Enhanced cellular uptake and nuclear accumulation of drug-peptide nanomedicines prepared by enzyme-instructed self-assembly

Liang, Chaoyun; Yan, Xuzhong; Zhang, Renshu; Xu, Tengyan; Zheng, Debing; Tan, Zhaoqi; Chen, Yaoxia; Gao, Zhan; Wang, Ling; Li, Xingyi; Yang, Zhimou

doi:10.1016/j.jconrel.2019.11.028

Cited by 69 publications

(37 citation statements)

References 65 publications

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“…The formation of micelles of pS1 likely facilitates the cellular uptake by caveolin-mediated endocytosis, similar to the cellular uptake of peptide amphiphiles. [18][19][20][21] We first incubated HeLa cells with CellLight® Golgi-RFP 22 for 24 hours to transfect RFP at the Golgi, then incubated the HeLa cells with pS1 (10 M) for 8 minutes (Figure 1). The fluorescence from the assemblies of S1 overlaps with the red fluorescence from all Golgi-RFP, confirming that pS1 targets the Golgi of the HeLa cells.…”

Section: Scheme 1 Illustration Of Thiophosphopeptides Instantly Targmentioning

confidence: 99%

Thiophosphopeptides Instantly Targeting Golgi Apparatus and Selectively Killing Cancer Cells

Tan

Zhang

Wang

et al. 2021

Preprint

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Golgi apparatus is emerging as a key signaling hub of cells, but there are few approaches for targeting Golgi and selectively killing cancer cells. Here we show an unexpected result that changing an oxygen atom of the phosphoester bond in phosphopeptides by a sulfur atom enables instantly targeting Golgi apparatus (GA) and selectively killing cancer cells by enzymatic self-assembly. Specifically, conjugating cysteamine S-phosphate to the C-terminal of a self-assembling peptide generates a thiophosphopeptide. Being a substrate of alkaline phosphatase (ALP), the thiophosphopeptide undergoes rapid ALP-catalyzed dephosphorylation to form a thiopeptide that self-assembles. The thiophosphopeptide enters cells via caveolin-mediated endocytosis and macropinocytosis and instantly accumulates in GA because of dephosphorylation and formation of disulfide bonds in Golgi. Moreover, the thiophosphopeptide, targeting Golgi, potently and selectively inhibits cancer cells (e.g., HeLa) with the IC50 (about 3 μM), which is an order of magnitude more potent than that of the parent phosphopeptide. This work, as the first report of thiophosphopeptide for targeting Golgi, illustrates a new molecular platform for designing enzyme responsive molecules that target subcellular compartment for functions.

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Section: Scheme 1 Illustration Of Thiophosphopeptides Instantly Targmentioning

confidence: 99%

Thiophosphopeptides Instantly Targeting Golgi Apparatus and Selectively Killing Cancer Cells

Tan

Zhang

Wang

et al. 2021

Preprint

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“…The coming of magnetic, self-assembled nanomedicines gained a lot of popularity in the last decade, which were made up of two or more individual components. These intermediary components when brought together under appropriate physical and chemical conditions in the body, formed structures or complexes as the finished product suitable for addressing the disease in humans [66][67][68]. The otherwise complex manufacturing steps involved to produce stable nanopharmaceutical drug were circumvented using this technique, which significantly reduced the cost and complexities of manufacturing.…”

Section: In Situ Assembled Nanoformulationsmentioning

confidence: 99%

An Elucidative Review to Analytically Sieve the Viability of Nanomedicine Market

et al. 2020

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The advent of the twenty-first century marked a paradigm shift in the healthcare sector with coming of automated, sensitive, targeted medicines and technologies having diagnostic, prophylactic and therapeutic effects. Nanomedicines also attained wide acclamation in their initial years, but the transformation from being the proof of concept to successfully marketed products seems very daunting. Although the reason for this may be attributed to slow but incremental character of many present-day technologies, the review asserts that there are other significant facets that may purvey a thorough explanation of this scenario. The article elaborately discusses the hurdles hindering clinical translation of nanomedicines including scale-up challenges, in vitro in vivo cascade of toxicology assays, along with unrefined manufacturing guidelines, inadequate regulatory approvals, competitive conventional market, etc., leading to hesitant investments by pharmaceutical giants. The paper also explores the economic viability of nanobiotechnology sector through an empirical investigation of the revenue data of various pharmaceutical industries manufacturing nano-based drugs, which indicates minor commercial importance of these medicines. We also laid down a comprehensive set of recommendations to smoothen the translational pathway of nanomedicines from an idea to reality, efface the consumer distrust and push boundaries for development and launching of safe, efficient and commercially successful products. Keywords Nanobiotechnology. Nanomedicines. Nanopharmaceuticals. Clinical translation For the past few decades, nanobiotechnology has been proclaimed as the 'revolution in making' with the potential Highlights • Nanomedicines are extensively researched for their highly claimed efficacy, biocompatibility and unexplored potential. • The clinical translation of nanopharmaceuticals from laboratory to market undergoes many challenges on their pathway. • Major hurdles restricting the market dominance of nanomedicines includes limited investments by pharmaceutical, toxicological assays, biocompatibility risks, scale-up issues, regulatory limitations, etc. • Comparative analysis of annual reports of big pharmaceutical companies for gross sales and revenue contributed by nanomedicines. Recommendations to improve the research, development, manufacture and sales of nanopharmaceuticals.

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“…[ 117 ] Elsewhere, an enzyme instructed self‐assembly hydrogel was used to deliver a p53 targeting peptide directly to tumor in a liver xenograft model resulted in inhibited tumor growth following repeated nanoconstruct administration (85% smaller than nontreated animals. [ 118 ] As a final example, in a unique study a doxorubicin and Bcl‐2 siRNA‐loaded cationic poly[2‐(dimethylamino)ethyl methacrylate] and poly(3‐azido‐2‐hydroxypropyl methacrylate) and galactose micelle was intravenously administered into xenograft and orthotropic in vivo test models (the importance of the selection of physiologically relevant test system is expanded upon in detail in Section 3.3.1. The authors showed that the NM‐induced combination chemotherapy inhibited tumor volume by 84% as compared to negative control after 21 days of treatment.…”

Section: Nanomedicines Designed For Targeting and Treatment Of Cancersmentioning

confidence: 99%

A Review of the Current State of Nanomedicines for Targeting and Treatment of Cancers: Achievements and Future Challenges

Kermanizadeh

Jacobsen

Murphy

et al. 2020

Advanced Therapeutics

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The design and utilization of nanomedicines offers great potential for treating various diseases including cancers. Current challenges with traditional cancer treatment strategies include but are not limited to lack of specific targeting, overt systemic toxicity and low efficacy. The use of nanomaterials show particular promise as candidates for cancer treatment due to their high surface to volume ratio and tuneable size, shape, and surface chemistry, which in combination, allow for improved tumor targeting and enhanced therapeutic efficacy. The scrutinization of the literature demonstrates the potential of nanosized carrier systems over traditional approaches (at the molecular level) for specific targeting of the tumors. Despite the great promise showing in preclinical studies, the number of nanomedicines reaching clinical testing is still very low. This review attempts to address this issue by using a weight of evidence approach to the different strategies for use of nanomedicines in combating cancer, as well as highlighting a number of areas that the field of nanomedicines is clearly lagging behind in, as compared to conventional drug discovery and development. It is hoped that the recommendations in this review will allow for better translation of nanomedicines reaching clinical trials.

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Enhanced cellular uptake and nuclear accumulation of drug-peptide nanomedicines prepared by enzyme-instructed self-assembly

Cited by 69 publications

References 65 publications

Thiophosphopeptides Instantly Targeting Golgi Apparatus and Selectively Killing Cancer Cells

Thiophosphopeptides Instantly Targeting Golgi Apparatus and Selectively Killing Cancer Cells

An Elucidative Review to Analytically Sieve the Viability of Nanomedicine Market

A Review of the Current State of Nanomedicines for Targeting and Treatment of Cancers: Achievements and Future Challenges

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