bims-novged Biomed News
on Non-viral vectors for gene delivery
Issue of 2023–05–21
fiveteen papers selected by
the Merkel lab, Ludwig-Maximilians University
  1. Microfluidic mixing as platform technology for production of chitosan nanoparticles loaded with different macromolecules.
  2. Effective mRNA Delivery by Condensation with Cationic Nanogels Incorporated into Liposomes.
  3. Induction of Bleb Structures in Lipid Nanoparticle Formulations of mRNA Leads to Improved Transfection Potency.
  4. Ammonium trifluoroborate-modified poly(β-aminoesters): A case study for PET-guided in vivo pharmacokinetic studies of a non-viral gene delivery system.
  5. Optimization of formulation and atomization of lipid nanoparticles for the inhalation of mRNA.
  6. Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy.
  7. Enhanced lysosomal escape of cell penetrating peptide-functionalized metal-organic frameworks for co-delivery of survivin siRNA and oridonin.
  8. Lipopolymeric nanocarrier enables effective delivery of CRISPR/Cas9 expressing plasmid.
  9. Non-Viral Gene Delivery to Hepatocellular Carcinoma via Intra-Arterial Injection.
  10. Poly(β-amino ester)s-based nanovehicles: Structural regulation and gene delivery.
  11. Self-Assembly of Peptide-Lipid Nanoparticles for the Efficient Delivery of Nucleic Acids.
  12. The role of formulation approaches in presenting targeting ligands on lipid nanoparticles.
  13. Increase Nebulization Stability of Lipid Nanoparticles by Integrating a DNA Supramolecular Hydrogel.
  14. Molecular Dynamics Simulation Studies of Bile, Bile Salts, Lipid-Based Drug Formulations, and mRNA-Lipid Nanoparticles: A Review.
  15. Redox-responsive nanomicelles with intracellular targeting and programmable drug release for targeted tumor therapy.
  1. Eur J Pharm Biopharm. 2023 May 15. pii: S0939-6411(23)00124-8. [Epub ahead of print]
    Microfluidic mixing as platform technology for production of chitosan nanoparticles loaded with different macromolecules.
    Antonietta Greco, Bettina Gabold, Siyu Chen, Xiaoxuan Wang, Zehua Xu, Achim Hartschuh, Enrica Chiesa, Ida Genta, Christian L Ried, Thomas Merdan, Olivia M Merkel.
      In recent decades, biotechnological drugs have emerged as relevant therapeutic tools. However, therapeutic molecules can exert their activity only if properly formulated and delivered into the body. In this regard, nano-sized drug delivery systems have been shown to provide protection, stability, and controlled release of payloads, increasing their therapeutic efficacy. In this work, a microfluidic mixing technique for the preparation of chitosan-based nanoparticles was established with the capability of easily exchanging macromolecular biological cargos such as the model protein β-Galactosidase, mRNA, and siRNA. The nanoparticles obtained showed hydrodynamic diameters ranging from 75 nm to 105 nm, low polydispersity of 0.15 to 0.22 and positive zeta potentials of 6 mV to 17 mV. All payloads were efficiently encapsulated (> 80 %) and the well-known cytocompatibility of chitosan-based nanoparticles was confirmed. Cell culture studies demonstrated increased cellular internalization of loaded nano-formulations compared to free molecules as well as successful gene silencing with nano-formulated siRNA, suggesting the ability of these nanoparticles to escape the endosome.
    Keywords:  Chitosan; drug delivery systems; mRNA; microfluidic; nanoplatforms; protein; siRNA
    DOI:  https://doi.org/10.1016/j.ejpb.2023.05.010
  2. Mol Pharm. 2023 May 15.
    Effective mRNA Delivery by Condensation with Cationic Nanogels Incorporated into Liposomes.
    Nevena Duskunovic, San Hae Im, Juhee Lee, Hyun Jung Chung.
      The challenge in effective delivery of mRNA has been a major hurdle in their development as therapeutics. Herein, we present that the incorporation of cationic nanogels as the condensing material for mRNA into liposomes enables stable and enhanced mRNA delivery to cells in vitro. We prepared dextran-based nanogel particles, which were surface functionalized with oligoarginine peptide (DNPR9) and complexed with mRNA for incorporation into liposomes (LipoDNPR9). The use of DNPR9 with the liposomes resulted in enhanced internalization, as well as a 4-fold increase in transfection of luciferase mRNA when treated with A549 cells in vitro, compared to control liposomes. The enhancement in transfection efficiency was also observed in various cell lines while causing low cytotoxicity. The versatility of the strategy was also investigated by applying DNPR9 for mRNA condensation to ionizable lipid particles, which resulted in an ∼55% increase in transfection. The current development based on nanogel-incorporated liposomes introduces an effective platform for mRNA delivery, while the condensation strategy using DNPR9 can be widely applied for various lipid-based formulations to enhance their efficacy.
    Keywords:  dextran; liposomes; mRNA delivery; nanogels; oligoarginine
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00089
  3. Adv Mater. 2023 May 12. e2303370
    Induction of Bleb Structures in Lipid Nanoparticle Formulations of mRNA Leads to Improved Transfection Potency.
    Miffy Hok Yan Cheng, Jerry Leung, Yao Zhang, Colton Strong, Genc Basha, Arash Momeni, Yihang Chen, Eric Jan, Amir Abdolahzadeh, Xinying Wang, Jayesh A Kulkarni, Dominik Witzigmann, Pieter R Cullis.
      The transfection potency of lipid nanoparticle (LNP) mRNA systems is critically dependent on the ionizable cationic lipid component. LNP mRNA systems composed of optimized ionizable lipids often display distinctive mRNA rich "bleb" structures. Here we show that such structures can also be induced for LNP containing nominally less active ionizable lipids by formulating in the presence of high concentrations of pH 4 buffers such as sodium citrate, leading to improved transfection potencies both in vitro and in vivo. Induction of bleb structure and improved potency is dependent on the type of pH 4 buffer employed, with LNP mRNA systems prepared using 300 mM sodium citrate buffer displaying maximum transfection. The improved transfection potencies of LNP mRNA systems displaying bleb structure can be attributed, at least in part, to enhanced integrity of the encapsulated mRNA. It is concluded that enhanced transfection can be achieved by optimizing formulation parameters to improve mRNA stability and that optimization of ionizable lipids to achieve enhanced potency may well lead to improvements in mRNA integrity through formation of bleb structure rather than enhanced intracellular delivery. This article is protected by copyright. All rights reserved.
    Keywords:  Lipid nanoparticles; bleb structure; mRNA delivery; phase separation
    DOI:  https://doi.org/10.1002/adma.202303370
  4. J Control Release. 2023 May 17. pii: S0168-3659(23)00330-9. [Epub ahead of print]
    Ammonium trifluoroborate-modified poly(β-aminoesters): A case study for PET-guided in vivo pharmacokinetic studies of a non-viral gene delivery system.
    Raúl Cosialls, Odile Fernández, Cristina Simó, Krishna R Pulagam, Marta Guerra-Rebollo, Jordi Llop, Cristina Fornaguera, Ana B Cuenca, Salvador Borrós.
      Nucleic acid-based therapies have become a game-changing player in our way of conceiving pharmacology. Nevertheless, the inherent lability of the phosphodiester bond of the genetic material with respect to the blood nucleases severely hampers its delivery in naked form, therefore making it necessary to use delivery vectors. Among the potential non-viral vectors, polymeric materials such as the poly(β-aminoesters) (PBAEs) stand out as promising gene carriers thanks to their ability to condense nucleic acids in the form of nanometric polyplexes. To keep advancing these systems into their translational preclinical phases, it would be highly valuable to gain accurate insights of their in vivo pharmacokinetic profile. We envisaged that positron emission tomography (PET)-guided imaging could provide us with both, an accurate assessment of the biodistribution of PBAE-derived polyplexes, as well shed light on their clearance process. In this sense, taking advantage of the efficient [19F]-to-[18F]‑fluorine isotopic exchange presented by the ammonium trifluoroborate (AMBF3) group, we have designed and synthesized a new 18F-PET radiotracer based on the chemical modification of a linear poly(β-aminoester). As proof of concept, the incorporation of the newly developed 18F-PBAE into a model nanoformulation was shown to be fully compatible with the formation of the polyplexes, their biophysical characterization, and all their in vitro and in vivo functional features. With this tool in hand, we were able to readily obtain key clues about the pharmacokinetic behavior of a series of oligopeptide-modified PBAEs (OM-PBAEs). The observations described in this study allow us to continue supporting these polymers as an outstanding non-viral gene delivery vector for future applications.
    Keywords:  18-Fluor; Ammonium trifluoroborate; Gene delivery; Non-viral vectors; PBAES; PET; Poly(β-aminoesters); Positron emission tomography
    DOI:  https://doi.org/10.1016/j.jconrel.2023.05.017
  5. Int J Pharm. 2023 May 16. pii: S0378-5173(23)00470-2. [Epub ahead of print]640 123050
    Optimization of formulation and atomization of lipid nanoparticles for the inhalation of mRNA.
    Hao Miao, Ke Huang, Yingwen Li, Renjie Li, Xudong Zhou, Jingyu Shi, Zhenbo Tong, Zhenhua Sun, Aibing Yu.
      Lipid nanoparticles (LNPs) have demonstrated efficacy and safety for mRNA vaccine administration by intramuscular injection; however, the pulmonary delivery of mRNA encapsulated LNPs remains challenging. The atomization process of LNPs will cause shear stress due to dispersed air, air jets, ultrasonication, vibrating mesh etc., leading to the agglomeration or leakage of LNPs, which can be detrimental to transcellular transport and endosomal escape. In this study, the LNP formulation, atomization methods and buffer system were optimized to maintain the LNP stability and mRNA efficiency during the atomization process. Firstly, a suitable LNP formulation for atomization was optimized based on the in vitro results, and the optimized LNP formulation was AX4, DSPC, cholesterol and DMG-PEG2K at a 35/16/46.5/2.5 (%) molar ratio. Subsequently, different atomization methods were compared to find the most suitable method to deliver mRNA-LNP solution. Soft mist inhaler (SMI) was found to be the best for pulmonary delivery of mRNA encapsulated LNPs. The physico-chemical properties such as size and entrapment efficiency (EE) of the LNPs were further improved by adjusting the buffer system with trehalose. Lastly, the in vivo fluorescence imaging of mice demonstrated that SMI with proper LNPs design and buffer system hold promise for inhaled mRNA-LNP therapies.
    Keywords:  Atomization; Lipid nanoparticles (LNPs); Messenger RNA (mRNA); Nebulizer; Pulmonary drug delivery; Soft mist inhaler
    DOI:  https://doi.org/10.1016/j.ijpharm.2023.123050
  6. Adv Mater. 2023 May 17. e2303261
    Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy.
    Yan Zong, Yi Lin, Tuo Wei, Qiang Cheng.
      Messenger RNA (mRNA) has received great attention in the prevention and treatment of various diseases due to the success of COVID-19 mRNA vaccines (Comirnaty and Spikevax). To meet the therapeutic purpose, it is required that mRNA must enter the target cells and express sufficient proteins. Therefore, the development of effective delivery systems is necessary and crucial. Lipid nanoparticle (LNP) represents a remarkable vehicle that has indeed accelerated mRNA applications in humans, as several mRNA-based therapies have already been approved or are in clinical trials. In this review, we focus on mRNA-LNP mediated anticancer therapy. We summarize the main development strategies of mRNA-LNP formulations, discuss representative therapeutic approaches in cancer, and point out current challenges and possible future directions of this research field. We hope these delivered messages could help further improve the application of mRNA-LNP technology in cancer therapy. This article is protected by copyright. All rights reserved.
    Keywords:  cancer therapy; lipid nanoparticle; mRNA delivery; mRNA therapeutics
    DOI:  https://doi.org/10.1002/adma.202303261
  7. J Colloid Interface Sci. 2023 Apr 28. pii: S0021-9797(23)00719-1. [Epub ahead of print]646 370-380
    Enhanced lysosomal escape of cell penetrating peptide-functionalized metal-organic frameworks for co-delivery of survivin siRNA and oridonin.
    Mengru Cai, Yu Yao, Dongge Yin, Rongyue Zhu, Tingting Fu, Jiahui Kong, Kaixin Wang, Jing Liu, Aina Yao, Yidan Ruan, Wenjuan Shi, Qian Zhu, Jian Ni, Xingbin Yin.
      In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the clinical application of siRNA faces several challenges. Insufficient efficacy, poor bioavailability, poor stability, and lack of responsiveness to a single therapy are the main problems affecting tumor therapy. Here, we designed a cell-penetrating peptide (CPP)-modified metal organic framework nanoplatform (named PEG-CPP33@ORI@survivin siRNA@ZIF-90, PEG-CPP33@NPs) for targeted co-delivery of oridonin (ORI), a natural anti-tumor active ingredient) and survivin siRNA in vivo. This can improve the stability and bioavailability of siRNA and the efficacy of siRNA monotherapy. The high drug-loading capacity and pH-sensitive properties of zeolite imidazolides endowed the PEG-CPP33@NPs with lysosomal escape abilities. The Polyethylene glycol (PEG)-conjugated CPP (PEG-CPP33) coating significantly improved the uptake in the PEG-CPP33@NPs in vitro and in vivo. The results showed that the co-delivery of ORI and survivin siRNA greatly enhanced the anti-tumor effect of PEG-CPP33@NPs, demonstrating the synergistic effect between ORI and survivin siRNA. In summary, the novel targeted nanobiological platform loaded with ORI and survivin siRNA presented herein showed great advantages in cancer therapy, and provides an attractive strategy for the synergistic application of chemotherapy and gene therapy.
    Keywords:  CPP33; Metal organic frameworks; Oridonin; Survivin siRNA
    DOI:  https://doi.org/10.1016/j.jcis.2023.04.126
  8. Macromol Rapid Commun. 2023 Apr 25. e2300101
    Lipopolymeric nanocarrier enables effective delivery of CRISPR/Cas9 expressing plasmid.
    Deepak Kumar Sahel, Sangam Giri Goswami, Reena Jatyan, Anupma Kumari, Anupama Mittal, Sivaprakash Ramalingam, Deepak Chitkara.
      CRISPR/Cas9 has proven its accuracy and precision for gene editing by making a double-strand break at the predetermined nucleic acid sequence. Despite being a mainstream gene editing tool, CRISPR/Cas9 has limitations for its in vivo delivery due to the physico-chemical properties such as high molecular weight, supranegative charge, degradation in the presence of nucleases in the biological fluid, etc. Viral vector has been vastly used to deliver CRISPR/Cas components but possesses ample drawbacks and is challenging to translate. We hereby explored a cationic lipopolymer, i.e, mPEG b-(CB-{g-cationic chain; g-Chol; g-Morph}) for its efficiency in delivering CRISPR/Cas9 plasmid (pCas9) in vitro and in vivo. The polymer was utilized to form blank cationic nanoplexes having a zeta potential of +15.8 ± 0.7 mV. Being cationic, the blank nanoplexes were able to condense the pCas9 plasmid at a ratio of 1:20 with a complexation efficiency of ∼98% and showed a size and zeta potential of ∼141 ± 16 nm and 4.2 mV ± 0.7, respectively. The pCas9-loaded nanoplexes showed a transfection efficiency of ∼69% in ARPE-19 cells and showed ∼22% of indel frequency indicating the successful translation of Cas9 protein and guide RNA in the cytosol. Further, they were found to be stable under in vivo environment when given intravenously in Swiss albino mice. These lipopolymeric nanoplexes could be a potential carrier for CRISPR plasmids for genome editing applications. This article is protected by copyright. All rights reserved.
    Keywords:  CRISPR/Cas9; Cationic polymer; Gene editing; Nanoplexes
    DOI:  https://doi.org/10.1002/marc.202300101
  9. Int J Nanomedicine. 2023 ;18 2525-2537
    Non-Viral Gene Delivery to Hepatocellular Carcinoma via Intra-Arterial Injection.
    Hannah J Vaughan, Camila G Zamboni, Kathryn M Luly, Ling Li, Kathleen L Gabrielson, Laboni F Hassan, Nicholas P Radant, Pranshu Bhardwaj, Florin M Selaru, Martin G Pomper, Jordan J Green.
       Purpose: Hepatocellular carcinoma (HCC) has limited treatment options, and modest survival after systemic chemotherapy or procedures such as transarterial chemoembolization (TACE). There is therefore a need to develop targeted therapies to address HCC. Gene therapies hold immense promise in treating a variety of diseases, including HCC, though delivery remains a critical hurdle. This study investigated a new approach of local delivery of polymeric nanoparticles (NPs) via intra-arterial injection for targeted local gene delivery to HCC tumors in an orthotopic rat liver tumor model.
    Methods: Poly(beta-amino ester) (PBAE) nanoparticles were formulated and assessed for GFP transfection in N1-S1 rat HCC cells in vitro. Optimized PBAE NPs were next administered to rats via intra-arterial injection with and without orthotopic HCC tumors, and both biodistribution and transfection were assessed.
    Results: In vitro transfection of PBAE NPs led to >50% transfected cells in adherent and suspension culture at a variety of doses and weight ratios. Administration of NPs via intra-arterial or intravenous injection demonstrated no transfection of healthy liver, while intra-arterial NP injection led to transfection of tumors in an orthotopic rat HCC model.
    Conclusion: Hepatic artery injection is a promising delivery approach for PBAE NPs and demonstrates increased targeted transfection of HCC tumors compared to intravenous administration, and offers a potential alternative to standard chemotherapies and TACE. This work demonstrates proof of concept for administration of polymeric PBAE nanoparticles via intra-arterial injection for gene delivery in rats.
    Keywords:  gene therapy; liver cancer; nanoparticle; poly(beta-amino ester); targeted
    DOI:  https://doi.org/10.2147/IJN.S390384
  10. Mol Ther Nucleic Acids. 2023 Jun 13. 32 568-581
    Poly(β-amino ester)s-based nanovehicles: Structural regulation and gene delivery.
    Jiayu Zhang, Xiaomeng Cai, Rui Dou, Chen Guo, Jiaruo Tang, Yi Hu, Hanqing Chen, Jun Chen.
      The first poly(β-amino) esters (PβAEs) were synthesized more than 40 years ago. Since 2000, PβAEs have been found to have excellent biocompatibility and the capability of ferrying gene molecules. Moreover, the synthesis process of PβAEs is simple, the monomers are readily available, and the polymer structure can be tailored to meet different gene delivery needs by adjusting the monomer type, monomer ratio, reaction time, etc. Therefore, PβAEs are a promising class of non-viral gene vector materials. This review paper presents a comprehensive overview of the synthesis and correlated properties of PβAEs and summarizes the progress of each type of PβAE for gene delivery. The review focuses in particular on the rational design of PβAE structures, thoroughly discusses the correlations between intrinsic structure and effect, and then finishes with the applications and perspectives of PβAEs.
    Keywords:  MT: Delivery Strategies; Poly(β-amino) esters (PβAEs); gene delivery; polymer; vaccines
    DOI:  https://doi.org/10.1016/j.omtn.2023.04.019
  11. Langmuir. 2023 May 17.
    Self-Assembly of Peptide-Lipid Nanoparticles for the Efficient Delivery of Nucleic Acids.
    Jiaojiao Zhang, Zixuan Wang, Jiwei Min, Xuelin Zhang, Rongxin Su, Yuefei Wang, Wei Qi.
      A transfection formulation is successfully developed to deliver nucleic acids by adding an auxiliary lipid (DOTAP) to the peptide, and the transfection efficiency of pDNA reaches 72.6%, which is close to Lipofectamine 2000. In addition, the designed KHL peptide-DOTAP complex exhibits good biocompatibility by cytotoxicity and hemolysis analysis. The mRNA delivery experiment indicates that the complex had a 9- or 10-fold increase compared with KHL or DOTAP alone. Intracellular localization shows that KHL/DOTAP can achieve good endolysosomal escape. Our design provides a new platform for improving the transfection efficiency of peptide vectors.
    DOI:  https://doi.org/10.1021/acs.langmuir.3c00834
  12. Nanomedicine (Lond). 2023 May 18.
    The role of formulation approaches in presenting targeting ligands on lipid nanoparticles.
    Robert Castro, Elizabeth Aisenbrey, Liwei Hui.
      Aims: The density of functional ligands on lipid nanoparticles (LNPs) greatly determined its capability of postfunctionalization and targetability for the applications of personalized nanomedicine and drug/gene delivery. This work is to investigate whether and how formulation methods influence the presentation of surface ligands. Methods: Biotin-modified LNPs as a functional LNP model were synthesized by four different formulation methods. The biotin ligand density and targetability of biotin-LNPs were evaluated and compared. Results: Both the ligand density and targetability of biotin-LNPs formulated by four different formulation methods exhibited a similar trend: homogenization > extrusion > wave-shaped micromixer ≈ Y-shaped micromixer. Conclusion: Formulation methods could modulate the presentation of targeting ligands on LNPs, which could guide future formulation screening and nanomedicine engineering.
    Keywords:  drug delivery; extrusion; formulation; functionalization; homogenization; liposome; microfluidic mixing; nanomedicine; targeting
    DOI:  https://doi.org/10.2217/nnm-2023-0052
  13. ACS Macro Lett. 2023 May 19. 745-750
    Increase Nebulization Stability of Lipid Nanoparticles by Integrating a DNA Supramolecular Hydrogel.
    Xunan Wei, Yujie Li, Xingdi Cheng, Yixing Wen, Wei Yuan, Ruofan Chen, Siwen Meng, Xueguang Lu, Zhiyong Yu, Lijin Xu, Dongsheng Liu, Yuanchen Dong.
      Nebulized lipid nanoparticles (LNPs) have been considered as potential therapies for genetic disease as well as infectious disease. However, the sensitivity of LNPs to high shear stress during the nebulization process results in loss of the integrity of the nanostructure and the capability of delivering active pharmaceutical ingredients. Herein we have provided a fast extrusion method to prepare liposomes incorporated with a DNA hydrogel (hydrogel-LNPs) to improve the stability of the LNPs. Taking advantage of the good cellular uptake efficiency, we also demonstrated the potential of hydrogel-LNPs in delivering small molecular doxorubicin (Dox) and nucleic acid drugs. This work provides not only highly biocompatible hydrogel-LNPs for aerosol delivery, but also a strategy to regulate the elasticity of LNPs, which will benefit the potential optimization of drug delivery carriers.
    DOI:  https://doi.org/10.1021/acsmacrolett.3c00183
  14. Mol Pharm. 2023 May 17.
    Molecular Dynamics Simulation Studies of Bile, Bile Salts, Lipid-Based Drug Formulations, and mRNA-Lipid Nanoparticles: A Review.
    Amali G Guruge, Dallas B Warren, Colin W Pouton, David K Chalmers.
      Lipid-based formulation (LBF) is an effective approach for delivering hydrophobic drugs into the systemic circulation by oral administration. However, much of the physical detail regarding the colloidal behavior of LBFs and their interactions with the contents of the gastrointestinal (GI) environment is not well characterized. Recently, researchers have started to use molecular dynamics (MD) simulations to investigate the colloidal behavior of LBF systems and their interactions with bile and other materials present in the GI tract. MD is a computational method, based on classical mechanics, that simulates the physical movements of atoms and provides atomic-scale information that cannot easily be retrieved using experimental investigations. MD can provide insight into assist the development of drug formulations in a cost and time-effective manner. This review summarizes the application of MD simulation to the study of bile, bile salts, and LBFs and their behavior within the GI environment and also discusses MD simulations of lipid-based mRNA vaccine formulations.
    Keywords:  bile; bile salts; colloids; drug formulations; gastrointestinal tract; lipid nanoparticles; lipid-based formulations; mRNA delivery; molecular dynamics simulations; solubility; surfactants
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00049
  15. Curr Drug Deliv. 2023 May 15.
    Redox-responsive nanomicelles with intracellular targeting and programmable drug release for targeted tumor therapy.
    Yaxin Yang, Wei Shi, Ziyi Zhang, Fawu Gong, Xuman Feng, Chenxi Guo, Yajuan Qi, Zhanjun Liu.
       INTRODUCTION: Anti-inflammatory medications, in particular aspirin, have chemopreventive and anticancer adjuvant effects on specific types of cancers, according to ongoing anti-tumor research. Additionally, efforts have been made to transform Poly(salicylic acid) (PSA) into delivery-related nanocarriers. to transport anticancer medications into nanocarriers. However, tumor cell targeting and tumor selectivity were lacking in the salicylic acid polymer-based nanocarriers, preventing them from performing to their full potential.
    OBJECTIVE: The objective of this study is to prepare targeting and reduction-responsive poly pre-drug nanocarriers (HA-ss-PSA NPs) and to investigate the feasibility of delivering adriamycin (DOX) as nanocarriers.
    METHOD: The structures of the polymers were confirmed by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR) and infrared spectroscopy (IR); the encapsulation rate and drug loading of DOX-loaded nanoparticles were determined by HPLC; and the anti-tumor effects of the carriers were evaluated by MTT experiments and in vivo experiments.
    RESULTS: The prepared nanocarriers had uniform particle size distribution. The drug release rate was up to 80% within 48 h in the tumor environment. DOX/HA-ss-PSA NPs showed significant cytostatic effects. In addition, HA-ss-PSA NPs showed significant targeting and inhibition of cell migration in cell uptake and scratch assays. In vivo experiments showed that the prepared carriers had high tumor inhibition rates, good targeting effects on the liver and tumor, and significantly reduced toxicity to other tissues.
    CONCLUSION: The prepared HA-ss-PSA NPs could effectively inhibit the growth of HepG2 cells and tumors in vivo, indicating that PSA could be used as a backbone component of a safe and reliable drug delivery system, providing a new strategy for the treatment of liver cancer.
    Keywords:  cancer; disulfide bond; hyaluronic acid; polyprodrug nanomedicines; reduction response; salicylic acid
    DOI:  https://doi.org/10.2174/1567201820666230515111328
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