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Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines.

ABSTRACT:

Introduction

Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in facilitating cargo delivery. However, it is unknown whether polyarginine can work to overcome the membrane interface in an inserted pattern for cyclic peptide ligand-mediated active targeting drug delivery. Here, we conducted a study to test the hypothesis that tandem-insert nona-arginine (tiR₉) can act as an accelerating component for intracellular internalization, enhance cellular penetration, and promote antitumor efficacy of active targeted cyclic asparagine-glycine-arginine (cNGR)-decorated nanoliposomes.

Methods

Polyarginine was coupled with the polyethylene glycol (PEG) chain and the cNGR moiety, yielding a cNGR-tiR₉-PEG_2,000-distearoylphosphatidylethanolamine conjugate.

Results

The accelerating active targeted liposome (Lip) nanocarrier (cNGR-tiR₉-Lip-doxorubicin [Dox]) constructed in this study held suitable physiochemical features, such as appropriate particle size of ~150 nm and sustained-release profiles. Subsequently, tiR₉ was shown to enhance cellular drug delivery of Dox-loaded active targeted systems (cNGR-Lip-Dox) significantly. Layer-by-layer confocal microscopy indicated that the tandem-insert polyarginine accelerated active targeted system entry into deeper intracellular regions based on observations at marginal and center locations. tiR₉ enhanced the penetration depth of cNGR-Lip-coumarin 6 through subcellular membrane barriers and caused its specific accumulation in mitochondria, endoplasmic reticulum, and Golgi apparatus. It was also obvious that cNGR-tiR₉-Lip-Dox induced enhanced apoptosis and activated caspase 3/7. Moreover, compared with cNGR-Lip-Dox, cNGR-tiR₉-Lip-Dox induced a significantly higher antiproliferative effect and markedly suppressed tumor growth in HT1080-bearing nude mice.

Conclusion

This active tumor-targeting nanocarrier incorporating a tandem-insert polyarginine (tiR₉) as an accelerating motif shows promise as an effective drug-delivery system to accelerate translocation of drugs across tumor-cell/subcellular membrane barriers to achieve improved specific tumor therapy.

SUBMITTER: Shi NQ

PROVIDER: S-EPMC6154709 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines.

Shi Nian-Qiu NQ Li Yan Y Zhang Yong Y Li Zheng-Qiang ZQ Qi Xian-Rong XR

International journal of nanomedicine 20180919

<h4>Introduction</h4>Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in facilitating cargo delivery. However, it is unknown whether polyarginine can work to overcome the membrane interface in an inserted pattern for cyclic peptide ligand-mediated acti ...[more]

PMID: 30271146

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Project description:Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (K D) mainly varying in their dissociation rates (k off) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (K D = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (K D = 0.54 or 46 nM) due to the slow k off from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (K D = 130 nM) and a faster k off. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.

Dataset Information

Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines.

Introduction

Methods

Results

Conclusion

Publications

Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines.

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