Targeting Of Nanoparticles Research Articles

Towards Steering Magnetic Nanoparticles in Drug Targeting Using a Linear Halbach Array

Abstract. Magnetic nanoparticles offer numerous promising biomedical applications, e.g. magnetic drug targeting. Here, magnetic drug carriers inside the human body are directed towards tumorous tissue by an external magnetic field. However, the success of the treatment strongly depends on the amount of drug carriers, reaching the desired tumor region. This steering process is still an open research topic. In this paper, the previous study of a linear Halbach array is extended by an additional Halbach array with different magnetization angles between two adjacent magnets and investigated numerically using COMSOL Multiphysics. The Halbach arrays are arranged with permanent magnets and generate a relatively large region of a moderately homogeneous, high magnetic field while having a strong gradient. This results in a strong magnetic force, trapping many particles at the magnets. Afterwards, to avoid particle agglomeration, the Halbach array is flipped to its weak side. Therefore, the magnetic flux density, its gradient and the resulting magnetic force are computed for the different Halbach arrays with different constellations of magnetization directions. Since the calculation of the gradient can lead to high errors due to the used mesh in Comsol, the gradient was derived analytically by investigating two different fitting functions. Overall, the array with a 90∘ shifted magnetization performs best, changing the magnetic sides of the array easily and deflecting more particles. Besides, the results revealed that the magnetic force dominates directly underneath the magnets compared to the other existing forces on the SPIONS. Summarized, the results depict that the magnetic force and, thus, the region where the particles are able to get washed out, can be adjusted using low-cost permanent magnets.

Laser-activated nanoparticles for ultrasound/photoacoustic imaging-guided prostate cancer treatment.

Prostate cancer (PCa) is the most common malignant tumor in men. Prostate-specific membrane antigen (PSMA), which is overexpressed on the surface of Prostate cancer cells, may serve as a potential therapeutic target. Recently, image-guided and targeted therapy for prostate cancers has attracted much attention by using Prostate-specific membrane antigen targeting nanoparticle. In this study, we produced PSMA-targeted light-responsive nanosystems. These nanosystems of liquid perfluorocarbon cores and polymer shells were loaded with the photosensitizer IR780 and therapeutic drugs paclitaxel. The liquid perfluorocarbon (PFP) in nanoparticles can perform ultrasound-enhanced imaging by liquid-gas transition and promote the deliver and release of paclitaxel. IR780 can perform photothermal therapy (PTT) guided by photoacoustic (PA) imaging. Combination treatment with photothermal therapy and chemotherapy exhibited excellent inhibition of cell proliferation in vitro and a significant therapeutic effect in vivo. In conclusion, we successfully formulated PSMA-targeted nanosystems with precision targeting and ultrasound/PA dual-modality imaging for anti-tumor effects.

Targeted therapeutic effects of oral magnetically driven pectin nanoparticles containing chlorogenic acid on colon cancer

Oral colonic nano-drug delivery system has attracted growing attention in treating colon cancer for their excellent characteristics. However, the unique and complex structure of the gastrointestinal tract is still an obstacle to the safe delivery of drugs targeting sites in colon tumors. Here, we designed magnetically driven dual-targeted oral colonic nanoparticles loaded with chlorogenic acid using pectin and oleic acid-modified iron oxide (Fe3O4@OA). Specific degradation of pectin by pectinase produced by colonic flora and magnetic fields applied to the colon confers specific targeting of nanoparticles to the colon. In order to overcome the challenge of preparing magnetically driven nanoparticles with small and homogeneous particle sizes by a single conventional method, we developed the combined ultrasound-emulsification technique. The average particle size of the prepared nanoparticles was 81.04 ± 1.02 nm, which showed good drug release in the simulated colonic environment. In vitro anticancer studies, the drug-loaded nanoparticles possess an obvious toxicity and apoptosis-inducing ability against cancer cells. Meanwhile, the hemolysis results demonstrated the safety of the nanoplatform (PET/CGA/Fe3O4@OA). This work holds broad prospects as a new treatment modality for colon cancer.

Valency and affinity control of aptamer-conjugated nanoparticles for selective cancer cell targeting.

Nanoparticles (NPs) are commonly functionalized using targeting ligands to drive their selective uptake in cells of interest. Typical target cell types are cancer cells, which often overexpress distinct surface receptors that can be exploited for NP therapeutics. However, these targeted receptors are also moderately expressed in healthy cells, leading to unwanted off-tumor toxicities. Multivalent interactions between NP ligands and cell receptors have been investigated to increase the targeting selectivity towards cancer cells due to their non-linear response to receptor density. However, to exploit the multivalent effect, multiple variables have to be considered such as NP valency, ligand affinity, and cell receptor density. Here, we synthesize a panel of aptamer-functionalized silica-supported lipid bilayers (SSLB) to study the effect of valency, aptamer affinity, and epidermal growth factor receptor (EGFR) density on targeting specificity and selectivity. We show that there is an evident interplay among those parameters that can be tuned to increase SSLB selectivity towards high-density EGFR cells and reduce accumulation at non-tumor tissues. Specifically, the combination of high-affinity aptamers and low valency SSLBs leads to increased high-EGFR cell selectivity. These insights provide a better understanding of the multivalent interactions of NPs with cells and bring the nanomedicine field a step closer to the rational design of cancer nanotherapeutics.

Preparation and characterization of PLGA-based magnetic polymer nanoparticles for targeting pancreatic adenocarcinoma.

This study aims to develop a novel tumor-targeted molecular probe for pancreatic cancer imaging. The objective of this is to prepare a CKAAKN peptide-conjugated poly (lactic-co-glycolic acid)-poly (ethylene glycol) amphiphilic polymer (CKAAKN-PEG-PLGA) for the tumor-targeted delivery of magnetic resonance imaging (MRI) contrast agent ultrasmall superparamagnetic iron oxide (USPIO). The early diagnosis of pancreatic cancer is crucial for improving its prognosis, but the clinical application of many diagnostic methods is limited owing to a lack of specificity and sensitivity. Methods CKAAKN-PEG-PLGA was synthesized by the amidation reaction. USPIO-loaded polymeric magnetic nanoparticles (USPIO@CKAAKN-PEG-PLGA) were prepared by the emulsion solvent evaporation method. The in vitro tumor targeting and bio-safety of nanoparticles were evaluated by targeted cellular uptake, MR imaging and MTT assay. Results USPIO@CKAAKN-PEG-PLGA nanoparticles showed excellent biosafety with an average diameter of 104.5 ± 4.1 nm. Modification of CKAAKN peptide could improve USPIO binding ability to internalize into CKAAKN-positive BxPC-3 cells compared with non-targeting nanoparticles and the control group. The relative fluorescence intensity in BxPC-3 and HPDE6-C7 cells was 23.77 ± 4.18 and 6.44 ± 2.10 (p＜0.01), and respectively became 16.13 ± 0.83 and 11.74 ± 1.74 after the addition of free CKAAKN peptide. In vitro MR imaging studies showed that an obvious decrease in the signal intensity was observed in the targeted nanoparticles group incubated with BxPC-3 and HPDE6-C7 cells (P<0.05). Conclusion USPIO@CKAAKN-PEG-PLGA nanoparticles could significantly enhance the tumor specificity of USPIO in CKAAKN-positive pancreatic cancer cell BxPC-3, which is expected as a promising candidate of MRI contrast enhancement for the early diagnosis of pancreatic cancer.

The role of acoustofluidics and microbubble dynamics for therapeutic applications and drug delivery.

Targeted drug delivery is proposed to reduce the toxic effects of conventional therapeutic methods. For that purpose, nanoparticles are loaded with drugs called nanocarriers and directed toward a specific site. However, biological barriers challenge the nanocarriers to convey the drug to the target site effectively. Different targeting strategies and nanoparticle designs are used to overcome these barriers. Ultrasound is a new, safe, and non-invasive drug targeting method, especially when combined with microbubbles. Microbubbles oscillate under the effect of the ultrasound, which increases the permeability of endothelium, hence, the drug uptake to the target site. Consequently, this new technique reduces the dose of the drug and avoids its side effects. This review aims to describe the biological barriers and the targeting types with the critical features of acoustically driven microbubbles focusing on biomedical applications. The theoretical part covers the historical developments in microbubble models for different conditions: microbubbles in an incompressible and compressible medium and bubbles encapsulated by a shell. The current state and the possible future directions are discussed.

The application of nanoparticles in immunotherapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths worldwide, however, current clinical diagnostic and treatment approaches remain relatively limited, creating an urgent need for the development of effective technologies. Immunotherapy has emerged as a powerful treatment strategy for advanced cancer. The number of clinically approved drugs for HCC immunotherapy has been increasing. However, it remains challenging to improve their transport and therapeutic efficiency, control their targeting and release, and mitigate their adverse effects. Nanotechnology has recently gained attention for improving the effectiveness of precision therapy for HCC. We summarize the key features of HCC associated with nanoparticle (NPs) targeting, release, and uptake, the roles and limitations of several major immunotherapies in HCC, the use of NPs in immunotherapy, the properties of NPs that influence their design and application, and current clinical trials of NPs in HCC, with the aim of informing the design of delivery platforms that have the potential to improve the safety and efficacy of HCC immunotherapy，and thus, ultimately improve the prognosis of HCC patients.

A Novel “Inside‐Out” Intraocular Nanomedicine Delivery Mode for Nanomaterials’ Biological Effect Enhanced Choroidal Neovascularization Occlusion and Microenvironment Regulation (Adv. Mater. 10/2023)

Drug Delivery In article number 2209690, Jia Qu, Yingwei Yang, Bailiang Wang, and co-workers demonstrate the function of Müller cells as a “new door” for the precise delivery of choroidal neovascular targeting nanoparticles into the fundus in an “inside-out” manner. This will provide a comprehensive treatment strategy for choroidal neovascularization (CNV), including enhanced photodynamic occlusion of neovascular and microenvironment regulation.

Enhanced glypican-3-targeted identification of hepatocellular carcinoma with liver fibrosis by pre-degrading excess fibrotic collagen.

Most hepatocellular carcinomas (HCCs) occur in cirrhotic livers, but unequivocal diagnosis of early HCC from the fibrotic microenvironment remains a formidable challenge with conventional imaging strategies, mainly because of the massive fibrotic collagen deposition leading to hepatic nodules formation and dysfunction of contrast agent metabolism. Here, we developed a "sweep-and-illuminate" imaging strategy, pre-degrade hepatic fibrotic collagen with collagenase I conjugated human serum albumin (HSA-C) and then targeting visualize HCC lesion with GPC3 targeting nanoparticles (TSI NPs, TJ2 peptide-superparamagnetic iron oxide-indocyanine green) via fluorescence imaging (FLI) and magnetic particle imaging (MPI). TSI NPs delineated a clear boundary of HCC and normal liver, and the tumor-to-background ratios (TBRs) detected by FLI and MPI were 5.43- and 1.34-fold higher than the non-targeted group, respectively. HSA-C could degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. In a pathological state in which HCC occurs in the fibrotic microenvironment, HSA-C-mediated pre-degradation of fibrotic collagen reduced background signal interference in fibrotic tissues and enhanced the intratumoral uptake of TSI NPs, resulting in the clear demarcation between HCC and liver fibrosis, and the TBR was increased 2.61-fold compared to the group without HSA-C pretreatment. We demonstrated the feasibility of combined pre-degradation of fibrotic collagen and application of a GPC3-targeted FLI/MPI contrast agent for early HCC identification, as well as its clinical value in the management of patients with advanced liver fibrosis. STATEMENT OF SIGNIFICANCE: Given that liver fibrosis hinders early detection and treatment options of hepatocellular carcinomas (HCCs), we report a "sweep-and-illuminate" imaging strategy to enhance the efficiency of HCC identification by modulating the irreversible liver fibrosis. We first "sweep" nonspecific interference of contrast agent by pre-degrading fibrotic collagen with human serum albumin-carried collagenase I (HSA-C); and then specifically "illuminate" HCC lesions with GPC3-targeted-SPIO-ICG nanoparticles (TSI NPs). HSA-C can degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. Furthermore, in HCC models coexisting with liver fibrosis, the combined application of HSA-C and TSI NPs can clarify the demarcation between HCC and liver fibrosis with a 2.61-fold increase in the tumor-to-background ratio. This study may expand the potential of combinatorial biomaterials for early HCC diagnosis.

H2O2-triggered "off/on signal" nanoparticles target P-selectin for the non-invasive and contrast-enhanced theranostics for arterial thrombosis.

Pathological coagulation within an injured artery and the subsequent cardiovascular complications, such as stroke and heart attack, greatly threaten human life. Inspired by the biochemical features of acute arterial thrombosis, such as abundant activated platelets and hydrogen peroxide (H2O2), we constructed platelet-targeted theranostic nanoparticles (CyBA/PFM NPs) with H2O2-triggered photoacoustic contrast enhancement and antithrombotic capabilities. CyBA/PFM NPs were designed to target platelet-rich clots via fucoidan segment within the carrier, which could be activated by H2O2 to produce fluorescent "CyOH" molecules, thus turning on the photoacoustic signal. CyBA/PFM NPs showed obvious amplification of fluorescence following incubation with fresh clots, exhibiting efficient scavenging ability of intracellular reactive oxygen species (ROS). In a FeCl3-induced mouse model of carotid thrombosis, CyBA/PFM NPs significantly amplified the photoacoustic contrast in thrombogenic tissues, effectively eliminated ROS within the occlusion site, and suppressed the thrombus formation, accompanied by a normalization of the soluble CD40L level. Given their accurate imaging potential, potent antithrombotic activities and acceptable biosafety, CyBA/PFM NPs hold strong potential as nanoscale theranostics for H2O2-correlated cardiovascular diseases. STATEMENT OF SIGNIFICANCE: In this study, we developed a platelet-targeted and H2O2-triggered nanosystem self-assembled from phenylboronated fucoidan/maltodextrin polymers and responsive near-infrared probes. The fucoidan segment within the carrier could facilitate the specific delivery of the therapeutic polymers and probes to the platelet-rich arterial thrombus. In a mouse model of FeCl3-induced arterial thrombosis, the system could be activated by H2O2 to produce fluorescent "CyOH" molecules, thus turning on the photoacoustic signal and specifically imaging thrombosed tissues. Besides, CyBA/PFM NPs significantly effectively eliminated ROS within the occlusion site and suppressed the thrombus formation. Given their theranostic potential and acceptable biosafety, this system has great potential for H2O2-correlated cardiovascular diseases.

Homologous cancer cell membrane-camouflaged nanoparticles target drug delivery and enhance the chemotherapy efficacy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common digestive tract malignancy that seriously threatens human life and health. Early HCC may be treated by intervention, surgery, and internal radiotherapy, while the choice for late HCC is primarily chemotherapy to prolong patient survival. Lenvatinib (LT) is a Food and Drug Administration (FDA)-approved frontline drug for the treatment of advanced liver cancer and has achieved excellent clinical efficacy. However, its poor solubility and severe side effects cannot be ignored. In this study, a bionic nanodrug delivery platform was successfully constructed. The platform consists of a core of Lenvatinib wrapped with a pH-sensitive polymer, namely, poly(β-amino ester)-polyethylene glycol-amine (PAE-PEG-NH2), and a shell formed by a cancer cell membrane (CCM). The prepared nanodrugs have high drug loading capacity, long-term stability, good biocompatibility, and a long retention time. In addition, the targeting effect of tumor cell membranes and the pH-responsive characteristics of the polymer materials enable them to precisely target tumor cells and achieve responsive release in the tumor microenvironment, which makes them suitable for effective drug delivery. In vivo experiments revealed that the nanodrug showed superior tumor accumulation and therapeutic effects in subcutaneous tumor mice model and could effectively eliminate tumors within 21 days. As a result, it opens up a new way to reduce side effects and improve the specific therapeutic effect of first-line clinical medications to treat tumors.

Nanoparticle-mediated targeting of the fusion gene RUNX1/ETO in t(8;21)-positive acute myeloid leukaemia

A hallmark of acute myeloid leukaemias (AMLs) are chromosomal rearrangements that give rise to novel leukaemia-specific fusion genes. Most of these fusion genes are both initiating and driving events in AML and therefore constitute ideal therapeutic targets but are challenging to target by conventional drug development. siRNAs are frequently used for the specific suppression of fusion gene expression but require special formulations for efficient in vivo delivery. Here we describe the use of siRNA-loaded lipid nanoparticles for the specific therapeutic targeting of the leukaemic fusion gene RUNX1/ETO. Transient knockdown of RUNX1/ETO reduces its binding to its target genes and alters the binding of RUNX1 and its co-factor CBFβ. Transcriptomic changes in vivo were associated with substantially increased median survival of a t(8;21)-AML mouse model. Importantly, transient knockdown in vivo causes long-lasting inhibition of leukaemic proliferation and clonogenicity, induction of myeloid differentiation and a markedly impaired re-engraftment potential in vivo. These data strongly suggest that temporary inhibition of RUNX1/ETO results in long-term restriction of leukaemic self-renewal. Our results provide proof for the feasibility of targeting RUNX1/ETO in a pre-clinical setting and support the further development of siRNA-LNPs for the treatment of fusion gene-driven malignancies.

Lyophilized Nasal Inserts of Atomoxetine HCl Solid Lipid Nanoparticles for Brain Targeting as a Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD): A Pharmacokinetics Study on Rats.

The study aims to investigate the ability of lyophilized nasal inserts of nanosized atomoxetine HCl solid lipid nanoparticles (ATM-SLNs) to transport atomoxetine (ATM) directly to the brain and overcome the first-pass metabolism. In this case, 16 formulae of (ATM-SLNs) were prepared using hot melt emulsification, stirring and ultrasonication method technique. A full factorial design was established with 24 trials by optimization of four variables; lipid type (Compritol 888 ATO or stearic acid) (X1), lipid to drug ratio [(1:2) or (2:1)] (X2), span 60: Pluronic f127 ratio [(1:3) or (3:1)] (X3) and probe sonication time (five or ten minutes) (X4). The prepared SLNs were characterized for entrapment efficiency (EE%), in-vitro drug release after 30 min (Q30min), particle size (PS), zeta potential (ZP) and polydispersity index (PDI). Design Expert® software was used to select the optimum two formulae. The morphological examination for the optimum two formulae was carried out using a transmission electron microscope (TEM). Furthermore, eight lyophilized nasal inserts were prepared by using a 23 full factorial design by optimization of three variables: type of (ATM-SLNs) formula (X1), type of polymer (NOVEON AA1 or HPMC K100m) (X2) and concentration of polymer (X3). They were evaluated for nasal inserts' physicochemical properties. The two optimum inserts were selected by Design Expert® software. The two optimum insets with the highest desirability values were (S4 and S8). They were subjected to DSC thermal stability study and in-vivo study on rats. They were compared with atomoxetine oral solution, atomoxetine (3 mg/kg, intraperitoneal injection) and the pure atomoxetine solution loaded in lyophilized insert. (ATM-SLNs) showed EE% range of (41.14 mg ± 1.8% to 90.6 mg ± 2.8%), (Q30min%) of (27.11 ± 5.9% to 91.08 ± 0.15%), ZP of (-8.52 ± 0.75 to -28.4 ± 0.212% mV), PS of (320.9 ± 110.81% nm to 936.7 ± 229.6% nm) and PDI of (0.222 ± 0.132% to 0.658 ± 0.03%). Additionally, the two optimum (ATM-SLNs) formulae chosen, i.e., F7 and F9 showed spherical morphology. Nasal inserts had assay of drug content of (82.5 ± 2.5% to 103.94 ± 3.94%), Q15min% of (89.9 ± 6.4% to 100%) and Muco-adhesion strength of (3510.5 ± 140.21 to 9319.5 ± 39.425). DSC results of S4 and S8 showed compatibility of (ATM) with the other excipients. S8 and S4 also showed higher trans-nasal permeation to the brain with brain targeting efficiency of (211.3% and 177.42%, respectively) and drug transport percentages of (52.7% and 43.64%, respectively). To conclude, lyophilized nasal inserts of (ATM-SLNs) enhanced (ATM) trans-nasal drug targeting permeation and brain targeting efficiency.

Dual Effect of Chemo-PDT with Tumor Targeting Nanoparticles Containing iRGD Peptide

Nanotechnology, including self-aggregated nanoparticles, has shown high effectiveness in the treatment of solid tumors. To overcome the limitations of conventional cancer therapies and promote therapeutic efficacy, a combination of PDT and chemotherapy can be considered an effective strategy for cancer treatment. This study presents the development of tumor-targeting polysialic acid (PSA) nanoparticles for chemo-PDT to increase the cellular uptake and cytotoxic effect in cancer cells. Chlorin e6 (Ce6), a photosensitizer, and the iRGD peptide (sequence; cCRGDKGPDC) were conjugated to the amine of N-deacetylated PSA. They generate reactive oxygen species (ROS), especially singlet oxygen (1O2), and target integrin αvβ3 on the cancer cell surface. To offer a chemotherapeutic effect, doxorubicin (Dox) was assembled into the core of hydrophobically modified PSA by connecting it with Ce6; this was followed by its sustained release from the nanoparticles. These nanoparticles are able to generate ROS under 633 nm visible-light irradiation, resulting in the strong cytotoxicity of Dox with anticancer effects in HCT116 cells. PSA nanoparticles with the dual effect of chemo-PDT improve conventional PDT, which has a poor ability to deliver photosensitizers to cancer cells. Using their combination with Dox chemotherapy, rapid removal of cancer cells can be expected.

Functionalized Hybrid Iron Oxide–Gold Nanoparticles Targeting Membrane Hsp70 Radiosensitize Triple-Negative Breast Cancer Cells by ROS-Mediated Apoptosis

Triple-negative breast cancer (TNBC) a highly aggressive tumor entity with an unfavorable prognosis, is treated by multimodal therapies, including ionizing radiation (IR). Radiation-resistant tumor cells, as well as induced normal tissue toxicity, contribute to the poor clinical outcome of the disease. In this study, we investigated the potential of novel hybrid iron oxide (Fe3O4)-gold (Au) nanoparticles (FeAuNPs) functionalized with the heat shock protein 70 (Hsp70) tumor-penetrating peptide (TPP) and coupled via a PEG4 linker (TPP-PEG4-FeAuNPs) to improve tumor targeting and uptake of NPs and to break radioresistance in TNBC cell lines 4T1 and MDA-MB-231. Hsp70 is overexpressed in the cytosol and abundantly presented on the cell membrane (mHsp70) of highly aggressive tumor cells, including TNBCs, but not on corresponding normal cells, thus providing a tumor-specific target. The Fe3O4 core of the NPs can serve as a contrast agent enabling magnetic resonance imaging (MRI) of the tumor, and the nanogold shell radiosensitizes tumor cells by the release of secondary electrons (Auger electrons) upon X-ray irradiation. We demonstrated that the accumulation of TPP-PEG4-FeAuNPs into mHsp70-positive TNBC cells was superior to that of non-conjugated FeAuNPs and FeAuNPs functionalized with a non-specific, scrambled peptide (NGL). After a 24 h co-incubation period of 4T1 and MDA-MB-231 cells with TPP-PEG4-FeAuNPs, but not with control hybrid NPs, ionizing irradiation (IR) causes a cell cycle arrest at G2/M and induces DNA double-strand breaks, thus triggering apoptotic cell death. Since the radiosensitizing effect was completely abolished in the presence of the ROS inhibitor N-acetyl-L-cysteine (NAC), we assume that the TPP-PEG4-FeAuNP-induced apoptosis is mediated via an increased production of ROS.

Folic acid-decorated alginate nanoparticles loaded hydrogel for the oral delivery of diferourylmethane in colorectal cancer

The disease-related suffering in colorectal cancer remains prevalent despite advancements in the field of drug delivery. Chemotherapy-related side effects and non-specificity remain a challenge in drug delivery. The great majority of hydrophobic drugs cannot be successfully delivered to the colon orally mainly due to poor solubility, low bioavailability, pH differences, and food interactions. Polymeric nanoparticles are potential drug delivery candidates but there are numerous limitations to their usefulness in colon cancer. The nanoparticles are removed from the body rapidly by p-glycoprotein efflux, inactivation, or breakdown by enzymes limiting their efficiency. Furthermore, there is a lack of selectivity in targeting cancer cells; nanoparticles may also target healthy cells, resulting in toxicity and adverse effects. The study aimed to use nanoparticles for specific targeting of the colorectal tumor cells via the oral route of administration without adverse effects. Folic acid (FA), a cancer-targeting ligand possessing a high affinity for folate receptors overexpressed in colorectal cancers was conjugated to sodium alginate- nanoparticles by NH2-linkage. The folic-acid conjugated nanoparticles (FNPs) were delivered to the colon by a pH-sensitive hydrogel synthesized by the free radical polymerization method to provide sustained drug release. The developed system referred to as the “Hydrogel-Nano (HN) drug delivery system,” was specifically capable of delivering diferourylmethane to the colon. The HN system was characterized by DLS, FTIR, XRD, TGA, DSC, and SEM. The FNPs size, polydispersity index, and zeta potential were measured. The folic acid-conjugation to nanoparticles' surface was studied by UV–visible spectroscopy using Beer-Lambert's law. In-vitro studies, including sol-gel, porosity, drug loading, entrapment efficiency, etc., revealed promising results. The swelling and release studies showed pH-dependent release of the drug in colonic pH 7.4. Cellular uptake and cytotoxicity studies performed on FR-overexpressed Hela cell lines and FR-negative A-549 cell lines showed facilitated uptake of nanoparticles by folate receptors. A threefold increase in Cmax and prolongation of the mean residence time (MRT) to 14.52 +/− 0.217 h indicated sustained drug release by the HN system. The findings of the study can provide a sufficient ground that the synergistic approach of the HN system can deliver hydrophobic drugs to colorectal cancer cells via the oral route, but further in-vivo animal cancer model studies are required.

A bibliometric analysis of 16,826 triple-negative breast cancer publications using multiple machine learning algorithms: Progress in the past 17 years.

Triple-negative breast cancer (TNBC) is proposed at the beginning of this century, which is still the most challenging breast cancer subtype due to its aggressive behavior, including early relapse, metastatic spread, and poor survival. This study uses machine learning methods to explore the current research status and deficiencies from a macro perspective on TNBC publications. PubMed publications under "triple-negative breast cancer" were searched and downloaded between January 2005 and 2022. R and Python extracted MeSH terms, geographic information, and other abstracts from metadata. The Latent Dirichlet Allocation (LDA) algorithm was applied to identify specific research topics. The Louvain algorithm established a topic network, identifying the topic's relationship. A total of 16,826 publications were identified, with an average annual growth rate of 74.7%. Ninety-eight countries and regions in the world participated in TNBC research. Molecular pathogenesis and medication are most studied in TNBC research. The publications mainly focused on three aspects: Therapeutic target research, Prognostic research, and Mechanism research. The algorithm and citation suggested that TNBC research is based on technology that advances TNBC subtyping, new drug development, and clinical trials. This study quantitatively analyzes the current status of TNBC research from a macro perspective and will aid in redirecting basic and clinical research toward a better outcome for TNBC. Therapeutic target research and Nanoparticle research are the present research focus. There may be a lack of research on TNBC from a patient perspective, health economics, and end-of-life care perspectives. The research direction of TNBC may require the intervention of new technologies.

Development of Spleen Targeting H2S Donor Loaded Liposome for the Effective Systemic Immunomodulation and Treatment of Inflammatory Bowel Disease.

Nanoparticles are primarily taken up by immune cells after systemic administration. Thus, they are considered an ideal drug delivery vehicle for immunomodulation. Because the spleen is the largest lymphatic organ and regulates the systemic immune system, there have been studies to develop spleen targeting nanoparticles for immunomodulation of cancer and immunological disorders. Inflammatory bowel disease (IBD) includes disorders involving chronic inflammation in the gastrointestinal tract and is considered incurable despite a variety of treatment options. Hydrogen sulfide (H2S) is one of the gasotransmitters that carries out anti-inflammatory functions and has shown promising immunomodulatory effects in various inflammatory diseases including IBD. Herein, we developed a delicately tuned H2S donor delivering liposome for spleen targeting (ST-H2S lipo) and studied its therapeutic effects in a dextran sulfate sodium (DSS) induced colitis model. We identified the ideal PEG type and ratio of liposome for a high stability, loading efficiency, and spleen targeting effect. In the treatment of the DSS-induced colitis model, we found that ST-H2S lipo and conventional long-circulating liposomes loaded with H2S donors (LC-H2S lipo) reduced the severity of colitis, whereas unloaded H2S donors did not. Furthermore, the therapeutic effect of ST-H2S lipo was superior to that of LC-H2S lipo due to its better systemic immunomodulatory effect than that of LC-H2S lipo. Our findings demonstrate that spleen targeting H2S lipo may have therapeutic potential for IBD.

Computational Assessment of Magnetic Nanoparticle Targeting Efficiency in a Simplified Circle of Willis Arterial Model.

This paper presents the methodology and computational results of simulated medical drug targeting (MDT) via induced magnetism intended for administering intravenous patient-specific doses of therapeutic agents in a Circle of Willis (CoW) model. The multi-physics computational model used in this work is from our previous works. The computational model is used to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a magnetized region using the magnetic properties of magnetite (Fe3O4) and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil. A Eulerian-Lagrangian technique is implemented to resolve the hemodynamic flow and the motion of particles under the influence of a range of magnetic field strengths (Br = 2T, 4T, 6T, and 8T). Particle diameter sizes of 10 nm to 4 µm in diameter were assessed. Two dimensionless numbers are also investigated a priori in this study to characterize relative effects of Brownian motion (BM), magnetic force-induced particle motion, and convective blood flow on particle motion. Similar to our previous works, the computational simulations demonstrate that the greatest particle capture efficiency results for particle diameters within the micron range, specifically in regions where flow separation and vortices are at a minimum. Additionally, it was observed that the capture efficiency of particles decreases substantially with smaller particle diameters, especially in the superparamagnetic regime. The highest capture efficiency observed for superparamagnetic particles was 99% with an 8T magnetic field strength and 95% with a 2T magnetic field strength when analyzing 100 nm particles. For 10 nm particles and an 8T magnetic field strength, the particle capture efficiency was 48%, and for a 2T magnetic field strength the particle capture efficiency was 33%. Furthermore, it was found that larger magnetic field strengths, large particle diameter sizes (1 µm and above), and slower blood flow velocity increase the particle capture efficiency. The key finding in this work is that favorable capture efficiencies for superparamagnetic particles were observed in the CoW model for weak fields (Br < 4T) which demonstrates MDT as a possible viable treatment candidate for cardiovascular disease.

Ultra-small superparamagnetic iron oxide nanoparticles for intra-articular targeting of cartilage in early osteoarthritis.

Early diagnosis of osteoarthritis (OA) is critical for effective cartilage repair. However, lack of blood vessels in articular cartilage poses a barrier to contrast agent delivery and subsequent diagnostic imaging. To address this challenge, we proposed to develop ultra-small superparamagnetic iron oxide nanoparticles (SPIONs, 4 nm) that can penetrate into the matrix of articular cartilage, and further modified with the peptide ligand WYRGRL (particle size, 5.9 nm), which allows SPIONs to bind to type II collagen in the cartilage matrix and increase the retention of probes. Type II collagen in the cartilage matrix is gradually lost with the progression of OA, consequently, the binding of peptide-modified ultra-small SPIONs to type II collagen in the OA cartilage matrix is less, thus presenting different magnetic resonance (MR) signals in OA group from the normal ones. By introducing the AND logical operation, damaged cartilage can be differentiated from the surrounding normal tissue on T1 and T2 AND logical map of MR images, and this was also verified in histology studies. Overall, this work provides an effective strategy for delivering nanosized imaging agents to articular cartilage, which could potentially be used to diagnosis joint-related diseases such as osteoarthritis.