bims-novged 2022-10-16 papers

bims-novged

Biomed News

on Non-viral vectors for gene delivery

Issue of 2022–10–16
fiveteen papers selected by
the Merkel lab, Ludwig-Maximilians University

Design Strategies for and Stability of mRNA-Lipid Nanoparticle COVID-19 Vaccines.
Microfluidic production of mRNA-loaded lipid nanoparticles for vaccine applications.
Overcoming the non-kinetic activity of EGFR1 using multi-functionalized mesoporous silica nanocarrier for in vitro delivery of siRNA.
Molecular Insights into the Binding of Linear Polyethylenimines and Single-Stranded DNA Using Raman Spectroscopy: A Quantitative Approach.
Computer Aided Development of Nucleic Acid Applications in Nanotechnologies.
Cheminformatics Modeling of Gene Silencing for Both Natural and Chemically Modified siRNAs.
A Bayesian implementation of Quality-by-Design for the development of Cationic Nano-Lipid for siRNA Transfection.
Discrete Libraries of Amphiphilic Poly(ethylene glycol) Graft Copolymers: Synthesis, Assembly, and Bioactivity.
Highly Branched Betulin Based Polyanhydrides for Self-Assembled Micellar Nanoparticles Formulation.
Deep learning potential of mean force between polymer grafted nanoparticles.
Integrative Expression, Survival Analysis and Cellular miR-2909 Molecular Interplay in MRN Complex Check Point Sensor Genes (MRN-CSG) Involved in Breast Cancer.
Twin-screw continuous mixing can produce dry powder inhalation mixtures for pulmonary delivery.
Interplay between mucus mobility and alveolar macrophage targeting of surface-modified liposomes.
Long-Term Vaccine Delivery and Immunological Responses Using Biodegradable Polymer-Based Carriers.
Therapeutic Nanocarriers Inhibit Chemotherapy-Induced Breast Cancer Metastasis.

Polymers (Basel). 2022 Oct 06. pii: 4195. [Epub ahead of print]14(19):

Design Strategies for and Stability of mRNA-Lipid Nanoparticle COVID-19 Vaccines.

Ting Liu, Yang Tian, Aiping Zheng, Chunying Cui.

  Messenger RNA (mRNA) vaccines have shown great preventive potential in response to the novel coronavirus (COVID-19) pandemic. The lipid nanoparticle (LNP), as a non-viral vector with good safety and potency factors, is applied to mRNA delivery in the clinic. Among the recently FDA-approved SARS-CoV-2 mRNA vaccines, lipid-based nanoparticles have been shown to be well-suited to antigen presentation and enhanced immune stimulation to elicit potent humoral and cellular immune responses. However, a design strategy for optimal mRNA-LNP vaccines has not been fully elaborated. In this review, we comprehensively and systematically discuss the research strategies for mRNA-LNP vaccines against COVID-19, including antigen and lipid carrier selection, vaccine preparation, quality control, and stability. Meanwhile, we also discuss the potential development directions for mRNA-LNP vaccines in the future. We also conduct an in-depth review of those technologies and scientific insights in regard to the mRNA-LNP field.

Keywords:  COVID-19; lipid nanoparticle; mRNA; preparation; quality control; stability

DOI:  https://doi.org/10.3390/polym14194195
Expert Opin Drug Deliv. 2022 Oct 12.

Microfluidic production of mRNA-loaded lipid nanoparticles for vaccine applications.

Carolina Lopes, Joana Cristóvão, Vânia Silvério, Paulo Roque Lino, Pedro Fonte.

   INTRODUCTION: During past years, lipid nanoparticles (LNPs) have emerged as promising carriers for RNA delivery, with several clinical trials focusing on both infectious diseases and cancer. More recently, the success of messenger RNA (mRNA) vaccines for the treatment of severe diseases such as acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partially justified by the development of LNPs encapsulating mRNA for efficient cytosolic delivery.
AREAS COVERED: This review examines the production and formulation of LNPs by using microfluidic devices, the status of mRNA-loaded LNPs therapeutics and explores spray drying process, as a promising dehydration process to enhance LNP stability and provide alternative administration routes.
EXPERT OPINION: Microfluidic techniques for preparation of LNPs based on organic solvent injection method promotes the generation of stable, uniform, and monodispersed nanoparticles enabling higher encapsulation efficiency. In particular, the application of microfluidics for the fabrication of mRNA-loaded LNPs is based on rapid mixing of small volumes of ethanol solution containing lipids and aqueous solution containing mRNA. Control of operating parameters and formulation has enabled the optimization of nanoparticle physicochemical characteristics and encapsulation efficiency.

Keywords:  Drug delivery; Lipid nanoparticle; Microencapsulation; Microfluidics; Spray drying; Vaccine; mRNA

DOI:  https://doi.org/10.1080/17425247.2022.2135502
Sci Rep. 2022 Oct 14. 12(1): 17208

Overcoming the non-kinetic activity of EGFR1 using multi-functionalized mesoporous silica nanocarrier for in vitro delivery of siRNA.

Javad Parnian, Leila Ma'mani, Mohamad Reza Bakhtiari, Maliheh Safavi.

Triple-negative breast cancer (TNBC) does not respond to HER2-targeted and hormone-based medicines. Epidermal growth factor receptor 1 (EGFR1) is commonly overexpressed in up to 70% of TNBC cases, so targeting cancer cells via this receptor could emerge as a favored modality for TNBC therapy due to its target specificity. The development of mesoporous silica nanoparticles (MSNs) as carriers for siRNAs remains a rapidly growing area of research. For this purpose, a multi-functionalized KIT-6 containing the guanidinium ionic liquid (GuIL), PEI and PEGylated folic acid (FA-PEG) was designed. Accordingly, KIT-6 was fabricated and modified with FA-PEG and PEI polymers attached on the surface and the GuIL placed in the mesopores. Subsequent to confirming the structure of this multi-functionalized KIT-6- based nanocarrier using TEM, SEM, AFM, BET, BJH, DLS and Zeta Potential, it was investigated for uploading and transferring the anti-EGFR1 siRNAs to the MD-MBA-231 cell line. The rate of cellular uptake, cellular localization and endolysosomal escape was evaluated based on the fluorescent intensity of FAM-labelled siRNA using flowcytometry analysis and confocal laser scanning microscopy (CLSM). The 64% cellular uptake after 4 h incubation, clearly suggested the successful delivery of siRNA into the cells and, CLSM demonstrated that siRNA@[FA-PEGylated/PEI@GuIL@KIT-6] may escape endosomal entrapment after 6 h incubation. Using qPCR, quantitative evaluation of EGFR1 gene expression, a knockdown of 82% was found, which resulted in a functional change in the expression of EGFR1 targets. Co-treatment of chemotherapy drug "carboplatin" in combination with siRNA@[FA-PEGylated/PEI@GuIL@KIT-6] exhibited a remarkable cytotoxic effect in comparison to carboplatin alone.

DOI: https://doi.org/10.1038/s41598-022-21601-w
J Phys Chem B. 2022 Oct 12.

Molecular Insights into the Binding of Linear Polyethylenimines and Single-Stranded DNA Using Raman Spectroscopy: A Quantitative Approach.

Rusul Mustafa, Maria Fitian, Nicholas B Hamilton, Jianing Li, W Ruchira Silva, David Punihaole.

Establishing how polymeric vectors such as polyethylenimine (PEI) bind and package their nucleic acid cargo is vital toward developing more efficacious and cost-effective gene therapies. To develop a molecular-level picture of DNA binding, we examined how the Raman spectra of PEIs report on their local chemical environment. We find that the intense Raman bands located in the 1400-1500 cm-1 region derive from vibrations with significant CH2 scissoring and NH bending character. The Raman bands that derive from these vibrations show profound intensity changes that depend on both the local dielectric environment and hydrogen bonding interactions with the secondary amine groups on the polymer. We use these bands as spectroscopic markers to assess the binding between low molecular weight PEIs and single-stranded DNA (ssDNA). Analysis of the Raman spectra suggest that PEI primarily binds via electrostatic interactions to the phosphate backbone, which induces the condensation of the ssDNA. We additionally confirm this finding by conducting molecular dynamics simulations. We expect that the spectral correlations determined here will enable future studies to investigate important gene delivery activities, including how PEI interacts with cellular membranes to facilitate cargo internalization into cells.

DOI: https://doi.org/10.1021/acs.jpcb.2c04939
Small. 2022 Oct 10. e2204408

Computer Aided Development of Nucleic Acid Applications in Nanotechnologies.

Markéta Paloncýová, Martin Pykal, Petra Kührová, Pavel Banáš, Jiří Šponer, Michal Otyepka.

  Utilization of nucleic acids (NAs) in nanotechnologies and nanotechnology-related applications is a growing field with broad application potential, ranging from biosensing up to targeted cell delivery. Computer simulations are useful techniques that can aid design and speed up development in this field. This review focuses on computer simulations of hybrid nanomaterials composed of NAs and other components. Current state-of-the-art molecular dynamics simulations, empirical force fields (FFs), and coarse-grained approaches for the description of deoxyribonucleic acid and ribonucleic acid are critically discussed. Challenges in combining biomacromolecular and nanomaterial FFs are emphasized. Recent applications of simulations for modeling NAs and their interactions with nano- and biomaterials are overviewed in the fields of sensing applications, targeted delivery, and NA templated materials. Future perspectives of development are also highlighted.

Keywords:  MD simulations; biosensors; force fields; lipid nanoparticles; nucleic acid templated assemblies; nucleic acids

DOI:  https://doi.org/10.1002/smll.202204408
Molecules. 2022 Sep 28. pii: 6412. [Epub ahead of print]27(19):

Cheminformatics Modeling of Gene Silencing for Both Natural and Chemically Modified siRNAs.

Xialan Dong, Weifan Zheng.

  In designing effective siRNAs for a specific mRNA target, it is critically important to have predictive models for the potency of siRNAs. None of the published methods characterized the chemical structures of individual nucleotides constituting a siRNA molecule; therefore, they cannot predict the potency of gene silencing by chemically modified siRNAs (cm-siRNA). We propose a new approach that can predict the potency of gene silencing by cm-siRNAs, which characterizes each nucleotide (NT) using 12 BCUT cheminformatics descriptors describing its charge distribution, hydrophobic and polar properties. Thus, a 21-NT siRNA molecule is described by 252 descriptors resulting from concatenating all the BCUT values of its composing nucleotides. Partial Least Square is employed to develop statistical models. The Huesken data (2431 natural siRNA molecules) were used to perform model building and evaluation for natural siRNAs. Our results were comparable with or superior to those from Huesken's algorithm. The Bramsen dataset (48 cm-siRNAs) was used to build and test the models for cm-siRNAs. The predictive r2 of the resulting models reached 0.65 (or Pearson r values of 0.82). Thus, this new method can be used to successfully model gene silencing potency by both natural and chemically modified siRNA molecules.

Keywords:  BCUT descriptors; chemically modified siRNA; cheminformatics; gene silencing; siRNA

DOI:  https://doi.org/10.3390/molecules27196412
IEEE Trans Nanobioscience. 2022 Oct 10. PP

A Bayesian implementation of Quality-by-Design for the development of Cationic Nano-Lipid for siRNA Transfection.

Thierry Bastogne, Lucie Hassler, Jonathan Bruniaux, Magalie Thomassin, Xavier Gidrol, Eric Sulpice, Fabrice P Navarro.

Unlike Quality by Testing approach, where products were tested only after drug manufacturing, Quality by Design (QbD) is a proactive control quality paradigm, which handles risks from the early development steps. In QbD, regression models built from experimental data are used to predict a risk mapping called Design Space in which the developers can identify values of critical input factors leading to acceptable probabilities to meet the efficacy and safety specifications for the expected product. These empirical models are often limited to quantitative responses. Moreover, in practice the smallness and incompleteness of datasets degrade the quality of predictions. In this study, a Bayesian approach including variable selection, parameter estimation and model quality assessment is proposed and assessed using a real case study devoted to the development of a Cationic Nano-Lipid Structures for siRNA Transfection. Two original model structures are also included to describe both binary and percentage response variables. The results confirm the practical relevance and applicability of the Bayesian implementation of the QbD analysis.

DOI: https://doi.org/10.1109/TNB.2022.3213412
J Am Chem Soc. 2022 Oct 14.

Discrete Libraries of Amphiphilic Poly(ethylene glycol) Graft Copolymers: Synthesis, Assembly, and Bioactivity.

Junfeng Chen, Aoon Rizvi, Joseph P Patterson, Craig J Hawker.

Poly(ethylene glycol) (PEG) is an important and widely used polymer in biological and pharmaceutical applications for minimizing nonspecific binding while improving blood circulation for therapeutic/imaging agents. However, commercial PEG samples are polydisperse, which hampers detailed studies on chain length-dependent properties and potentially increases antibody responses in pharmaceutical applications. Here, we report a practical and scalable method to prepare libraries of discrete PEG analogues with a branched, nonlinear structure. These lipid-PEG derivatives have a monodisperse backbone with side chains containing a discrete number of ethylene glycol units (3 or 4) and unique functionalizable chain ends. Significantly, the branched, nonlinear structure is shown to allow for efficient nanoparticle assembly while reducing anti-PEG antibody recognition when compared to commercial polydisperse linear systems, such as DMG-PEG2000. By enabling the scalable synthesis of a broad library of graft copolymers, fundamental self-assembly properties can be understood and shown to directly correlate with the total number of PEG units, nature of the chain ends, and overall backbone length. These results illustrate the advantages of discrete macromolecules when compared to traditional disperse materials.

DOI: https://doi.org/10.1021/jacs.2c07859
Int J Mol Sci. 2022 Sep 28. pii: 11462. [Epub ahead of print]23(19):

Highly Branched Betulin Based Polyanhydrides for Self-Assembled Micellar Nanoparticles Formulation.

Daria Niewolik, Barbara Bednarczyk-Cwynar, Piotr Ruszkowski, Grzegorz Dzido, Katarzyna Jaszcz.

  Polyanhydrides based on betulin are promising materials for use in controlled drug delivery systems. Due to the broad biological activity of betulin derivatives and lack of toxicity in vitro and in vivo, these polymers can be used both as polymeric prodrug and as carriers of other biologically active compounds. In this study, we develop a novel amphiphilic branched polyanhydrides synthesized by the two-step melt polycondensation of betulin disuccinate (DBB) and a tricarboxylic derivative of poly(ethylene glycol) (PEG_COOH). DBB and PEG_COOH were used as the hydrophobic and hydrophilic segments, respectively. The content of DBB in copolymers was from 10 to 95 wt%. Copolymers were assessed for their cytostatic activity against various cancer cell lines. Compared to linear DBB and PEG-based polyanhydrides, the branched polyanhydrides exhibited higher anticancer activity. The obtained polymers were able to self-assemble in water to form micelles with hydrodynamic diameters from 144.8 to 561.8 nm. and are stable over a concentration range from 12.5 µg/mL to 6.8 mg/mL. The formed micelles were found to be spherical in shape using a scanning electron microscope. It was found that the structure and composition of polyanhydrides affected the hydrodynamic diameter of the micelles. The branched betulin-based polyanhydrides have the potential to serve as biodegradable polymer prodrugs or carriers for other bioactive compounds.

Keywords:  betulin; biodegradable polymers; cytostatic activity; polyanhydrides; polymeric micelles

DOI:  https://doi.org/10.3390/ijms231911462
Soft Matter. 2022 Oct 13.

Deep learning potential of mean force between polymer grafted nanoparticles.

Sachin M B Gautham, Tarak K Patra.

Grafting polymer chains on the surfaces of nanoparticles is a well-known route to control their self-assembly and distribution in a polymer matrix. A wide variety of self-assembled structures are achieved by changing the grafting patterns on the surface of an individual nanoparticle. However, an accurate estimation of the effective potential of mean force between a pair of grafted nanoparticles that determines their assembly and distribution in a polymer matrix is an outstanding challenge in nanoscience. We address this problem via deep learning. As a proof of concept, here we report a deep learning framework that learns the interaction between a pair of single-chain grafted spherical nanoparticles from their molecular dynamics trajectory. Subsequently, we carry out the deep learning potential of mean force-based molecular simulation that predicts the self-assembly of a large number of single-chain grafted nanoparticles into various anisotropic superstructures, including percolating networks and bilayers depending on the nanoparticle concentration in three-dimensions. The deep learning potential of mean force-predicted self-assembled superstructures are consistent with the actual superstructures of single-chain polymer grafted spherical nanoparticles. This deep learning framework is very generic and extensible to more complex systems including multiple-chain grafted nanoparticles. We expect that this deep learning approach will accelerate the characterization and prediction of the self-assembly and phase behaviour of polymer-grafted and unfunctionalized nanoparticles in free space or a polymer matrix.

DOI: https://doi.org/10.1039/d2sm00945e
Clin Breast Cancer. 2022 Sep 09. pii: S1526-8209(22)00192-6. [Epub ahead of print]

Integrative Expression, Survival Analysis and Cellular miR-2909 Molecular Interplay in MRN Complex Check Point Sensor Genes (MRN-CSG) Involved in Breast Cancer.

Jitender Singh, Namrata Sangwan, Arushi Chauhan, Pramod K Avti.

   BACKGROUND: Breast cancer, an emerging global challenge, is evidenced by recent studies of miRNAs involvement in DNA repair gene variants (MRE11, RAD50, and NBN as checkpoint sensor genes (CSG) - MRN-CSG). The identification of various mutations in MRN-CSG and their interactions with miRNAs is still not understood. The emerging studies of miR-2909 involvement in other cancers led us to explore its role as molecular mechanistic marker in breast cancer.
MATERIALS AND METHODS: The genomic and proteomic data of MRN-CSG of breast cancer patients (8426 samples) was evaluated to identify the mutation types linked with the patient's survival rate. Additionally, molecular, 3D-structural and functional analysis was performed to identify miR-2909 as regulator of MRN-CSG.
RESULTS: The genomic and proteomic data analysis shows genetic alterations with majority of missense mutations [RAD50 (0.7%), MRE11 (1.5%), and NBN (11%)], though with highest MRE11 mRNA expression in invasive ductal breast carcinoma as compared to other breast cancer types. The Kaplan-Meier survival curves suggest higher survival rate for unaltered groups as compared to the altered group. Network analysis and disease association of miR-2909 and MRN-CSG shows strong interactions with other partners. The molecular hybridization between miR-2909-RAD50 and miR-2909-MRE11 complexes showed thermodynamically stable structures. Further, argonaute protein, involved in RNA silencing, docking studies with miR-MRE11-mRNA and miR-RAD50-mRNA hybridized complexes showed strong binding affinity.
CONCLUSION: The results suggest that miR-2909 forms strong thermodynamically stable molecular hybridized complexes with MRE11 and RAD50 mRNAs which further strongly interacts with argonaute protein to show potential molecular mechanistic role in breast cancer.

Keywords:  Breast cancer; Gibbs free energy and hybridization; MRN complex; Network; miR-2909

DOI:  https://doi.org/10.1016/j.clbc.2022.09.002
J Pharm Sci. 2022 Oct 10. pii: S0022-3549(22)00460-9. [Epub ahead of print]

Twin-screw continuous mixing can produce dry powder inhalation mixtures for pulmonary delivery.

Angela Ren, John J Koleng, Mark Costello, Jamie E Spahn, Hugh D C Smyth, Feng Zhang.

  The feasibility of twin-screw corotating extruder as a continuous process mixer to prepare dry powder inhalation (DPI) powders was investigated. Interactive mixtures of 1% micronized budesonide, 0.3% magnesium stearate and 98.7% alpha-lactose monohydrate were manufactured using a Leistritz Nano-16 extruder at various processing conditions. One set of GFM (grooved mixing) elements were included in the screw profile to provide distributive mixing of conveyed powders with the goal of resulting in a homogeneous mixture. Residence time in the twin-screw mixer was modelled to quantify mixing efficiency. Comparative powders were also prepared using either low or high-shear batch mixing to compare the effect of mixing methods on the properties of the budesonide dry powder inhalation formulation. Twin screw mixing results in homogeneous mixtures with aerosol performance comparable to that of high-shear batch mixing. Scanning electron microscopy confirmed that twin screw mixing produces particles with morphology like that of low and high-shear batch mixing. X-ray diffraction (XRD) analysis verified that there was no form change of the drug due to twin-screw processing. Statistical regression was used to probe the relationship between twin screw mixing process parameters such as screw speed and feed rate and aerosol performance. The twin screw mixing process was found to be robust, as no significant differences in aerosol performance were found for various processing parameters.

Keywords:  Aerosol; Continuous processing; Extrusion; Inhalation; Interactive mixtures; Mixing; Residence time

DOI:  https://doi.org/10.1016/j.xphs.2022.10.007
J Control Release. 2022 Oct 06. pii: S0168-3659(22)00676-9. [Epub ahead of print]

Interplay between mucus mobility and alveolar macrophage targeting of surface-modified liposomes.

Kamila Bohne Japiassu, Francois Fay, Alessandro Marengo, Younès Louaguenouni, Catherine Cailleau, Stéphanie Denis, David Chapron, Nicolas Tsapis, Thais Leite Nascimento, Eliana Martins Lima, Elias Fattal.

  Alveolar macrophages play a crucial role in the initiation and resolution of the immune response in the lungs. Pro-inflammatory M1 alveolar macrophages are an interesting target for treating inflammatory and infectious pulmonary diseases. One commune targeting strategy is to use nanoparticles conjugated with hyaluronic acid, which interact with CD44 overexpressed on the membrane of those cells. Unfortunately, this coating strategy may be countered by the presence on the surface of the nanoparticles of a poly(ethylene glycol) corona employed to improve nanoparticles' diffusion in the lung mucus. This study aims to measure this phenomenon by comparing the behavior in a murine lung inflammation model of three liposomal platforms designed to represent different poly(ethylene glycol) and hyaluronic acid densities (Liposome-PEG, Liposome-PEG-HA and Liposome-HA). In this work, the liposomes were obtained by one-step ethanol injection method. Their interaction with mucin and targeting ability toward pro-inflammatory macrophages were then investigated in vitro and in vivo in a LPS model of lung inflammation. In vitro, poly(ethylene glycol) free HA-liposomes display a superior targeting efficiency toward M1 macrophages, while the addition of poly(ethylene glycol) induces better mucus mobility. Interestingly in vivo studies revealed that the three liposomes showed distinct cell specificity with alveolar macrophages demonstrating an avidity for poly(ethylene glycol) free HA-liposomes, while neutrophils favored PEGylated liposomes exempt of HA. Those results could be explained by the presence of two forces exercising a balance between mucus penetration and receptor targeting. This study corroborates the importance of considering the site of action and the targeted cells when designing nanoparticles to treat lung diseases.

Keywords:  CD44; Hyaluronic acid; Liposome; Lung injury; M1 macrophages; Poly(ethylene glycol)

DOI:  https://doi.org/10.1016/j.jconrel.2022.10.006
ACS Appl Bio Mater. 2022 Oct 10.

Long-Term Vaccine Delivery and Immunological Responses Using Biodegradable Polymer-Based Carriers.

Atefeh Malek-Khatabi, Zahra Tabandeh, Akram Nouri, Elaheh Mozayan, Rossella Sartorius, Shahnaz Rahimi, Rezvan Jamaledin.

  Biodegradable polymers are largely employed in the biomedical field, ranging from tissue regeneration to drug/vaccine delivery. The biodegradable polymers are highly biocompatible and possess negligible toxicity. In addition, biomaterial-based vaccines possess adjuvant properties, thereby enhancing immune responses. This Review introduces the use of different biodegradable polymers and their degradation mechanism. Different kinds of vaccines, as well as the interaction between the carriers with the immune system, then are highlighted. Natural and synthetic biodegradable micro-/nanoplatforms, hydrogels, and scaffolds for local or targeted and controlled vaccine release are subsequently discussed.

Keywords:  biodegradable; hydrogel; microneedle; microparticles; vaccine

DOI:  https://doi.org/10.1021/acsabm.2c00638
Adv Sci (Weinh). 2022 Oct 11. e2203949

Therapeutic Nanocarriers Inhibit Chemotherapy-Induced Breast Cancer Metastasis.

Tianyu Li, Tolulope Akinade, Jie Zhou, Hongxia Wang, Qisong Tong, Siyu He, Emily Rinebold, Luis E Valencia Salazar, Divya Bhansali, Yiling Zhong, Jing Ruan, Jinzhi Du, Piero Dalerba, Kam W Leong.

  Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric nanoparticles that deliver chemotherapeutics and scavenge proinflammatory factors simultaneously to inhibit chemotherapy-induced breast cancer metastasis are developed. The cationic nanoparticles can adsorb cell-free nucleic acids (cfNAs) based on charge-charge interaction, which downregulates the expression of Toll-like receptors and then reduces the secretion of inflammatory cytokines. Through in vitro structural optimization, cationic polyamidoamine (PAMAM) dendrimers modified with drug-binding dodecyl groups and diethylethanolamine surface groups (PAMAM-G3-C125 -DEEA20 ) exhibit the most desirable combination of nanoparticle size (≈140 nm), drug loading, cytotoxicity, cfNA binding, and anti-inflammatory activity. In the mouse models of breast cancer metastasis, paclitaxel-loaded nanoparticles reduce serum levels of cfNAs and inflammatory cytokines compared with paclitaxel treatment alone and inhibit both primary tumor growth and tumor metastasis. Additionally, no significant side effects are detected in the serum or major organs. These results provide a strategy to deliver chemotherapeutics to primary tumors while reducing the prometastatic effects of chemotherapy.

Keywords:  breast cancer; cell-free nucleic acid; chemotherapy; metastasis; nanocarrier; scavenger

DOI:  https://doi.org/10.1002/advs.202203949