Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion–drug conjugates with cell-membrane affinity

Chen, Siqin; Zhong, Yin; Fan, Wufa; Xiang, Jiajia; Wang, Guowei; Zhou, Quan; Wang, Jinqiang; Yang, Geng; Sun, Rui; Zhang, Zhen; Piao, Ying; Wang, Jianguo; Zhuo, Jianyong; Cong, Hailin; Jiang, Haiping; Ling, Jun; Li, Zi‐Chen; Yang, Dong; Yao, Xin; Xu, Xiao; Zhou, Zhuxian; Tang, Jianbin; Shen, Youqing

doi:10.1038/s41551-021-00701-4

Cited by 192 publications

(169 citation statements)

References 78 publications

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“…OPDMA‐PCL and OPDEA‐PCL were synthesized as shown in Scheme S1 (Supporting Information). We used to prepare PTAO through post‐oxidation of poly(tertiary amine) using hydrogen peroxide [ 14 ] or meta‐chloroperbenzoic acid (mCPBA), [ 12 ] which requires strict control of reaction conditions. In this work, we developed a more facile method to produce PTAO‐containing block copolymers with defined structures ( Figure 1 a ).…”

Section: Resultsmentioning

confidence: 99%

“…[ 22 ] Interestingly, OPDEA, albeit zwitterionic, can be easily internalized by cells. [ 12 , 14 ] We investigated whether the micellar formulations of OPDMA and OPDEA still retain this property. Fluorescently labeled micelles, OPDMA‐ Cy5 PCL, OPDEA‐ Cy5 PCL, and PEG‐ Cy5 PCL, were used to avoid interference from the release and fluorescence self‐quenching issues of DOX.…”

Section: Resultsmentioning

confidence: 99%

“…The phospholipid affinity allows OPDEA to weakly bind to cells, which can trigger transcytosis‐mediated active extravasation and tumor penetration, as well as efficient cellular internalization. [ 12 ] Compared with passive diffusion‐based extravasation and penetration that relies on the leaky tumor vasculatures and is generally limited by the dense and heterogeneous tumor microenvironment, transcytosis‐mediated processes leverage the intrinsic active transport pathways of endothelial cells and tumor cells and can significantly improve the tumor accumulation and infiltration of nanomedicines. [ 13 ] OPDEA also exhibits a remarkable mitochondrial targeting ability.…”

Section: Introductionmentioning

confidence: 99%

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Multipotent Poly(Tertiary Amine‐Oxide) Micelles for Efficient Cancer Drug Delivery

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The cancer drug delivery process involves a series of biological barriers, which require the nanomedicine to exhibit different, even opposite properties for high therapeutic efficacy. The prevailing design philosophy, i.e., integrating these properties within one nanomedicine via on‐demand property transitions such as PEGylation/dePEGylation, complicates nanomedicines’ composition and thus impedes clinical translation. Here, polyzwitterionic micelles of poly(tertiary amine‐oxide)‐ block ‐poly( ε ‐caprolactone) (PTAO‐PCL) amphiphiles that enable all the required functions are presented. The zwitterionic nature and unique cell membrane affinity confer the PTAO micelles long blood circulation, efficient tumor accumulation and penetration, and fast cellular internalization. The mitochondrial targeting capability allows drug delivery into the mitochondria to induce mitochondrial dysfunction and overcome tumor multidrug resistance. As a result, the PTAO/drug micelles exhibit potent anticancer efficacy. This simple yet multipotent carrier system holds great promise as a generic platform for potential clinical translation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multipotent Poly(Tertiary Amine‐Oxide) Micelles for Efficient Cancer Drug Delivery

et al. 2022

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“…After embedding in the PEGylated NPs, GQDs are more persistent in the blood circulation than GQDs alone in vivo. It's widely documented that more extended blood circulation could provide more chance for NPs to reach the tumor through the enhanced permeability and retention (EPR) effect (33). The concentration profiles of NPC-GQDs-PEG and GQDs in tumors to times were further investigated (Fig.…”

Section: Npc-gqds-peg Undergo Slower Blood Clearance and Higher Tumor...mentioning

confidence: 99%

Planting graphene quantum dots in PEGylated nanoparticles for enhanced and multimodal in vivo imaging of tumor

Wang

et al. 2022

Preprint

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Photoluminescent graphene quantum dots (GQDs) have recently attracted considerable attention for biomedical applications owing to the interesting physicochemical and photophysical properties, and prominent biocompatibility and biosafety. However, although much progress has been achieved in therapy and in vitro bioimaging, broad and crucial in vivo fluorescence bioimaging and synergistically working with other nanomedicine are very challenging and limited. Herein, we in situ implanted GQDs in the PEGylated layer of nanoparticles (NPs) via a bottom-up approach to obtain the NPs (core)-GQDs-PEG multifunctional nanoprobe (NPC-GQDs-PEG), which prolonged the blood circulation of GQDs more than four times and increased the tumor accumulation 7~8 times than GQDs used alone. Under assisted by the flexible microscope, the GQDs were successfully used for in vivo real-time monitoring of local NPs pharmacokinetics, in vivo multimodality imaging, and fluorescence imaging-guided tumor surgery. The approach of implanting GQDs in PEGylated nanomedicine and synergistic working provide a new strategy for in vivo biomedical applications of GQDs.

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confidence: 99%

A Transformable Amphiphilic and Block Polymer−Dendron Conjugate for Enhanced Tumor Penetration and Retention with Cellular Homeostasis Perturbation via Membrane Flow

Duan

Rothenberg

et al. 2022

Advanced Materials

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An approach for stealthy-to-sticky transition of nanomedicines has been demonstrated to augment the therapeutic efficacy: the nanomedicines are nonsticky (or "stealthy") during circulation in the bloodstream, but become sticky at tumor sites for effective interaction with cell membranes during capillary extravasation and cellular internalization. [2] For example, the pH-triggered charge reversal of tumor microenvironment-responsive nanomedicines has been reported to facilitate extravasation and penetration of anticancer agents into tumor tissues. [3] However, pH-triggered charge reversal cannot be realized in luminal or perivascular compartments due to their neutral pH environments. The mildly acidic regions in tumor tissues are often 100-200 µm away from the tumor vascular network, which prevents effective extravasation and penetration of anticancer agents via this approach. [3c,4] Additionally, the published work has been focused on the tumor penetration while the retention of delivered therapeutic agents at the tumor site is overlooked, which is another major bottleneck in tumor therapy.Enzymes that are abundantly expressed at the tumor invasion margin or in the angiogenesis area may serve as better alternative triggers for the stealthy-to-sticky transformation. Efficient penetration and retention of therapeutic agents in tumor tissuescan be realized through rational design of drug delivery systems. Herein, a polymer−dendron conjugate, POEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), is presented, which allows a cathepsin-B-triggered stealthy-to-sticky structural transformation. The compositions and ratios are optimized through dissipative particle dynamics simulations. GFLG-DP displays tumor-specific transformation and the consequently released dendron-Ppa is found to effectively accumulate on the tumor cell membrane. The interaction between the dendron-Ppa and the tumor cell membrane results in intracellular and intercellular transport via membrane flow, thus achieving efficient deep penetration and prolonged retention of therapeutic agents in the solid tumor tissues. Meanwhile, the interaction of dendron-Ppa with the endoplasmic reticulum disrupts cell homeostasis, making tumor cells more vulnerable and susceptible to photodynamic therapy. This platform represents a versatile approach to augmenting the tumor therapeutic efficacy of a nanomedicine via manipulation of its interactions with tumor membrane systems.

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Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion–drug conjugates with cell-membrane affinity

Cited by 192 publications

References 78 publications

Multipotent Poly(Tertiary Amine‐Oxide) Micelles for Efficient Cancer Drug Delivery

Multipotent Poly(Tertiary Amine‐Oxide) Micelles for Efficient Cancer Drug Delivery

Planting graphene quantum dots in PEGylated nanoparticles for enhanced and multimodal in vivo imaging of tumor

A Transformable Amphiphilic and Block Polymer−Dendron Conjugate for Enhanced Tumor Penetration and Retention with Cellular Homeostasis Perturbation via Membrane Flow

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