bims-drudre 2022-02-27 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–02–27
eight papers selected by
Ceren Kimna, Technical University of Munich

Mucus Penetrating and cell-binding Polyzwitterionic Micelles as Potent Oral Nanomedicine for Cancer Drug Delivery.
Anionic Lipid Nanoparticles Preferentially Deliver mRNA to the Hepatic Reticuloendothelial System.
Carrier-Free Trehalose-Based Nanomotors Targeting Macrophages in Inflammatory Plaque for Treatment of Atherosclerosis.
Tuning the Hydrophilic - Hydrophobic Balance of Molecular Polymer Bottlebrushes Enhances their Tumor Homing Properties.
Background-suppressed tumor-targeted photoacoustic imaging using bacterial carriers.
A Metabolic Multistage Glutathione Depletion Used for Tumor-Specific Chemodynamic Therapy.
Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications.
Personalized functional profiling using ex-vivo patient-derived spheroids points out the potential of an antiangiogenic treatment in a patient with a metastatic lung atypical carcinoid.

Adv Mater. 2022 Feb 23. e2109189

Mucus Penetrating and cell-binding Polyzwitterionic Micelles as Potent Oral Nanomedicine for Cancer Drug Delivery.

Wufa Fan, Qiuyu Wei, Jiajia Xiang, Yisi Tang, Quan Zhou, Yu Geng, Yanpeng Liu, Rui Sun, Lei Xu, Guowei Wang, Ying Piao, Shiqun Shao, Zhuxian Zhou, Jianbin Tang, Tao Xie, Zichen Li, Youqing Shen.

  Orally administerable anticancer nanomedicines are highly desirable due to their easy and repeatable administration, but are not yet feasible because the current nanomedicine cannot simultaneously overcome the strong mucus and villi barriers and thus have very low bioavailability. Herein, we present the first polymeric micelle capable of fast mucus permeation and villi absorption and delivering paclitaxel (PTX) efficiently to tumors with therapeutic efficacy even better than intravenously administered PEG-based counterpart or free PTX. Poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), a water-soluble polyzwitterion, is highly non-fouling to proteins and other biomarcomolecules such as mucin but can weakly bind to phospholipids. Therefore, the micelle of its block copolymer with poly(ε-caprolactone) (OPDEA-PCL) can efficiently permeate through the viscous mucus and bind to villi, which triggers transcytosis-mediated transepithelial transport into blood circulation for tumor accumulation. The orally administered micelles deliver PTX to tumors, efficiently inhibiting the growth of HepG2 and patient-derived hepatocellular carcinoma xenografts and triple-negative breast tumors. These results demonstrate that OPDEA-based micelles may serve as an efficient oral nanomedicine for delivering other small molecules or even large molecules. This article is protected by copyright. All rights reserved.

Keywords:  cancer drug delivery; mucus penetrating; oral nanomedicine; polyzwitterionic micelle; transcytosis

DOI:  https://doi.org/10.1002/adma.202109189
Adv Mater. 2022 Feb 25. e2201095

Anionic Lipid Nanoparticles Preferentially Deliver mRNA to the Hepatic Reticuloendothelial System.

Roy Pattipeiluhu, Gabriela Arias-Alpizar, Genc Basha, Karen Y T Chan, Jeroen Bussmann, Thomas H Sharp, Mohammad-Amin Moradi, Nico Sommerdijk, Edward N Harris, Pieter R Cullis, Alexander Kros, Dominik Witzigmann, Frederick Campbell.

  Lipid nanoparticles (LNPs) are the leading non-viral technology for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by Onpattro® , an approved LNP-based RNA interference (RNAi) therapy, administered intravenously and targeted to parenchymal liver cells. The discovery of systemically administered LNP technologies capable of preferential RNA delivery beyond hepatocytes has, however, proven more challenging. Here, preceded by comprehensive mechanistic understanding of in vivo nanoparticle biodistribution and bodily clearance, we rationally design an LNP-based mRNA delivery platform to preferentially target the hepatic reticuloendothelial system (RES). Evaluated in embryonic zebrafish, validated in mice and directly compared to LNP-mRNA systems based on the lipid composition of Onpattro® , RES-targeted LNPs significantly enhance mRNA expression both globally within the liver and specifically within hepatic RES cell types. Hepatic RES targeting requires just a single lipid change within the formulation of Onpattro® to switch LNP surface charge from neutral to anionic. This technology not only provides new opportunities to treat liver-specific and systemic diseases in which RES cell types play a key role but, more importantly, exemplifies that rational design of advanced RNA therapies must be preceded by a robust understanding of the dominant nano-bio interactions involved. This article is protected by copyright. All rights reserved.

Keywords:  Stabilin-2; embryonic zebrafish; lipid nanoparticles; mRNA delivery; reticuloendothelial system

DOI:  https://doi.org/10.1002/adma.202201095
ACS Nano. 2022 Feb 24.

Carrier-Free Trehalose-Based Nanomotors Targeting Macrophages in Inflammatory Plaque for Treatment of Atherosclerosis.

Ziyu Wu, Min Zhou, Xueting Tang, Jiaqi Zeng, Yazhou Li, Yuning Sun, Jia Huang, Lin Chen, Mimi Wan, Chun Mao.

  Inducing autophagy of macrophages to improve abnormal lipid metabolism is an important way to treat atherosclerosis (AS). Yet, the current application of the mammalian target of rapamycin (mTOR)-dependent autophagy inducers is limited by the side effects and lack of targeting and low biological availability. Herein, a kind of nitric oxide (NO)-driven carrier-free nanomotor based on the reaction between trehalose (Tr, one of the mTOR-independent autophagy inducers), L-arginine (Arg), and phosphatidylserine (PS) is reported. The developed nanomotors use NO as the driving force, which is generated from the reaction between Arg and excessive reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) specifically presenting in the AS microenvironment. The high expression of ROS and iNOS in the AS site can be used as chemoattractants to induce chemotaxis behavior of the nanomotors to achieve the first-step targeting an AS plaque. Subsequently, the "eat me" signal sent by PS is exploited to precisely target to the macrophages in the AS plaque, realizing the plaque-macrophage-targeted effect by this step-by-step strategy. In vitro and in vivo results confirm that the introduction of the concept of carrier-free nanomotors has greatly improved the biological availability of trehalose (the dose can be reduced from 2.5 g kg-1 in previous reports to 0.01 g kg-1 in this work). Particularly, consumed ROS and the production of NO during the targeting process also play positive roles, in which the former regulates the M2 polarization of macrophages and the latter promotes the reconstruction of an endothelial barrier, which contributes to the multilink treatment of AS.

Keywords:  atherosclerosis; autophagy; carrier-free; macrophage; nanomotor; trehalose

DOI:  https://doi.org/10.1021/acsnano.1c08391
Adv Healthc Mater. 2022 Feb 20. e2200163

Tuning the Hydrophilic - Hydrophobic Balance of Molecular Polymer Bottlebrushes Enhances their Tumor Homing Properties.

Parathan Ramamurthi, Zhongchao Zhao, Eamonn Burke, Nicole F Steinmetz, Markus Müllner.

  Nanoparticle (NP)-based drug delivery systems are promising in anti-cancer therapy, capable of delivering cargo with superior selectivity and achieving enhanced tumor accumulation compared to small-molecule therapeutics. As more efforts are being devoted to NP development, molecular polymer bottlebrushes (MPBs) have gained attention as a potential drug delivery vehicle. To date, the influence of various MPB parameters such as size, shape, and surface charge in determining tumor penetrability have been systematically probed. However, the role of amphiphilicity, specifically the hydrophilic-hydrophobic balance, remains unexplored. In this study, we employ a series of MPBs with varied hydrophobicity levels to reveal a dependence between MPB composition, cell association and tumor homing. Our data indicates that increasing levels of hydrophobicity in MPBs (to a certain level) demonstrate only marginal effects in vitro but reveals enhanced tumor homing in a mouse model of ovarian cancer in vivo, where more hydrophilic MPBs exhibit low tissue deposition and low tumor homing. In contrast, more hydrophobic MPBs show significant tumor accumulation and homing due to their engineered hydrophobicity. This article is protected by copyright. All rights reserved.

Keywords:  3D cell culture; biodistribution; cellular interactions; polymer bottlebrushes; polymer nanoparticles; tumor mouse model

DOI:  https://doi.org/10.1002/adhm.202200163
Proc Natl Acad Sci U S A. 2022 Feb 22. pii: e2121982119. [Epub ahead of print]119(8):

Background-suppressed tumor-targeted photoacoustic imaging using bacterial carriers.

Rongkang Gao, Feng Liu, Wenfeng Liu, Silue Zeng, Jingqin Chen, Ruru Gao, Liang Wang, Chihua Fang, Liang Song, Adam C Sedgwick, Jonathan L Sessler, Jun Chu, Fei Yan, Chengbo Liu.

  Photoacoustic (PA) imaging offers promise for biomedical applications due to its ability to image deep within biological tissues while providing detailed molecular information; however, its detection sensitivity is limited by high background signals that arise from endogenous chromophores. Genetic reporter proteins with photoswitchable properties enable the removal of background signals through the subtraction of PA images for each light-absorbing form. Unfortunately, the application of photoswitchable chromoproteins for tumor-targeted imaging has been hampered by the lack of an effective targeted delivery scheme; that is, photoswitchable probes must be delivered in vivo with high targeting efficiency and specificity. To overcome this limitation, we have developed a tumor-targeting delivery system in which tumor-homing bacteria (Escherichia coli) are exploited as carriers to affect the point-specific delivery of genetically encoded photochromic probes to the tumor area. To improve the efficiency of the desired background suppression, we engineered a phytochrome-based reporter protein (mDrBphP-PCMm/F469W) that displays higher photoswitching contrast than those in the current state of the art. Photoacoustic computed tomography was applied to achieve good depth and resolution in the context of in vivo (mice) imaging. The present system effectively integrates a genetically encoded phytochrome-based reporter protein, PA imaging, and synthetic biology (GPS), to achieve essentially background-suppressed tumor-targeted PA monitoring in deep-seated tissues. The ability to image tumors at substantial depths may enable target-specific cancer diagnoses to be made with greater sensitivity, fidelity, and specificity.

Keywords:  Escherichia coli; photoacoustic imaging; photoswitching; tumor-targeted imaging; zero background

DOI:  https://doi.org/10.1073/pnas.2121982119
ACS Nano. 2022 Feb 25.

A Metabolic Multistage Glutathione Depletion Used for Tumor-Specific Chemodynamic Therapy.

Ying Huang, Si Wu, Lu Zhang, Qingqing Deng, Jinsong Ren, Xiaogang Qu.

  The high glutathione (GSH) content in tumor cells strongly affects the efficiency of chemodynamic therapy (CDT). Despite devoted efforts, it still remains a formidable challenge for manufacturing a tumor-specific CDT with rapid and thorough depletion of GSH. Herein, a multistage GSH-consuming and tumor-specific CDT is presented. By consuming the reserved GSH and inhibiting both the raw materials and energy supply of GSH synthesis in cancer cells, it achieves highly potent GSH exhaustion. Our used glycolysis inhibitor cuts off the specific glycolysis of tumor cells to increase the sensitivity to CDT. Furthermore, the starvation effect of glycolysis inhibitor can stimulate the protective mode of normal cells. Since the glycolysis inhibitor and nanocarrier are responsive to tumor microenvironment, this makes CDT more selective to tumor cells. Our work not only fabricates nanomedicine with GSH exhausted function for highly potent CDT but also uses metabolic differences to achieve tumor-specific therapy.

Keywords:  glutathione; glycolysis; metabolic; reactive oxygen species; tumor-specific

DOI:  https://doi.org/10.1021/acsnano.1c10231
Nat Commun. 2022 Feb 23. 13(1): 1017

Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications.

Xiang Xia, Zizhen Zhang, Chunchao Zhu, Bo Ni, Shuchang Wang, Shuofei Yang, Fengrong Yu, Enhao Zhao, Qing Li, Gang Zhao.

Postoperative abdominal infectious complication (AIC) is associated with metastasis in locally advanced gastric cancer (GC) patients after radical gastrectomy. However, the underlying mechanism remains unclear. Herein, we report that neutrophil extracellular traps (NETs), the DNA meshes released by neutrophils in response to infection, could promote GC cells proliferation, invasion, migration and epithelial-mesenchymal transition dependent on TGF-β signaling. Then we model nude mice with cecal puncture without ligation to simulate postoperative AIC and find that NETs in peripheral blood and ascites fluid facilitate GC cells extravasation and implantation into liver and peritoneum for proliferation and metastasis. Notably, TGF-β signaling inhibitor LY 2157299 could effectively impede liver and peritoneal metastasis but not concurrently aggravate sepsis in those AIC-bearing nude mice. These findings implicate that targeting downstream effectors of NETs such as TGF-β signaling might provide potential therapeutic prospect to reduce the risk of GC metastasis.

DOI: https://doi.org/10.1038/s41467-022-28492-5
Cancer Biol Ther. 2022 Dec 31. 23(1): 96-102

Personalized functional profiling using ex-vivo patient-derived spheroids points out the potential of an antiangiogenic treatment in a patient with a metastatic lung atypical carcinoid.

Hichul Kim, Victoria El-Khoury, Nadine Schulte, Tianzuo Zhan, Johannes Betge, Loic Cousin, Emanuele Felli, Patrick Pessaux, Arnaud Ogier, Oliver Opitz, Bosung Ku, Matthias P Ebert, Yong-Jun Kwon.

  Lung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivo spheroids obtained from the patient's liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.

Keywords:  Personalized functional profiling; antiangiogenic therapy; drug screening; lung carcinoid; neuroendocrine tumors; personalized medicine; pharmacotyping; precision medicine; spheroids

DOI:  https://doi.org/10.1080/15384047.2021.2021042