Micelle Nanoparticles Research Articles

Targeted Delivery of Nanoparticle-Conveyed Neutrophils to the Glioblastoma Site for Efficient Therapy.

Glioblastoma is a common brain tumor that poses considerable challenges in drug delivery. In this study, we investigated the potential of cell-based nanoparticles for targeted drug delivery to the glioblastoma sites. The anticancer drug of temozolomide (TMZ)-loaded T7-cholesterol nanoparticle micelles efficiently delivered nanoparticles to neutrophils and, subsequently, to the tumors. T7 is a cell-penetrating peptide that enhances the delivery of T7/TMZ to the target cells. T7 also serves as a transferrin target peptide, enabling targeted delivery to tumors. T7-conjugated cholesterol can self-assemble into micelles in aqueous solution and attach to the membrane of neutrophils. We confirmed that T7/TMZ nanoparticle micelles were efficiently located inside the neutrophils. Thereafter, T7/TMZ-conveyed neutrophils were administered to a glioblastoma mouse model, enabling neutrophils to penetrate the blood-brain barrier and deliver drugs directly to the tumor site. We evaluated the drug delivery efficiency and therapeutic effects of intravenous injection of T7/TMZ-conveyed neutrophils to a glioblastoma mouse model. These results demonstrate the promising role of neutrophil-based nanoparticle delivery systems in the targeted therapy of glioblastoma.

Ni-NHC Nanoparticles in Micelles as an Effective and Reusable Catalyst for Hydrogenations and Reductive-Aminations in Water

Ni-NHC Nanoparticles in Micelles as an Effective and Reusable Catalyst for Hydrogenations and Reductive-Aminations in Water

Biodegradation by Cancer Cells of Magnetite Nanoflowers with and without Encapsulation in PS-b-PAA Block Copolymer Micelles.

Magnetomicelles were produced by the self-assembly of magnetite iron oxide nanoflowers and the amphiphilic poly(styrene)-b-poly(acrylic acid) block copolymer to deliver a multifunctional theranostic agent. Their bioprocessing by cancer cells was investigated in a three-dimensional spheroid model over a 13-day period and compared with nonencapsulated magnetic nanoflowers. A degradation process was identified and monitored at various scales, exploiting different physicochemical fingerprints. At a collective level, measurements were conducted using magnetic, photothermal, and magnetic resonance imaging techniques. At the nanoscale, transmission electron microscopy was employed to identify the morphological integrity of the structures, and X-ray absorption spectroscopy was used to analyze the degradation at the crystalline phase and chemical levels. All of these measurements converge to demonstrate that the encapsulation of magnetic nanoparticles in micelles effectively mitigates their degradation compared to individual nonencapsulated magnetic nanoflowers. This protective effect consequently resulted in better maintenance of their therapeutic photothermal potential. The structural degradation of magnetomicelles occurred through the formation of an oxidized iron phase in ferritin from the magnetic nanoparticles, leaving behind empty spherical polymeric ghost shells. These results underscore the significance of encapsulation of iron oxides in micelles in preserving nanomaterial integrity and regulating degradation, even under challenging physicochemical conditions within cancer cells.

A high-throughput lysosome trafficking assay guides ligand selection and elucidates differences in CD22-targeted nanodelivery

ABSTRACT Targeted nanoparticles offer potential to selectively deliver therapeutics to cells; however, their subcellular fate following endocytosis must be understood to properly design mechanisms of drug release. Here we describe a nanoparticle platform and associated cell-based assay to observe lysosome trafficking of targeted nanoparticles in live cells. The nanoparticle platform utilizes two fluorescent dyes loaded onto PEG-poly(glutamic acid) and PEG-poly(Lysine) block co-polymers that also comprise azide reactive handles on PEG termini to attach antibody-based targeting ligands. Fluorophores were selected to be pH-sensitive (pHrodo Red) or pH-insensitive (Alexafluor 488) to report when nanoparticles enter low pH lysosomes. Dye-labelled block co-polymers were further assembled into polyion complex micelle nanoparticles and crosslinked through amide bond formation to form stable nano-scaffolds for ligand attachment. Cell binding and lysosome trafficking was determined in live cells by fluorescence imaging in 96-well plates and quantification of red- and green-fluorescence signals over time. The platform and assay was validated for selection of optimal antibody-derived targeting ligands directed towards CD22 for nanoparticle delivery. Kinetic analysis of uptake and lysosome trafficking indicated differences between ligand types and the ligand with the highest lysosome trafficking efficiency translated into effective DNA delivery with nanoparticles bearing the optimal ligand.

Polymeric micellar nanoparticles for effective CRISPR/Cas9 genome editing in cancer

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) gene editing has attracted extensive attentions in various fields, however, its clinical application is hindered by the lack of effective and safe delivery system. Herein, we reported a cationic micelle nanoparticle composed of cholesterol-modified branched small molecular PEI (PEI-CHO) and biodegradable PEG-b-polycarbonate block copolymer (PEG-PC), denoted as PEG-PC/PEI-CHO/pCas9, for the CRISPR/Cas9 delivery to realize genomic editing in cancer. Specifically, PEI-CHO condensed pCas9 into nanocomplexes, which were further encapsulated into PEG-PC nanoparticles (PEG-PC/PEI-CHO/pCas9). PEG-PC/PEI-CHO/pCas9 had a PEG shell, protecting DNA from degradation by nucleases. Enhanced cellular uptake of PEG-PC/PEI-CHO/pCas9 nanoparticles was observed as compared to that mediated by Lipo2k/pCas9 nanoparticles, thus leading to significantly elevated transfection efficiency after escaping from endosomes via the proton sponge effect of PEI. In addition, the presence of PEG shell greatly improved biocompatibility, and significantly enhanced the in vivo tumor retention of pCas9 compared to PEI-CHO/pCas9. Notably, apparent downregulation of GFP expression could be achieved both in vitro and in vivo by using PEG-PC/PEI-CHO/pCas9-sgGFP nanoparticles. Furthermore, PEG-PC/PEI-CHO/pCas9-sgMcl1 induced effective apoptosis and tumor suppression in a HeLa tumor xenograft mouse model by downregulating Mcl1 expression. This work may provide an alternative paradigm for the efficient and safe genome editing in cancer.

Star-polymer unimolecular micelle nanoparticles to deliver a payload across the blood-brain barrier.

Nanocarrier-mediated therapeutic delivery to brain tissue is impeded by tightly controlled transportation across the blood-brain barrier (BBB). Herein, we report a well-defined core-shell star-shaped unimolecular micelle (star-UMM; a single polymer entity) as an efficient BBB-breaching nanoparticle for brain-specific administration of the fluorescent anticancer drug doxorubicin and in vivo mapping of brain tissues by the near-infrared biomarker IR780 in mice. The star-UMM was engineered by precisely programming the polymer topology having hydrophobic and hydrophilic polycaprolactone blocks and in-built with lysosomal enzyme-biodegradation stimuli to deliver the payloads at intracellular compartments. In vivo imaging in mice revealed prolonged circulation of star-UMM in blood for >72 h, and whole-organ image-quantification substantiated its efficient ability to breach the BBB. Star UMM exhibited excellent stability in blood circulation and reduced cardiotoxicity, was non-hemolytic, had substantial uptake in the cortical neurons of the mouse brain, had lysosomal enzymatic-biodegradation, and exhibited negligible immunogenicity or necrosis. This newly designed star-UMM could have long-term applications in brain-specific drug delivery.

The preparation of pH-sensitive doxorubicin prodrug for enhanced antitumor efficacy

We have produced a micelle nanoparticle with intrinsic pH response, which is formed by self-assembled amphiphilic polyethylene glycol-Schiff-doxorubicin (PEG-Schiff-DOX) prodrug. These nanoparticles can maintain stability well under normal conditions and last for more than a week, but they will rapidly decompose in slightly acidic environments. The concentration of DOX in the nano solution is high with the drug loading ratio of 49.4%. This pH-responsive drug release behavior may lead to higher intracellular drug concentrations and prolonged action times. CCK-8 assays have shown that the nanosuspension exhibits superior anti-tumor activity against HeLa cells compared to free DOX. It is believed that these nanoparticle-based prodrug have great potential for developing DOX formulations for cancer therapy.

Schiff-linked prodrugs of pH-responsive nanoparticles to facilitate drug delivery

Endosomal pH-responsive micelle nanoparticles were prepared by self-assembly of amphiphilic polyethylene glycol Schiff-doxorubicin (PEG-Schiff-DOX) precursor drugs. The free DOX could be encapsulated in the hydrophobic core of the nanoparticles. These nanoparticles exhibited decompose rapidly in weakly acidic environments, but can keep excellent storage stability under normal conditions. Due to the differences in drug release mechanisms and rates between encapsulated DOX and linked DOX, programmed drug release behavior was observed, which may result in higher intracellular drug concentrations and longer duration of action.CCK-8 analysis showed that the nanoparticles showed better antitumor activity than free DOX. These nanomedicines based on precursor drugs have great potential for the development of transformational DOX agents for cancer therapy.

PH/Temperature Responsive Curcumin-Loaded Micelle Nanoparticles Promote Functional Repair after Spinal Cord Injury in Rats via Modulation of Inflammation.

The formation of an inhibitory inflammatory microenvironment after spinal cord injury (SCI) remains a great challenge for nerve regeneration. The poor local microenvironment exacerbates nerve cell death; therefore, the reconstruction of a favorable microenvironment through small-molecule drugs is a promising strategy for promoting nerve regeneration. In the present study, we synthesized curcumin-loaded micelle nanoparticles (Cur-NPs) to increase curcumin bioavailability and analyzed the physical and chemical properties of Cur-NPs by characterization experiments. We established an in vivo SCI model in rats and examined the ability of hind limb motor recovery using Basso-Beattie-Bresnahan scoring and hind limb trajectory assays. We also analyzed neural regeneration after SCI using immunofluorescence staining. The nanoparticles achieved the intelligent responsive release of curcumin while improving curcumin bioavailability. Most importantly, the released curcumin attenuated local inflammation by modulating the polarization of macrophages from an M1 pro-inflammatory phenotype to an M2 anti-inflammatory phenotype. M2-type macrophages can promote cell differentiation, proliferation, matrix secretion, and reorganization by secreting or expressing pro-repair cytokines to reduce the inflammatory response. The enhanced inflammatory microenvironment supported neuronal regeneration, nerve remyelination, and reduced scar formation. These effects facilitated functional repair in rats, mainly in the form of improved hindlimb movements. Here, we synthesized pH/temperature dual-sensitive Cur-NPs. While improving the bioavailability of the drug, they were also able to achieve a smart responsive release in the inflammatory microenvironment that develops after SCI. The Cur-NPs promoted the regeneration and functional recovery of nerves after SCI through anti-inflammatory effects, providing a promising strategy for the repair of SCIs.

Enhancement of cellular uptake by increasing the number of encapsulated gold nanoparticles in polymeric micelles

We apply a combination of polycaprolactone (PCL)-thiol ligand functionalization with flow-controlled microfluidic block copolymer self-assembly to produce biocompatible gold nanoparticle (GNP)-loaded micellar polymer nanoparticles (GNP-PNPs) in which GNPs are encapsulated within PCL cores surrounded by an external layer of poly(ethylene glycol) (PEG). By varying both the relative amount of block copolymer and the microfluidic flow rate, a series of GNP-PNPs are produced in which the mean number of GNPs per PNP in the < 50-nm fraction (Zave,d< 50 nm) varies between 0.1 and 1.9 while the external PEG surface is constant. Zave,d< 50 nm values are determined by statistical analysis of TEM images and compared with the results of cell uptake experiments on MDA-MB-231 cancer cells. For Zave,d< 50 nm ≤ 1 (including a control sample of individual GNPs also with a PEG surface layer), cell uptake is relatively constant, but increases sharply for Zave,d< 50 nm > 1, with a factor of 7 enhancement as Zave,d< 50 nm increases from 1 to ∼2. Enabled by the shear processing control provided by the microfluidic chip, these results provide the first evidence that cellular uptake can be enhanced specifically by increasing the number of GNPs per vector, with other parameters, including polymeric material, internal structure, and external surface chemistry, held constant. They also demonstrate a versatile platform for packaging GNPs in biocompatible polymeric carriers with flow-controlled formulation optimization for various therapeutic and diagnostic applications.

In vitro delivery of mTOR inhibitors by kidney-targeted micelles for autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and is characterized by the formation of renal cysts and the eventual development of end-stage kidney disease. One approach to treating ADPKD is through inhibition of the mammalian target of rapamycin (mTOR) pathway, which has been implicated in cell overproliferation, contributing to renal cyst expansion. However, mTOR inhibitors, including rapamycin, everolimus, and RapaLink-1, have off-target side effects including immunosuppression. Thus, we hypothesized that the encapsulation of mTOR inhibitors in drug delivery carriers that target the kidneys would provide a strategy that would enable therapeutic efficacy while minimizing off-target accumulation and associated toxicity. Toward eventual in vivo application, we synthesized cortical collecting duct (CCD) targeted peptide amphiphile micelle (PAM) nanoparticles and show high drug encapsulation efficiency (>92.6%). In vitro analysis indicated that drug encapsulation into PAMs enhanced the anti-proliferative effect of all three drugs in human CCD cells. Analysis of in vitro biomarkers of the mTOR pathway via western blotting confirmed that PAM encapsulation of mTOR inhibitors did not reduce their efficacy. These results indicate that PAM encapsulation is a promising way to deliver mTOR inhibitors to CCD cells and potentially treat ADPKD. Future studies will evaluate the therapeutic effect of PAM-drug formulations and ability to prevent off-target side effects associated with mTOR inhibitors in mouse models of ADPKD.

Targeting prostate cancer with docetaxel-loaded peptide 563-conjugated PEtOx-co-PEI30%-b-PCL polymeric micelle nanocarriers.

Prostate cancer is a global disease that negatively affects the quality of life. Although various strategies against prostate cancer have been developed, only a few achieved tumor-specific targeting. Therefore, a special emphasis has been placed on the treatment of cancer using nano-carrier-encapsulated chemotherapeutic agents conjugated with tumor-homing peptides. The targeting strategy coupling the drugs with nanotechnology helps to overcome the most common barriers, such as high toxicity and side effects. Prostate-specific membrane antigen has emerged as a promising target molecule for prostate cancer and shown to be targeted with high affinity by GRFLTGGTGRLLRIS peptide known as peptide 563 (P563). Here, we aimed to assess the in vitro and in vivo targeting efficiency, safety, and efficacy of P563-conjugated, docetaxel (DTX)-loaded polymeric micelle nanoparticles (P563-PEtOx-co-PEI30%-b-PCL-DTX) against prostate cancer. To this end, we analyzed the cytotoxic activity of P563-PEtOx-co-PEI30%-b-PCL and P563-PEtOx-co-PEI30%-b-PCL-DTX by a cell proliferation assay using PNT1A and 22Rv1 cells. We have also determined the targeting selectivity of P563-PEtOx-co-PEI30%-b-PCL-FITC by flow cytometry and assessed the induction of cell death by western blot and TUNEL assays for P563-PEtOx-co-PEI30%-b-PCL-DTX in 22Rv1 cells. To investigate the in vivo efficacy, we administered DTX in the free form or in polymeric micelle nanoparticles to athymic CD-1 nu/nu mice 22Rv1 xenograft models and performed histopathological analyses. Our study showed that targeting prostate cancer with P563-conjugated PEtOx-co-PEI30%-b-PCL polymeric micelles could exert a potent anti-cancer activity with low side effects.

Abstract 1810: Enhanced anti-breast tumor cancer activity using nano-formulated TLR 7/8 agonist and PI3K inhibitor

Abstract Triple-negative breast cancer (TNBC) is characterized by high cell proliferation, abundant heterogeneity, frequent incidence of lung and brain metastases, repeated disease recurrence, and the worst prognosis among all breast cancer subtypes. Extensive evidence from translational studies indicates immunosuppressive cell infiltration into the tumor microenvironment (TME) promotes tumor immune escape and inhibits the efficient antitumor immune response. Previously, we have shown that a large proportion of tumor-infiltrating lymphocytes in claudin-low subtype of TNBC are CD4+FoxP3+ Tregs. Infiltration of Treg in TME is associated with suppressing effector T cell responses, accelerated tumor growth, and poor clinical outcomes. Herein, to convert immunosuppressive TME of TNBC to immune-inflamed immunophenotype we used polymeric micelles nanoparticles for co-delivering immunomodulatory small molecule drugs. We used a novel Full Spectral Flow Cytometry approach for immunophenotyping tumors. We identified significant infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs) in the orthotopic T11 TNBC tumor. The small molecule resiquimod, an imidazoquinoline Toll-like receptor (TLR) 7/8 agonist, and idelalisib, an inhibitor of phosphatidylinositol 3-kinase (PI3K) p110δ were incorporated in poly(2-oxazoline) block copolymer polymeric micelle NPs. Drug exposure to tumor cells was increased by the small-size nanoparticles associated with the preferential accumulation of NPs in tumors. The resiquimod and idelalisib were used to differentiate MDSC and selectively decrease the number and function of Tregs in TME, respectively. Following targeted radiation therapy in combination with iv administration of nanoformulation to animals bearing orthotopic T11 TNBC tumors, we observed significant suppression of tumor growth and enhanced overall survival compared to targeted radiotherapy alone. Radiation therapy in combination with both nanoformulated resiquimod and idelalisib induced optimal tumor control, increasing median survival with over 50% complete response rate, while all mice in the nanoformulation groups or radiation alone group succumbed to tumor growth. Enhanced adaptive T cell immunity against TNBCs and effective therapeutic improvement in immunocompetent mice following radiotherapy were only observed with simultaneous depletion of Tregs and MDSC. These data suggest radiotherapy in combination with nanoparticle co-delivery of immunomodulators inhibiting MDSCs and Treg, has promising potential for future clinical trials and translation for the treatment of TNBC patients. Citation Format: Mostafa Yazdimamaghani, Oleg Kolupaev, Chaemin Lim, Duhyeong Hwang, Alexander Kabanov, Jonathan Serody. Enhanced anti-breast tumor cancer activity using nano-formulated TLR 7/8 agonist and PI3K inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1810.

Interplay of interactions in nanoparticle–surfactant complexes in aqueous salt solution

The evolution of phase behavior and interactions in anionic silica nanoparticles (Ludox HS40), surfactants [non-ionic decaethylene glycol mono-dodecyl ether (C12E10) and anionic sodium dodecyl sulfate (SDS)], and nanoparticle–surfactant solutions in the presence of salt (NaCl) has been studied using small-angle neutron scattering and dynamic light scattering. In an anionic silica nanoparticle solution (1 wt. %), the phase behavior is controlled by salt concentrations (0–1 M) through screening electrostatic interactions. In the case of 1 wt. % surfactant solutions, the anionic SDS surfactant micelles show significant growth upon adding salt, whereas non-ionic surfactant C12E10 micelles remain spherical until a high salt concentration (1 M). In the mixed system of HS40–C12E10, a transition from a highly stable transparent phase to a two-phase turbid system is observed with a small amount of salt addition CS* (∼0.06 M). The single transparent phase of this system corresponds to sterically stabilized micelles-decorated nanoparticles. For the turbid phase, the results are understood in terms of depletion attraction induced by non-adsorption of C12E10 micelles, which explains the appearance of turbidity at a much lower concentration of salt. In the mixed system of similarly charged nanoparticles and micelles (HS40-SDS), the phase behavior is governed by no physical interaction between the components, and salt screens the repulsive interaction among nanoparticles. These results are further utilized to tune multicomponent interactions and phase behavior of nanoparticles with a mixed C12E10-SDS surfactant system in the presence of salt. The mixed surfactants provide tuning of nanoparticle–micelle as well as micelle–micelle interactions to dictate the phase behavior of a nanoparticle–surfactant solution. In these systems, the effective potential can be described by double-Yukawa potential taking account of attractive and repulsive parts at low and intermediate salt concentrations (&amp;lt;CS*). At high salt concentrations (&amp;gt;CS*), the aggregation of nanoparticles is characterized by fractal aggregates.

In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel

A recently developed inhibitor of retrograde transport, namely Retro-2.1, proved to be a potent and broad-spectrum lead in vitro against intracellular pathogens, such as toxins, parasites, intracellular bacteria and viruses. To circumvent its low aqueous solubility, a formulation in poly(ethylene glycol)-block-poly(D,L)lactide micelle nanoparticles was developed. This formulation enabled the study of the pharmacokinetic parameters of Retro-2.1 in mice following intravenous and intraperitoneal injections, revealing a short blood circulation time, with an elimination half-life of 5 and 6.7 h, respectively. To explain the poor pharmacokinetic parameters, the metabolic stability of Retro-2.1 was studied in vitro and in vivo, revealing fast cytochrome-P-450-mediated metabolism into a less potent hydroxylated analogue. Subcutaneous injection of Retro-2.1 formulated in a biocompatible and bioresorbable polymer-based thermosensitive hydrogel allowed for sustained release of the drug, with an elimination half-life of 19 h, and better control of its metabolism. This study provides a guideline on how to administer this promising lead in vivo in order to study its efficacy.

Analogous foliar uptake and leaf-to-root translocation of micelle nanoparticles in two dicot plants of diverse families

Bio-inspired nanoparticles, including metallic, micelles, and polymeric, have been explored as a novel tool in the quest for effective and safe agrochemicals. Although nanoparticles (NPs) are being rapidly investigated for their usefulness in agricultural production and protection, little is known about the behaviour and interaction of oil-in-water micelle nanoparticles or nano-micelles (NM) with plants. We loaded a bio-based resin inherent of tree from the Pinaceae family as active material and produced stable nano-micelles using a natural emulsifier system. Here, we show that foliar-applied nano-micelle can translocate in two dicot plants belonging to diverse families (Coriandrum sativum -Apiaceae and Trigonella foenumgraecum -Fabaceae) via similar mode. Fluorescent-tagged NM (average diameter 11.20nm) showed strong signals and higher intensities as revealed by confocal imaging and exhibited significant adhesion in leaf compared to control. The NM subsequently translocates to other parts of the plants. As observed by SEM, the leaf surface anatomies revealed higher stomata densities and uptake of NM by guard cells; furthermore, larger extracellular spaces in mesophyll cells indicate a possible route of NM translocation. In addition, NM demonstrated improved wetting-spreading as illustrated by contact angle measurement. In a field bioassay, a single spray application of NM offered protection from aphid infestation for at least 9 days. There were no signs of phytotoxicity in plants post-application of NM. We conclude that pine resin-based nano-micelle provides an efficient, safe, and sustainable alternative for agricultural applications.

A Hoechst Reporter Enables Visualization of Drug Engagement In Vitro and In Vivo: Toward Safe and Effective Nanodrug Delivery.

Assessment of drug activation and subsequent interaction with targets in living tissues could guide nanomedicine design, but technologies enabling insight into how a drug reaches and binds its target are limited. We show that a Hoechst-based reporter system can monitor drug release and engagement from a nanoparticle delivery system in vitro and in vivo, elucidating differences in target-bound drug distribution related to drug-linker and nanoparticle properties. Drug engagement is defined as chemical detachment of drug or reporter from a nanoparticle and subsequent binding to a subcellular target, which in the case of Hoechst results in a fluorescence signal. Hoechst-based nanoreporters for drug activation contain prodrug elements such as dipeptide linkers, conjugation handles, and nanoparticle modifications such as targeting ligands to determine how nanomedicine design affects distribution of drug engaged with a subcellular target, which is tracked via cellular nuclear fluorescence in situ. Furthermore, the nanoplatform is amenable toward common maleimide-based linkers found in many prodrug-based delivery systems including polymer-, peptide-, and antibody-drug conjugates. Findings from the Hoechst reporter system were applied to develop highly potent, targeted, anticancer micelle nanoparticles delivering a monomethyl auristatin E (MMAE) prodrug comprising the same linkers employed in Hoechst studies. MMAE nanomedicine with the optimal drug-linker resulted in effective tumor growth inhibition in mice without associated acute toxicity, whereas the nonoptimal linker that showed broader drug activation in Hoechst reporter studies resulted in severe toxicity. Our results demonstrate the potential to synergize direct visualization of drug engagement with nanomedicine drug-linker design to optimize safety and efficacy.

Long-Circulation and Brain Targeted Isoliquiritigenin Micelle Nanoparticles: Formation, Characterization, Tissue Distribution, Pharmacokinetics and Effectsfor Ischemic Stroke.

PurposeWe designed a novel isoliquiritigenin (ISL) loaded micelle prepared with DSPE-PEG2000 as the drug carrier modified with the brain-targeting polypeptide angiopep-2 to improve the poor water solubility and low bioavailability of ISL for the treatment of acute ischemic stroke.MethodsThin film evaporation was used to synthesize the ISL micelles (ISL-M) modified with angiopep-2 as the brain targeted ligands. The morphology of the micelles was observed by the TEM. The particle size and zeta potential were measured via the nanometer particle size analyzer. The drug loading, encapsulation and in vitro release rates of micelles were detected by the HPLC. The UPLC-ESI-MS/MS methods were used to measure the ISL concentrations of ISL in plasma and main tissues after intravenous administration, and compared the pharmacokinetics and tissue distributions between ISL and ISL-M. In the MCAO mice model, the protective effects of ISL and ISL-M were confirmed via the behavioral and molecular biology experiments.ResultsThe results showed that the drug loading of ISL-M was 7.63 ± 2.62%, the encapsulation efficiency was 68.17 ± 6.23%, the particle size was 40.87 ± 4.82 nm, and the zeta potential was −34.23 ± 3.35 mV. The in vitro release experiments showed that ISL-M had good sustained-release effect and pH sensitivity. Compared with ISL monomers, the ISL-M could significantly prolong the in vivo circulation time of ISL and enhance the accumulation in the brain tissues. The ISL-M could ameliorate the brain injury induced by the MCAO mice via inhibition of cellular autophagy and neuronal apoptosis. There were no the cellular structural damages and other adverse effects for ISL-M on the main tissues and organs.ConclusionThe ISL-M could serve as a promising and ideal drug candidate for the clinical application of ISL in the treatment of acute ischemic stroke.

Polymeric micelles and cancer therapy: an ingenious multimodal tumor-targeted drug delivery system.

Since the beginning of pharmaceutical research, drug delivery methods have been an integral part of it. Polymeric micelles (PMs) have emerged as multifunctional nanoparticles in the current technological era of nanocarriers, and they have shown promise in a range of scientific fields. They can alter the release profile of integrated pharmacological substances and concentrate them in the target zone due to their improved permeability and retention, making them more suitable for poorly soluble medicines. With their ability to deliver poorly soluble chemotherapeutic drugs, PMs have garnered considerable interest in cancer. As a result of their remarkable biocompatibility, improved permeability, and minimal toxicity to healthy cells, while also their capacity to solubilize a wide range of drugs in their micellar core, PMs are expected to be a successful treatment option for cancer therapy in the future. Their nano-size enables them to accumulate in the tumor microenvironment (TME) via the enhanced permeability and retention (EPR) effect. In this review, our major aim is to focus primarily on the stellar applications of PMs in the field of cancer therapeutics along with its mechanism of action and its latest advancements in drug and gene delivery (DNA/siRNA) for cancer, using various therapeutic strategies such as crossing blood-brain barrier, gene therapy, photothermal therapy (PTT), and immunotherapy. Furthermore, PMs can be employed as "smart drug carriers," allowing them to target specific cancer sites using a variety of stimuli (endogenous and exogenous), which improve the specificity and efficacy of micelle-based targeted drug delivery. All the many types of stimulants, as well as how the complex of PM and various anticancer drugs react to it, and their pharmacodynamics are also reviewed here. In conclusion, commercializing engineered micelle nanoparticles (MNPs) for application in therapy and imaging can be considered as a potential approach to improve the therapeutic index of anticancer drugs. Furthermore, PM has stimulated intense interest in research and clinical practice, and in light of this, we have also highlighted a few PMs that have previously been approved for therapeutic use, while the majority are still being studied in clinical trials for various cancer therapies.

Therapeutic Response of miR-145 Micelles on Patient-Derived Vascular Smooth Muscle Cells.

During atherosclerosis, vascular smooth muscle cells (VSMCs) undergo a phenotypic transition from a healthy contractile state into pathological phenotypes including a proliferative and migratory, synthetic phenotype and osteochondrogenic-like phenotype that exacerbate plaques. Thus, inhibiting the transition of healthy, quiescent VSMCs to atherogenic cell types has the potential to mitigate atherosclerosis. To that end, previously, we reported that delivery of microRNA-145 (miR-145, a potent gatekeeper of the contractile VSMC phenotype) using nanoparticle micelles limited atherosclerotic plaque growth in murine models of atherosclerosis. Building on this preclinical data and toward clinical application, in this study, we tested the therapeutic viability of miR-145 micelles on patient-derived VSMCs and evaluated their effects based on disease severity. We collected vascular tissues from 11 patients with healthy, moderate, or severe stages of atherosclerosis that were discarded following vascular surgery or organ transplant, and isolated VSMCs from these tissues. We found that with increasing disease severity, patient-derived VSMCs had decreasing levels of contractile markers (miR-145, ACTA2, MYH11) and increasing levels of synthetic markers (KLF4, KLF5, and ELK1). Treatment with miR-145 micelles showed that an increase in disease severity correlated with a more robust response to therapy in VSMCs. Notably, miR-145 micelle therapy rescued contractile marker expression to baseline contractile levels in VSMCs derived from the most severely diseased tissues. As such, we demonstrate the use of miR-145 micelles across different stages of atherosclerosis disease and present further evidence of the translatability of miR-145 micelle treatment for atherosclerosis.