CD44 (also referred to as homing cell adhesion molecule, HCAM), and vascular endothelial growth factor (VEGF) are highly expressed in ovarian cancer cells. Generation of active targeting nanoparticles involves modification with ligands that recognise cell surface receptors and thereby promote internalisation by cancer cells. Several poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently used for the treatment of high-grade serous ovarian carcinomas (HGSOC) or platinum-sensitive relapsed OC. However, PARP resistance and poor drug bioavailability are common challenges, highlighting the urgent need to develop novel, effective strategies for ovarian cancer treatment. This review evaluates the utility of nanoparticles in ovarian cancer therapy, with a specific focus on targeted approaches and the use of PARPi nanocarriers to optimise treatment outcomes.

Theranostic nanoparticles for detection and treatment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most recalcitrant cancers due to its late diagnosis, poor therapeutic response, and highly heterogeneous microenvironment. Nanotechnology has the potential to overcome some of the challenges to improve diagnostics and tumor-specific drug delivery but they have not been plausibly viable in clinical settings. The review focuses on active targeting strategies to enhance pancreatic tumor-specific uptake for nanoparticles. Additionally, this review highlights using actively targeted liposomes, micelles, gold nanoparticles, silica nanoparticles, and iron oxide nanoparticles to improve pancreatic tumor targeting. Active targeting of nanoparticles toward either differentially expressed receptors or PDAC tumor microenvironment (TME) using peptides, antibodies, small molecules, polysaccharides, and hormones has been presented. We focus on microenvironment-based hallmarks of PDAC and the potential for actively targeted nanoparticles to overcome the challenges presented in PDAC. It describes the use of nanoparticles as contrast agents for improved diagnosis and the delivery of chemotherapeutic agents that target various aspects within the TME of PDAC. Additionally, we review emerging nano-contrast agents detected using imaging-based technologies and the role of nanoparticles in energy-based treatments of PDAC. This article is categorized under: Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Development of pH-Sensitive Alendronate-Decorated Silk Fibroin/ Alginate Nanoparticles for Active Targeting of Doxorubicin to Bone Cancers

Development of pH-Sensitive Alendronate-Decorated Silk Fibroin/ Alginate Nanoparticles for Active Targeting of Doxorubicin to Bone Cancers

Quercetin-loaded PLGA nanoparticles coating with macrophage membranes for targeted delivery in acute liver injury

Quercetin (QU), a natural flavonoid with potent anti-inflammatory and antioxidant properties, holds promise in treating acute liver injury (ALI). Nonetheless, its limited solubility hampers its efficacy, and its systemic distribution lacks targeting, leading to off-target effects. To address these challenges, we developed macrophage membrane-coated quercetin-loaded PLGA nanoparticles (MVs-QU-NPs) for active ALI targeting. The resulting MVs-QU-NPs exhibited a spherical morphology with a clear core–shell structure. The average size and zeta potential were assessed as 141.70 ± 0.89 nm and –31.83 ± 0.76 mV, respectively. Further studies revealed sustained drug release characteristics from MVs-QU-NPs over a continuous period of 24 h. Moreover, these MVs-QU-NPs demonstrated excellent biocompatibility when tested on normal liver cells. The results of biodistribution analysis in ALI mice displayed the remarkable ALI-targeting ability of MVs-DiD-NPs, with the highest fluorescence intensity observed in liver tissue. This biomimetic approach combining macrophage membranes with nanoparticle delivery, holds great potential for targeted ALI treatment.

Multifunctional Nanoparticles for Enhanced Chemodynamic/Photodynamic Therapy through a Photothermal, H2O2-Elevation, and GSH-Consumption Strategy.

Chemodynamic therapy (CDT) has witnessed significant advancements in recent years due to its specific properties. Its association with photodynamic therapy (PDT) has also garnered increased attention due to its mutually reinforcing effects. However, achieving further enhancement of the CDT/PDT efficacy remains a major challenge. In this study, we have developed an integrated nanosystem comprising a Fenton catalyst and multifunctional photosensitizers to achieve triply enhanced CDT/PDT through photothermal effects, H2O2 elevation, and GSH consumption. We prepared nano-ZIF-8 vesicles as carriers to encapsulate ferrocene-(phenylboronic acid pinacol ester) conjugates (Fc-BE) and photosensitizers IR825. Subsequently, cinnamaldehyde-modified hyaluronic acid (HA-CA) was coated onto ZIF-8 through metal coordination interactions, resulting in the formation of active targeting nanoparticles (NPs@Fc-BE&IR825). Upon cellular internalization mediated by CD44 receptors, HA-CA elevated H2O2 levels, while released Fc-BE consumed GSH and catalyzed H2O2 to generate highly cytotoxic hydroxyl radicals (·OH). Furthermore, NIR irradiation led to increased ·OH production and the generation of singlet oxygen (1O2), accompanied by a greater GSH consumption. This accelerated and strengthened amplification of oxidative stress can be harnessed to develop highly effective CDT/PDT nanoagents.

Application of Nanoparticles in Cancer Treatment: A Concise Review.

Timely diagnosis and appropriate antitumoral treatments remain of utmost importance, since cancer remains a leading cause of death worldwide. Within this context, nanotechnology offers specific benefits in terms of cancer therapy by reducing its adverse effects and guiding drugs to selectively target cancer cells. In this comprehensive review, we have summarized the most relevant novel outcomes in the range of 2010-2023, covering the design and application of nanosystems for cancer therapy. We have established the general requirements for nanoparticles to be used in drug delivery and strategies for their uptake in tumor microenvironment and vasculature, including the reticuloendothelial system uptake and surface functionalization with protein corona. After a brief review of the classes of nanovectors, we have covered different classes of nanoparticles used in cancer therapies. First, the advances in the encapsulation of drugs (such as paclitaxel and fisetin) into nanoliposomes and nanoemulsions are described, as well as their relevance in current clinical trials. Then, polymeric nanoparticles are presented, namely the ones comprising poly lactic-co-glycolic acid, polyethylene glycol (and PEG dilemma) and dendrimers. The relevance of quantum dots in bioimaging is also covered, namely the systems with zinc sulfide and indium phosphide. Afterwards, we have reviewed gold nanoparticles (spheres and anisotropic) and their application in plasmon-induced photothermal therapy. The clinical relevance of iron oxide nanoparticles, such as magnetite and maghemite, has been analyzed in different fields, namely for magnetic resonance imaging, immunotherapy, hyperthermia, and drug delivery. Lastly, we have covered the recent advances in the systems using carbon nanomaterials, namely graphene oxide, carbon nanotubes, fullerenes, and carbon dots. Finally, we have compared the strategies of passive and active targeting of nanoparticles and their relevance in cancer theranostics. This review aims to be a (nano)mark on the ongoing journey towards realizing the remarkable potential of different nanoparticles in the realm of cancer therapeutics.

Levan nanoparticles with intrinsic CD44-targeting ability for tumor-targeted drug delivery

Existing anticancer therapeutics exhibit short half-lives, non-specificity, and severe side effects. To address this, active-targeting nanoparticles have been developed; however, the complex fabrication procedures, scale-up, and low reproducibility delay FDA approval, particularly for functionalized nanoparticles. We developed levan nanoparticles via simple one-pot nanoprecipitation for specific anticancer drug delivery. Levan is a plant polysaccharide which has a binding affinity to CD44 receptors and amphiphilicity. The nanoparticles are self-assembled and enable active-targeting without chemical modifications. The paclitaxel-loaded levan nanoparticles (PTX@LevNP) demonstrated a sustained PTX release and long-term stability. The LevNP can bind CD44 receptors on cancer cells, and PTX@LevNP showed enhanced anticancer activity in CD44-positive cells (SCC7 cells). In SCC7 tumor-bearing mice, the accumulation of LevNP in tumor tissue was 3.7 times higher than that of the free-dye, resulting in improved anticancer efficacy of PTX@LevNP. This new strategy using levan can produce nanoparticles for effective cancer treatment without complex fabrication procedures.

Generation Natural Killer Cell-Mimic Nanoparticles for Active Targeting of Acute Myeloid Leukemia

Natural killer (NK) cells play a crucial role in recognizing and killing emerging tumor cells. Via an array of activating and inhibitory receptors, NK cells can target and kill abnormal cells, including tumor cells, without prior antigen sensitization. However, fully-established tumors employ numerous mechanisms to inactivate NK cells or hide from them, for example by shedding NK cell-activating ligands, like NK2GD (Chiossone et al., 2018). Here, we describe the engineering of nanoparticles (NPs) functionalized with tumor-recognizing and cytotoxic components of NK cells to address this problem and develop a nanoparticle-based treatment strategy simulating NK cell functionality. Liposomes were synthesized using the thin film hydration method followed by extrusion and functionalized them with the death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), immunoglobulin Fc-binding peptide (FCP, replicating the function of NK CD16 receptor) and the therapeutic antibody, anti-CD38 (daratumumab, Panel A) to target acute myeloid leukemia (AML). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to monitor morphology and size of liposomes. The potential of NK cell-mimic NPs (CD38-NK.NPs) to target and kill AML cells was evaluated on primary AML blasts and a disseminated AML xenograft for which the CD38-positive AML cell line, OCI-AML2 was engrafted into 8-9 week-old female NSG mice. Upon establishment of AML, the mice were injected intraperitoneally (i.p) with 5 doses of either naked liposomes (as vehicle control), soluble TRAIL protein (sTRAIL), LP/TRAIL or CD38-NK.NPs every two days. Tumor burden was monitored by determining the frequency of live human CD45+ cells in the peripheral blood, spleen and bone marrow with flow cytometry. Liposome was chosen as the base of the NP due to its high biocompatibility, biodegradability, cell-like characteristics and capability to penetrate through vessel walls (Pattni, Chupin and Torchilin, 2015). TEM and DLS measurements showed the generated NK.NPs were monodisperse with an average diameter of 145 nm, a size enabling vessel transmigration and avoiding kidney filtration (Gaumet et al., 2008). Immunofluorescent labelling of TRAIL, FCP and antibody verified CD38-NK.NPs functionalization. In vitro, both TRAIL-conjugated liposomes and CD38-NK.NPs were more effective in killing AML cell lines (ML-1, ML-2, Kasumi-1, and OCI-AML2) than sTRAIL, indicating that TRAIL-mediated cytotoxicity can be enhanced by presenting TRAIL in a conformation close to its membrane-bound structure. No significant difference could be detected between LP/TRAIL vs. CD38-NK.NP cytotoxicity in the in vitro assays. On the other hand, CD38-NK.NPs were more effective in killing primary AML blasts than non-targeted, NP-conjugated TRAIL (LP/TRAIL, 13±17% vs 4±15% killing, respectively). Moreover, CD38-NK.NPs showed considerably higher activity relative to the NK cell line, KHYG-1, against CD38-positive AML cell lines. Notably, CD38-NK.NPs showed no significant cytotoxic effect on non-malignant peripheral blood leukocytes. In vivo, NK cell-mimic NPs were more efficient in targeting and eradicating CD38-positive AML cells that either sTRAIL or LP/TRAIL, shown by the reduced percentage of circulating hCD45+ AML cells in treated mice (Panel B). CD38-NK.NPs were also more efficient in inhibiting accumulation of AML cells in the bone and spleen than sTRAIL and LP/TRAIL (Panel B), confirming the ability of CD38-NK.NPs to actively target AML cells expressing the targeted biomarker. Of note, CD38-NK.NPs showed no detectable systemic toxicity or damage to kidneys, liver and pancreas in healthy NSG mice. Overall, we have developed an NK cell-mimic nanoparticle able to actively target AML based on AML surface marker expression without any detectable systematic toxicity. Importantly, due to the modular built of the NK.NPs, they can be functionalized by any therapeutic tumor-targeting antibody via the immunoglobulin-binding peptide (FCP), thus enabling selective targeting tumor cells based on expression of tumor-specific markers and enabling personalized therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CD44 and CD221 directed magnetic cubosomes for the targeted delivery of helenalin to rhabdomyosarcoma cells

Confining chemotherapy to tumour sites by means of active targeting nanoparticles (NPs) may increase the treatment effectuality while reducing potential side effects. Cubosomes are one of the next-generation drug delivery nanocarriers by virtue of their biocompatibility and bioadhesion, sizeable payload encapsulation and high thermostability. Herein, an active tumour targeting system towards rhabdomyosarcoma (RMS) cells was evaluated. Cubosomes were loaded with helenalin (a secondary metabolite from Arnica plants), which we have previously shown to induce apoptosis in RMS cells. The functionalization of the cubosomes was accomplished to enable binding to membrane receptors and translocation under a magnetic field. RMS cells overexpress CD44 and CD221 on their membrane surface and, therefore, hyaluronic acid (HA, a ligand for CD44) and antibodies (Abs) against CD221 were coupled to cubosomes via electrostatic attraction and the thiol-Michael reaction, respectively. Magnetization of the cubic phase NPs was achieved by embedding superparamagnetic iron oxide NPs (SPIONPs) into the cubic matrix. Single-function and multi-function cubosomes had Im3m cubic phase structures with well-organized lattice patterns. Conjugation with 2% HA or anti-CD221 half Abs and/or 1% SPIONPs showed significantly higher uptake into RMS cells compared to unfunctionalized cubosomes. CD44 and CD221 directed magnetic (triple-function) cubosomes were capable of internalizing into RMS cells in an energy-independent mechanism. Helenalin-laden triple functionalized cubosomes showed limited impact on the viability of control fibroblast cells, while they induced a high degree cytotoxicity against RMS cells. Profound tumour cell death was observed in both two-dimensional (2D) culture and three-dimensional (3D) tumour spheroids.

Enhanced Oral Absorption and Liver Distribution of Polymeric Nanoparticles through Traveling the Enterohepatic Circulation Pathways of Bile Acid.

The intestinal epithelium is known to be a main hindrance to oral delivery of nanoparticles. Even though surface ligand modification can enhance cellular uptake of nanoparticles, the "easy entry and hard across" was frequently observed for many active targeting nanoparticles. Here, we fabricated polymeric nanoparticles relayed by bile acid transporters with monomethoxy poly(ethylene glycol)-poly(D,l-lactide) and deoxycholic acid-conjugated poly(2-ethyl-2-oxazoline)-poly(D,l-lactide) based on structural characteristics of intestine epithelium and the absorption characteristics of endogenous substances. As anticipated, deoxycholic acid-modified polymeric nanoparticles featuring good stability in simulated gastrointestinal fluid could notably promote the internalization of their payload by Caco-2 cells through mediation of apical sodium-dependent bile acid transporter (ASBT) and transmembrane transport of the nanoparticles across Caco-2 cell monolayers via relay-guide of ASBT, ileal bile acid-binding protein, and the heteromeric organic solute transporter (OSTα-OSTβ) along with multidrug resistance-associated protein 3 (MRP3) evidenced by competitive inhibition and fluorescence immunoassay, which was further visually confirmed by the stronger fluorescence from C6-labeled nanoparticles inside enterocytes and the basal side of the intestinal epithelium of mice. The transcellular transport of deoxycholic acid-modified nanoparticles in an intact form was mediated by caveolin/lipid rafts and clathrin with intracellular trafficking trace of endosome-lysosome-ER-Golgi apparatus and bile acid transport route. Furthermore, the increased uptake by HepG2 cells compared with unmodified nanoparticles evidenced the target ability of deoxycholic acid-modified nanoparticles to the liver, which was further supported by ex vivo imaging of excised major organs of mice. Thus, this study provided a feasible and potential strategy to further enhance transepithelial transport efficiency and liver-targeted ability of nanoparticles by means of the specific enterohepatic circulation pathways of bile acid.

Chitosan–Hyaluronic Acid Nanoparticles for Active Targeting in Cancer Therapy

Cancer is the most common cause of death worldwide; therefore, there is a need to discover novel treatment modalities to combat it. One of the cancer treatments is nanoparticle technology. Currently, nanoparticles have been modified to have desirable pharmacological effects by using chemical ligands that bind with their specific receptors on the surface of malignant cells. Chemical grafting of chitosan nanoparticles with hyaluronic acid as a targeted ligand can become an attractive alternative for active targeting. Hence, these nanoparticles can control drug release with pH- responsive stimuli, and high selectivity of hyaluronic acid to CD44 receptors makes these nanoparticles accumulate more inside cells that overexpress these receptors (cancer cells). In this context, we discuss the benefits and recent findings of developing and utilizing chitosan–hyaluronic acid nanoparticles against distinct forms of cancer malignancy. From here we know that chitosan–hyaluronic acid nanoparticles (CHA-Np) can produce a nanoparticle system with good characteristics, effectiveness, and a good active targeting on various types of cancer cells. Therefore, this system is a good candidate for targeted drug delivery for cancer therapy, anticipating that CHA-Np could be further developed for various cancer therapy applications.

Folate-Decorated Cross-Linked Cytochrome c Nanoparticles for Active Targeting of Non-Small Cell Lung Carcinoma (NSCLC).

The folate receptor alpha (FR), which is overexpressed in solid tumors including NSCLC, can be utilized for active tumor targeting to afford more effective cancer therapies. In this context, cytochrome c (Cyt c) has drawn attention to cancer research because it is non-toxic, yet, when delivered to the cytoplasm of cancer cells, can kill them by inducing apoptosis. Cyt c nanoparticles (NPs, 169 ± 9 nm) were obtained by solvent precipitation with acetonitrile, and stabilized by reversible homo-bifunctional crosslinking to accomplish a Cyt-c-based drug delivery system that combines stimulus-responsive release and active targeting. Cyt c was released under intracellular redox conditions, due to an S–S bond in the NPs linker, while NPs remained intact without any release under extracellular conditions. The NP surface was decorated with a hydrophilic folic acid–polyethylene glycol (FA–PEG) polymer for active targeting. The FA-decorated NPs specifically recognized and killed cancer cells (IC50 = 47.46 µg/mL) that overexpressed FR, but showed no toxicity against FR-negative cells. Confocal microscopy confirmed the preferential uptake and apoptosis induction of our NPs by FR-positive cancer cells. In vivo experiments using a Lewis lung carcinoma (LLC) mouse model showed visible NP accumulation within the tumor and inhibited the growth of LLC tumors.

Molecularly imprinted upconversion nanoparticles for active tumor targeting and microinvasive photothermal therapy

Molecularly imprinted upconversion nanoparticles for active tumor targeting and microinvasive photothermal therapy

Multi-scale modeling of folic acid-functionalized TiO2 nanoparticles for active targeting of tumor cells.

Strategies based on the active targeting of tumor cells are emerging as smart and efficient nanomedical procedures. Folic acid (FA) is a vitamin and a well-established tumor targeting agent because of its strong affinity for the folate receptor (FR), which is an overexpressed protein on the cell membranes of the tumor cells. FA can be successfully anchored to several nanocarriers, including inorganic nanoparticles (NPs) based on transition metal oxides. Among them, TiO2 is extremely interesting because of its excellent photoabsorption and photocatalytic properties, which can be exploited in photodynamic therapy. However, it is not yet clear in which respects direct anchoring of FA to the NP or the use of spacers, based on polyethylene glycol (PEG) chains, are different and whether one approach is better than the other. In this work, we combine Quantum Mechanics (QM) and classical Molecular Dynamics (MD) to design and optimize the FA functionalization on bare and PEGylated TiO2 models and to study the dynamical behavior of the resulting nanoconjugates in a pure water environment and in physiological conditions. We observe that they are chemically stable, even under the effect of increasing temperature (up to 500 K). Using the results from long MD simulations (100 ns) and from free energy calculations, we determine how the density of FA molecules on the TiO2 NP and the presence of PEG spacers impact on the actual exposure of the ligands, especially by affecting the extent of FA–FA intermolecular interactions, which are detrimental for the targeting ability of FA towards the folate receptor. This analysis provides a solid and rational basis for experimentalists to define the optimal FA density and the more appropriate mode of anchoring to the carrier, according to the final purpose of the nanoconjugate.

Octreotide-conjugated silver nanoparticles for active targeting of somatostatin receptors and their application in a nebulized rat model

Abstract Drug uptake and distribution through cell–receptor interactions are of prime interest in reducing the adverse effects and increasing the therapeutic effectiveness of delivered formulations. This study aimed to formulate silver nanoparticles (AgNPs) conjugated to somatostatin analogs for specific delivery through somatostatin receptors (SSTRs) expressed on cells and by nebulizing the prepared AgNPs formulations into lung cells for in vivo application. AgNPs were prepared using the citrate reduction method, yielding AgNPs–CTT, which was further chemically conjugated to octreotide (OCT) to form AgNPs–OCT through an amide linkage. The AgNPs–OCT formulation was coated using alginate to yield a carrier, AgNPs–OCT–Alg, feasible for drug delivery through nebulization. AgNPs were uniform in size with an acceptable range of zeta potential. Furthermore, the concentrations of AgNP formulations were found safe for the model cell lines used, and cell proliferation was significantly reduced in a dose-dependent manner (p < 0.05). In the healthy lung tissues, AgNPs–OCT–Alg accumulated at a concentration of 0.416 ± 5.7 mg/kgtissue, as determined via inductively coupled plasma optical emission spectrometry. This study established the accumulation of AgNPs, specifically the AgNPs–OCT–Alg, in lung tissues, and substantiated the active, specific, and selective targeting of SSTRs at pulmonary sites. The anticancer efficacy of the formulations was in vitro tested and confirmed in the MCF-7 cell lines. Owing to the delivery suitability and cytotoxic effects of the AgNPs–OCT–Alg formulation, it is a potential drug delivery formulation for lung cancer therapy in the future.

The other side to the use of active targeting ligands; the case of folic acid in the targeting of breast cancer

Due to its overexpression in cancer cells, the folate receptor (FR) is heavily exploited in the active targeting of nanoparticles (NPs). Its ligand, folic acid (FA) is as a consequence widely used as a NP targeting ligand. Although rather popular and successful in principle, recent data has shown that FA may result in breast cancer initiation and progression, which questions the suitability of FA as NP cancer targeting ligand. In this work, intravenous administration of free FA to healthy female mice resulted in breast tissue dysplasia, hyperplasia and in the increased expression of human epidermal growth factor receptor-2 (HER2), folate receptor (FR), cancer antigen 15–3 (CA15.3), vascular endothelial growth factor (VEGF), signal transducer and activator of transcription 3 (STAT3) and the pro-inflammatory cytokines, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6) and interleukin-1β. In addition to the reduction in IL2. To evaluate the suitability and safety of FA as NP targeting ligand in breast cancer, small (≈ 150 nm) and large (≈ 500 nm) chitosan NPs were formulated and decorated with two densities of FA. The success of active targeting by FA was confirmed in two breast cancer cell lines (MCF-7 and MDA-MB-231 cells) in comparison to HEK293 cells. FA modified NPs that demonstrated successful active targeting in-vitro were assessed in-vivo. Upon intravenous administration, large NPs modified with a high density of FA accumulated in the breast tissue and resulted in similar effects as those observed with free FA. These results therefore question the suitability of FA as a targeting ligand in breast cancer and shed light on the importance of considering the activity (other than targeting) of the ligands used in NP active targeting.

Hyaluronan-coated nanoparticles for active tumor targeting: Influence of polysaccharide molecular weight on cell uptake

Here we aimed to correlate different molecular weights of hyaluronic acid (HA), 200, 800 and 1437 kDa, used to decorate poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs), to their cell uptakes. NP internalization kinetics in CD44-overexpressing breast carcinoma cells were quantified, using healthy fibroblast cells as reference. Actually, NP uptake and selectivity by tumor cells were maximized for NPs HA 800 kDa, while being minimum for NPs HA1400 kDa. This unexpected result could be explained considering that the interaction between NPs and tumor cells is dictated by rearrangement and conformation of that segment of HA chain that actually protrudes from the NPs. Overall, results obtained in this work point at how HA molecular weight, is pivotal project parameter in NP formulation to promote active targeting in the CD44 overexpressing cancer cells.

PH-Sensitive Molecular-Switch-Containing Polymer Nanoparticle for Breast Cancer Therapy with Ferritinophagy-Cascade Ferroptosis and Tumor Immune Activation.

Ferritin internalized into tumor cells is degraded and releases iron ions via ferritinophagy. Iron ions participate in Fenton reaction to produce reactive oxygen species for lipid peroxidation and ferroptosis. Inhibition of indoleamine-2,3-dioxygenase (IDO) decreases tryptophan elimination to induce Tcells activation for tumor immunosuppression relief. The active tumor targeting nanoparticles containing ferritin and a pH-sensitive molecular-switch (FPBC@SN) are developed to utilize ferritinophagy-cascade ferroptosis and tumor immunity activation for cancer therapy. FPBC@SN disintegrates in acidic cytoplasm and releases sorafenib (SRF) and IDO inhibitor (NLG919). SRF upregulates nuclear receptor coactivator 4 (NCOA4) to induce ferritin and endogenous iron pool degradation by ferritinophagy, then obtained iron ions participate in the Fenton reaction to produce lipid peroxide (LPO). Meanwhile, SRF blocks glutathione synthesis to downregulate glutathione peroxidase 4 (GPX4) which can scavenge LPO as a different pathway from ferritinophagy to promote ferroptosis in tumor cells. NLG919 inhibits IDO to reduce tryptophan metabolism, so immunity in tumors is aroused to anti-tumor. In vitro and in vivo experiments prove FPBC@SN inhibits tumor cell growth and metastasis, indicating the potential of FPBC@SN for breast cancer therapy based on the combination of ferritinophagy-cascade ferroptosis and tumor immunity activation.