Subcellular visualization: Organelle-specific targeted drug delivery and discovery

Shao, Xintian; Meng, Chen; Song, Wenjing; Zhang, Tao; Chen, Qixin

doi:10.1016/j.addr.2023.114977

Cited by 13 publications

(1 citation statement)

References 257 publications

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“…Selecting optimal targeting ligands through understanding subcellular processes associated with productive delivery will enable improved design of nano-delivery systems. Further refinement of drug delivery systems to dial-in subcellular function could be critical to realize next-generation systems with improved therapeutic index [ 64 , 65 ]. Furthermore, the basic assay design described here could be further expanded-on to answer more complex questions regarding trafficking and function of targeted NPs and further guide NP design.…”

Section: Resultsmentioning

confidence: 99%

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

Vaughan,

Est-Witte,

Dockery

et al. 2024

Science and Technology of Advanced Materials

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

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Section: Resultsmentioning

confidence: 99%

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

Vaughan,

Est-Witte,

Dockery

et al. 2024

Science and Technology of Advanced Materials

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Dendritic Polymer‐Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response

Zhang,

Fang,

Pan

et al. 2024

Advanced Materials

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The dense extracellular matrix (ECM) in solid tumors, contributed by cancer‐associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. We proposed a sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. We developed dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)‐based nanomedicines (P‐DAS and P‐Epi) for sequential delivery of DAS and Epi, respectively. P‐DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM could enhance tumor penetration of P‐Epi to strengthen its ICD effect, leading to an amplified anti‐tumor immune response. In breast cancer‐bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti‐PD‐1 therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P‐DAS and P‐Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.This article is protected by copyright. All rights reserved

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Intracellular Compartments and Drug Resistance

Mehraj,

Jan,

Fatima

et al. 2024

Drug Resistance in Cancer: Mechanisms and Strategies

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Subcellular visualization: Organelle-specific targeted drug delivery and discovery

Cited by 13 publications

References 257 publications

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

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

Dendritic Polymer‐Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response

Intracellular Compartments and Drug Resistance

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