bims-novged 2022-09-25 papers

bims-novged

Biomed News

on Non-viral vectors for gene delivery

Issue of 2022–09–25
thirteen papers selected by
the Merkel lab, Ludwig-Maximilians University

Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery.
Hepatocyte-Directed Delivery of Lipid-Encapsulated Small Interfering RNA.
Leveraging Biological Buffers for Efficient Messenger RNA Delivery via Lipid Nanoparticles.
Designing Synthetic Polymers for Nucleic Acid Complexation and Delivery: From Polyplexes to Micelleplexes to Triggered Degradation.
Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes.
Construction of PEI-EGFR-PD-L1-siRNA dual functional nano-vaccine and therapeutic efficacy evaluation for lung cancer.
Lipid Nanoparticles as Delivery Vehicles for Inhaled Therapeutics.
Nanomaterials Mediated Co-Stimulation of toll-like Receptors and CD40 for Antitumor Immunity.
Payload distribution and capacity of mRNA lipid nanoparticles.
Tailored polyethylene glycol grafting on porous nanoparticles for enhanced targeting and intracellular siRNA delivery.
Nanoparticles design considerations to co-deliver nucleic acids and anti-cancer drugs for chemoresistance reversal.
Novel pH-sensitive nanoparticles based on prodrug strategy to delivery All-Trans Retinoic Acid for breast cancer.
Research Progress on Nanoparticles-Based CRISPR/Cas9 System for Targeted Therapy of Tumors.

J Control Release. 2022 Sep 17. pii: S0168-3659(22)00613-7. [Epub ahead of print]

Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery.

Christoph M Zimmermann, Domizia Baldassi, Karen Chan, Nathan B P Adams, Alina Neumann, Diana Leidy Porras-Gonzalez, Xin Wei, Nikolaus Kneidinger, Mircea Gabriel Stoleriu, Gerald Burgstaller, Dominik Witzigmann, Paola Luciani, Olivia M Merkel.

  While all the siRNA drugs on the market target the liver, the lungs offer a variety of currently undruggable targets which could potentially be treated with RNA therapeutics. Hence, local, pulmonary delivery of RNA nanoparticles could finally enable delivery beyond the liver. The administration of RNA drugs via dry powder inhalers offers many advantages related to physical, chemical and microbial stability of RNA and nanosuspensions. The present study was therefore designed to test the feasibility of engineering spray dried lipid nanoparticle (LNP) powders. Spray drying was performed using 5% lactose solution (m/V), and the targets were set to obtain nanoparticle sizes after redispersion of spray-dried powders around 150 nm, a residual moisture level below 5%, and RNA loss below 15% at maintained RNA bioactivity. The LNPs consisted of an ionizable cationic lipid which is a sulfur-containing analog of DLin-MC3-DMA, a helper lipid, cholesterol, and PEG-DMG encapsulating siRNA. Prior to the spray drying, the latter process was simulated with a novel dual emission fluorescence spectroscopy method to preselect the highest possible drying temperature and excipient solution maintaining LNP integrity and stability. Through characterization of physicochemical and aerodynamic properties of the spray dried powders, administration criteria for delivery to the lower respiratory tract were fulfilled. Spray dried LNPs penetrated the lung mucus layer and maintained bioactivity for >90% protein downregulation with a confirmed safety profile in a lung adenocarcinoma cell line. Additionally, the spray dried LNPs successfully achieved up to 50% gene silencing of the house keeping gene GAPDH in ex vivo human precision-cut lung slices at without increasing cytokine levels. This study verifies the successful spray drying procedure of LNP-siRNA systems maintaining their integrity and mediating strong gene silencing efficiency on mRNA and protein levels both in vitro and ex vivo. The successful spray drying procedure of LNP-siRNA formulations in 5% lactose solution creates a novel siRNA-based therapy option to target respiratory diseases such as lung cancer, asthma, COPD, cystic fibrosis and viral infections.

Keywords:  Formulation screening; Human precision-cut lung slices; LNP; Lipid nanoparticles; Onpattro®; Pulmonary delivery; RNA therapeutics; Respiratory diseases; Spray drying; siRNA delivery

DOI:  https://doi.org/10.1016/j.jconrel.2022.09.021
Methods Mol Biol. 2022 ;2544 95-106

Hepatocyte-Directed Delivery of Lipid-Encapsulated Small Interfering RNA.

Laura Morán, Marius Maximilian Woitok, Matthias Bartneck, Francisco Javier Cubero.

  Lipid formulations for cell transfection are among the most efficient systems for nucleic acid delivery. During the COVID-19 pandemic, lipid-encapsulated RNA (lipid nanoparticles, LNP) has succeeded as a superior vaccine. Moreover, other similar lipid nanocarriers for siRNA are approved and many are on the pipelines. While lipid encapsulation required several devices for the mixing of components, lipoplex technology allows to rapidly mix nucleic acids and positively charged lipids for cell transfection. In vivo, hepatocytes are important target cells of lipid formulated RNAi. This chapter describes the state-of-the-art lipoplex and LPN manufacturing for treating primary hepatocytes with lipid formulations. Furthermore, protocols for isolating murine hepatocytes and for transfecting these cells with pharmaceutically relevant lipid formulations are provided and discussed.

Keywords:  Lipid nanoparticles; RNAi; lipoplex; primary hepatocytes; siRNA; transfection

DOI:  https://doi.org/10.1007/978-1-0716-2557-6_6
Mol Pharm. 2022 Sep 21.

Leveraging Biological Buffers for Efficient Messenger RNA Delivery via Lipid Nanoparticles.

Michael I Henderson, Yulia Eygeris, Antony Jozic, Marco Herrera, Gaurav Sahay.

  Lipid nanoparticles containing messenger RNA (mRNA-LNPs) have launched to the forefront of nonviral delivery systems with their realized potential during the COVID-19 pandemic. Here, we investigate the impact of commonly used biological buffers on the performance and durability of mRNA-LNPs. We tested the compatibility of three common buffers─HEPES, Tris, and phosphate-buffered saline─with a DLin-MC3-DMA mRNA-LNP formulation before and after a single controlled freeze-thaw cycle. We hypothesized that buffer composition would affect lipid-aqueous phase separation. Indeed, the buffers imposed structural changes in LNP morphology as indicated by electron microscopy, differential scanning calorimetry, and membrane fluidity assays. We employed in vitro and in vivo models to measure mRNA transfection and found that Tris or HEPES-buffered LNPs yielded better cryoprotection and transfection efficiency compared to PBS. Understanding the effects of various buffers on LNP morphology and efficacy provides valuable insights into maintaining the stability of LNPs after long-term storage.

Keywords:  cryopreservation; lipid nanoparticles; messenger RNA; nanoparticle stability

DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00587
Biomacromolecules. 2022 Sep 20.

Designing Synthetic Polymers for Nucleic Acid Complexation and Delivery: From Polyplexes to Micelleplexes to Triggered Degradation.

Le Zhou, Miracle Emenuga, Shreya Kumar, Zachary Lamantia, Marxa Figueiredo, Todd Emrick.

Gene delivery as a therapeutic tool continues to advance toward impacting human health, with several gene therapy products receiving FDA approval over the past 5 years. Despite this important progress, the safety and efficacy of gene therapy methodology requires further improvement to ensure that nucleic acid therapeutics reach the desired targets while minimizing adverse effects. Synthetic polymers offer several enticing features as nucleic acid delivery vectors due to their versatile functionalities and architectures and the ability of synthetic chemists to rapidly build large libraries of polymeric candidates equipped for DNA/RNA complexation and transport. Current synthetic designs are pursuing challenging objectives that seek to improve transfection efficiency and, at the same time, mitigate cytotoxicity. This Perspective will describe recent work in polymer-based gene complexation and delivery vectors in which cationic polyelectrolytes are modified synthetically by introduction of additional components─including hydrophobic, hydrophilic, and fluorinated units─as well as embedding of degradable linkages within the macromolecular structure. As will be seen, recent advances employing these emerging design strategies are promising with respect to their excellent biocompatibility and transfection capability, suggesting continued promise of synthetic polymer gene delivery vectors going forward.

DOI: https://doi.org/10.1021/acs.biomac.2c00767
Biomedicines. 2022 Sep 03. pii: 2182. [Epub ahead of print]10(9):

Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes.

Abdullah A Alamoudi, Paula A Méndez, David Workman, Andreas G Schätzlein, Ijeoma F Uchegbu.

  Therapeutic gene silencing in the brain is usually achieved using highly invasive intracranial administration methods and/or comparatively toxic vectors. In this work, we use a relatively biocompatible vector: poly(ethylene glycol) star-shaped polymer capped with amine groups (4APPA) via the nose to brain route. 4APPA complexes anti- itchy E3 ubiquitin protein ligase (anti-ITCH) siRNA to form positively charged (zeta potential +15 ± 5 mV) 150 nm nanoparticles. The siRNA-4APPA polyplexes demonstrated low cellular toxicity (IC50 = 13.92 ± 6 mg mL-1) in the A431 cell line and were three orders of magnitude less toxic than Lipofectamine 2000 (IC50 = 0.033 ± 0.04 mg mL-1) in this cell line. Cell association and uptake of fluorescently labelled siRNA bound to siRNA-4APPA nanoparticles was demonstrated using fluorescent activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), respectively. Gene silencing of the ITCH gene was observed in vitro in the A431 cell line (65% down regulation when compared to the use of anti-ITCH siRNA alone). On intranasal dosing with fluorescently labelled siRNA-4APPA polyplexes, fluorescence was seen in the cells of the olfactory bulb, cerebral cortex and mid-brain regions. Finally, down regulation of ITCH was seen in the brain cells (54 ± 13% ITCH remaining compared to untreated controls) in a healthy rat model, following intranasal dosing of siRNA-4APPA nanoparticles (0.15 mg kg-1 siRNA twice daily for 3 days). Gene silencing in the brain may be achieved by intranasal administration of siRNA- poly(ethylene glycol) based polyplexes.

Keywords:  brain; gene silencing; intranasal; nanoparticles; polyethylene glycol (PEG); siRNA delivery

DOI:  https://doi.org/10.3390/biomedicines10092182
Thorac Cancer. 2022 Sep 18.

Construction of PEI-EGFR-PD-L1-siRNA dual functional nano-vaccine and therapeutic efficacy evaluation for lung cancer.

Guixue Yang, Dong Zhou, Yin Dai, Yanqi Li, Jiang Wu, Quanxing Liu, Xufeng Deng.

   BACKGROUND: PD-1/PD-L1 tumor immunotherapy shows effective anticancer in treatment of solid tumors, so PEI lipid nanoparticles (PEI-LNP)/siRNA complex (EPV-PEI-LNP-SiRNA) with the therapeutic function of PD-L1-siRNA and EGFR short peptide/PD-L1 double immune-enhancing function were constructed for the prevention and treatment of EGFR-positive lung cancer in this study.
METHOD: In this study, PEI lipid nanoparticles (PEI-LNP)/siRNA complex (EPV-PEI-LNP-siRNA) with the therapeutic function of PD-L1-siRNA and EGFR short peptide/PD-L1 double immune-enhancing function were constructed for the prevention and treatment of EGFR-positive lung cancer and functional evaluation was conducted.
RESULTS: On the basis of the construction of the composite nano-drug delivery system, the binding capacity, cytotoxicity, apoptosis and uptake capacity of siRNA and EPV-PEI-LNP were tested in vitro, and the downregulation effect of PD-L1 on A549 cancer cells and the cytokine levels of cocultured T cells were tested. Lipid nanoparticles delivered siRNA and EGFR short peptide vaccine to non-small cell lung cancer (NSCLC), increasing tumor invasion and activation of CD8 + T cells. Combination therapy is superior to single target therapy.
CONCLUSION: Our constructed lipid nanoparticles of tumor targeted therapy gene siRNA combination had the ability to target cells in vitro and downregulate the expression of PD-L1, realizing the tumor-specific expression of immune-stimulating cytokines, which is a highly efficient and safe targeted therapy nano-vaccine.

Keywords:  PEI-EGFR-PD-L1-siRNA; lung cancer; therapy; vaccine

DOI:  https://doi.org/10.1111/1759-7714.14618
Biomedicines. 2022 Sep 02. pii: 2179. [Epub ahead of print]10(9):

Lipid Nanoparticles as Delivery Vehicles for Inhaled Therapeutics.

Ellenmae W X Leong, Ruowen Ge.

  Lipid nanoparticles (LNPs) have emerged as a powerful non-viral carrier for drug delivery. With the prevalence of respiratory diseases, particularly highlighted by the current COVID-19 pandemic, investigations into applying LNPs to deliver inhaled therapeutics directly to the lungs are underway. The progress in LNP development as well as the recent pre-clinical studies in three main classes of inhaled encapsulated drugs: small molecules, nucleic acids and proteins/peptides will be discussed. The advantages of the pulmonary drug delivery system such as reducing systemic toxicity and enabling higher local drug concentration in the lungs are evaluated together with the challenges and design considerations for improved formulations. This review provides a perspective on the future prospects of LNP-mediated delivery of inhaled therapeutics for respiratory diseases.

Keywords:  inhalation drug delivery; lipid nanoparticles (LNPs); lung; respiratory diseases

DOI:  https://doi.org/10.3390/biomedicines10092179
Adv Mater. 2022 Sep 19. e2207486

Nanomaterials Mediated Co-Stimulation of toll-like Receptors and CD40 for Antitumor Immunity.

Jingyue Yan, Yuebao Zhang, Shi Du, Xucheng Hou, Wenqing Li, Chunxi Zeng, Chengxiang Zhang, Jeffrey Cheng, Binbin Deng, David W McComb, Weiyu Zhao, Yonger Xue, Diana D Kang, Xiaolin Cheng, Yizhou Dong.

  Toll-like Receptors (TLRs) and CD40 related-signaling pathways represent critical bridges between the innate and adaptive immune responses. Here, we develop an immunotherapy regimen that enables co-stimulation of TLR7/8 and CD40 mediated pathways. TLR7/8 agonist resiquimod (R848) derived amino lipids, RAL1 and RAL2, are synthesized and formulated into RAL-derived lipid nanoparticles (RAL-LNPs). The RAL2-LNPs show efficient CD40 mRNA delivery to DCs both in vitro (90.8 ± 2.7%) and in vivo (61.3 ± 16.4%). When combined with agonistic anti-CD40 antibody, this approach can produce effective antitumor activities in mouse melanoma tumor models, thereby suppressing tumor growth, prolonging mouse survival, and establishing antitumor memory immunity. Overall, RAL2-LNPs provide a novel platform towards cancer immunotherapy by integrating innate and adaptive immunity. This article is protected by copyright. All rights reserved.

Keywords:  CD40; immunotherapy; lipid nanoparticles; mRNA; resiquimod

DOI:  https://doi.org/10.1002/adma.202207486
Nat Commun. 2022 Sep 23. 13(1): 5561

Payload distribution and capacity of mRNA lipid nanoparticles.

Sixuan Li, Yizong Hu, Andrew Li, Jinghan Lin, Kuangwen Hsieh, Zachary Schneiderman, Pengfei Zhang, Yining Zhu, Chenhu Qiu, Efrosini Kokkoli, Tza-Huei Wang, Hai-Quan Mao.

Lipid nanoparticles (LNPs) are effective vehicles to deliver mRNA vaccines and therapeutics. It has been challenging to assess mRNA packaging characteristics in LNPs, including payload distribution and capacity, which are critical to understanding structure-property-function relationships for further carrier development. Here, we report a method based on the multi-laser cylindrical illumination confocal spectroscopy (CICS) technique to examine mRNA and lipid contents in LNP formulations at the single-nanoparticle level. By differentiating unencapsulated mRNAs, empty LNPs and mRNA-loaded LNPs via coincidence analysis of fluorescent tags on different LNP components, and quantitatively resolving single-mRNA fluorescence, we reveal that a commonly referenced benchmark formulation using DLin-MC3 as the ionizable lipid contains mostly 2 mRNAs per loaded LNP with a presence of 40%-80% empty LNPs depending on the assembly conditions. Systematic analysis of different formulations with control variables reveals a kinetically controlled assembly mechanism that governs the payload distribution and capacity in LNPs. These results form the foundation for a holistic understanding of the molecular assembly of mRNA LNPs.

DOI: https://doi.org/10.1038/s41467-022-33157-4
Nanoscale. 2022 Sep 22.

Tailored polyethylene glycol grafting on porous nanoparticles for enhanced targeting and intracellular siRNA delivery.

Jounghyun Yoo, Kyunghwan Kim, Suhyun Kim, Hee Ho Park, Heungsoo Shin, Jinmyoung Joo.

Surface functionalization of nanoparticles with polyethylene glycol (PEG) has been widely demonstrated as an anti-opsonization strategy to reduce protein corona formation which is one of the major concerns affecting target receptor recognition. However, excessive surface passivation with PEG can lead to the strong inhibition of cellular uptake and less efficient binding to target receptors, resulting in reduced potential of targeted delivery. To improve specific cell targeting while reducing the nonspecific protein adsorption, a secondary packaging of the nanoparticles with shorter PEG chains, making the targeting ligands densely stretched out for enhanced molecular recognition is demonstrated. Particularly, we report the tailored surface functionalization of the porous nanoparticles that require the stealth shielding onto the open-pore region. This study shows that, in addition to the surface chemistry, the conformation of the PEG layers controls the cellular interaction of nanoparticles. Since the distance between neighboring PEG chains determines the structural conformation of the grafted PEG molecules, tailored PEG combinations can efficiently resist the adsorption of serum proteins onto the pores by transitioning the conformation of the PEG chains, thus significantly enhance the targeting efficiency (>5-fold). The stretched brush PEG conformation with secondary packaging of shorter PEG chains could be a promising anti-opsonization and active targeting strategy for efficient intracellular delivery of nanoparticles.

DOI: https://doi.org/10.1039/d2nr02995b
Int J Pharm X. 2022 Dec;4 100126

Nanoparticles design considerations to co-deliver nucleic acids and anti-cancer drugs for chemoresistance reversal.

Sahar Eljack, Stephanie David, Areeg Faggad, Igor Chourpa, Emilie Allard-Vannier.

  Chemoresistance and hence the consequent treatment failure is considerably challenging in clinical cancer therapeutics. The understanding of the genetic variations in chemoresistance acquisition encouraged the use of gene modulatory approaches to restore anti-cancer drug efficacy. Many smart nanoparticles are designed and optimized to mediate combinational therapy between nucleic acid and anti-cancer drugs. This review aims to define a rational design of such co-loaded nanocarriers with the aim of chemoresistance reversal at various cellular levels to improve the therapeutic outcome of anticancer treatment. Going through the principles of therapeutics loading, physicochemical characteristics tuning, and different nanocarrier modifications, also looking at combination effectiveness on chemosensitivity restoration. Up to now, these emerging nanocarriers are in development status but are expected to introduce outstanding outcomes.

Keywords:  5-FU, 5-Flurouracil; ABCB, ATP Binding Cassette Subfamily B Member; AIF, Apoptosis-inducing factor; AKT, Serine/threonine kinase; ASGPR, The asialoglycoprotein receptor; ASO, Antisense oligonucleotides; Anti-cancer drugs; BBB, Blood-brain barrier; BCRP, Breast cancer-resistant protein; Bak, Bcl2-antagonist/killer; Bax, Bcl-2-associated X protein apoptotic activator; Bcl-2, B-cell lymphoma 2; Bcl-xl, B-cell lymphoma-extra large; CAV-1, Caveolin 1; CDK, Cyclin-dependent kinase; CI, Combination index; CMD, Carboxymethyl dextran; CPT, Camptothecin; CSCs, Cancer stem cells; CT, The computed tomography; ChNPs, Chitosan nanoparticles; Chemoresistance reversal; CisPt, Cisplatin; Combination therapy; DMSO, Dimethyl sulfoxide; DOPE, Dioleoylphosphatidylethanolamine; DOTAP, 1,2-Dioleoyl-3-trimethylammonium propane; DOX, Doxorubicin; DSPE, 1,2-Distearoyl-sn-glycerol-3-phosphoethanolamine; DTX, Docetaxel; E-CAD, E-cadherin; EC50, The half maximal effective concentration; EGFR, Epidermal growth factor receptor; EPR, The enhanced permeability and retention; ERK, Extracellular regulated kinase; EZH2, Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit; FAK, Focal adhesion kinase; FRα, Folate receptor-α; GEM, Gemcitabine; GSH, Glutathione; GalNAc, N-acetylgalactosamine; GnRH, Gonadotropin-releasing hormone; H1F1, Hypoxia-inducible factor 1; HRAS, GTPase HRas enzyme; IC50, The half-maximal inhibitory concentration; IL-17B, Interleukin 17B; ILK, Integrin-linked kinase; Kras, Kirsten rat sarcoma GTPase enzyme; LDL, Low-density lipoprotein; LHRH, Luteinizing hormone-releasing hormone; LHSSG2C, Ditetradecyl 2-(4-(2-(2-(2-(2-(2,6-diaminohexanamido)-3-(1H-imidazole-4-yl) propanamido) ethyl) disulfanyl) ethylamino)-4-oxobutanamido) pentanedioate; LRP, Lung resistant protein; MAPK, Mitogen-activated protein kinase; MDM, Mixed dendrimer micelles; MDR, Multidrug-resistant; MRI, Magnetic resonance images; MSNRs, Mesoporous silica nanorods; MTDH, Metadherin; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MVP, Major vault protein; NF-κB, Nuclear factor-kappa light chain enhancer of activated B cells; Nanoparticles; Notch-1, Notch homolog 1, translocation-associated; Nucleic acids; OEI, Oligoethylenimine; ORF, Open reading frame; OxaPt, Oxaliplatin; P-gp, P-glycoprotein; PAH, Poly (acrylhydrazine); PAMAM, Polyamidoamine; PBS, Phosphate Buffered Saline; PDMAPMA, Poly (3-dimethylaminopropyl methacrylamide); PDX, Patient-derived xenograft; PEG, Polyethylene glycol; PEI, Polyethyleneimine; PI3-kinase, Phosphatidylinositol 3′-kinase; PLA, Polylactic acid; PLGA, Poly (lactic-co-glycolic acid); PTEN, Phosphatase and tensin homolog; PTK-1, Protein tyrosine kinase 1; PTX, Paclitaxel; Polζ, Translesion DNA polymerase; Q, Combination efficacy; R, Resistance index; RES, Reticuloendothelial system; REV, Reversionless phenotype; RGD, The tripeptide arginine−glycine−aspartic sequence; RISC, RNA Induced Silencing Complex; Rac1, Ras-related C3 botulinum toxin substrate 1; SIP-1, Stress-induced protein 1; SLN, Solid lipid nanoparticles; SR-BI, Scavenger receptor class B type I; SSRTs, Somatostatin receptors; STAT-3, Signal transducer and activator of transcription 3; TGN, Brain targeting peptide; TIMP3, Tissue inhibitor of metalloproteinase 3; TLR4, Toll-like receptor 4; TLS, Translesion synthesis; TRAIL, Tumor necrosis factor (TNF)-related apoptosis-inducing ligand; USP9X, Ubiquitin specific peptidase 9, X-linked; VEGF, Vascular endothelial growth factor; ZEB, Zinc finger E-box-binding homeobox 1 transcription factor; c-Myc, C-Master regulator of cell cycle entry, proliferative and metabolism; miRNA, Micro ribonucleic acid; p27Kip1, Cell cycle inhibitor; pAKT, Phosphatidylinositol 3-kinase and Protein Kinase; pDNA, Plasmid deoxyribonucleic acid; shRNA, Short hairpin ribonucleic acid; siRNA, Small interfering ribonucleic acid

DOI:  https://doi.org/10.1016/j.ijpx.2022.100126
Colloids Surf B Biointerfaces. 2022 Sep 14. pii: S0927-7765(22)00521-5. [Epub ahead of print]219 112838

Novel pH-sensitive nanoparticles based on prodrug strategy to delivery All-Trans Retinoic Acid for breast cancer.

Weinan Li, HeXin Gong, Yuhan Fu, Jialin Sun, Yanhong Wang.

  Developing chemotherapy with nanoparticle-based prodrugs provides promising strategies for improving the safety and delivery of anti-cancer drugs therapeutics and effective cancer treatment. Herein, we developed a pH-sensitive prodrug delivery system (All-Trans-Retinoic Acid (ATRA) grafted poly (β-amino esters) (PBAE) copolymers, ATRA-g-PBAE) for delivery of ATRA with some physicochemical and biological properties. The in vitro release of ATRA-g-PBAE prodrug nanoparticles (PNPs) was sustained-release and pH-sensitive. The cytotoxicity and uptake of different preparations in vitro were evaluated on MCF-7 cells at pH 7.4 and 5.5. The carrier PBAE had no cytotoxicity, and ATRA-g-PBAE PNPs could significantly inhibit cell growth at pH 5.5. MCF-7 cells treated with Cy5.5 grafted PBAE (Cy5.5-PBAE) showed stronger fluorescence signals at pH 5.5. Meanwhile, ATRA-g-PBAE PNPs entered the cell via a clathrin-mediated endocytic pathway. Subsequently, PBAE protonation facilitated the escape of PNPs from the lysosome and released the drug. ATRA-g-PBAE seems promising as a novel pH-sensitive prodrug to overcome the limitations of ATRA for breast cancer therapy.

Keywords:  All-Trans-Retinoic Acid; Breast cancer; Pin1; Prodrug nanoparticles

DOI:  https://doi.org/10.1016/j.colsurfb.2022.112838
Biomolecules. 2022 Sep 05. pii: 1239. [Epub ahead of print]12(9):

Research Progress on Nanoparticles-Based CRISPR/Cas9 System for Targeted Therapy of Tumors.

Dengyun Nie, Ting Guo, Miao Yue, Wenya Li, Xinyu Zong, Yinxing Zhu, Junxing Huang, Mei Lin.

  Cancer is a genetic mutation disease that seriously endangers the health and life of all human beings. As one of the most amazing academic achievements in the past decade, CRISPR/Cas9 technology has been sought after by many researchers due to its powerful gene editing capability. CRISPR/Cas9 technology shows great potential in oncology, and has become one of the most promising technologies for cancer genome-editing therapeutics. However, its efficiency and the safety issues of in vivo gene editing severely limit its widespread application. Therefore, developing a suitable delivery method for the CRISPR/Cas9 system is an urgent problem to be solved at present. Rapid advances in nanomedicine suggest nanoparticles could be a viable option. In this review, we summarize the latest research on the potential use of nanoparticle-based CRISPR/Cas9 systems in cancer therapeutics, in order to further their clinical application. We hope that this review will provide a novel insight into the CRISPR/Cas9 system and offer guidance for nanocarrier designs that will enable its use in cancer clinical applications.

Keywords:  CRISPR/Cas9; cancer; delivery; nanoparticles; therapy

DOI:  https://doi.org/10.3390/biom12091239