Doxorubicin@ PEPylated interferon-polydisulfide: A multi-responsive nanoparticle for enhanced chemo–protein combination therapy

Wang, Hao; Hu, Yemin; Wang, Yaoyi; Lu, Junliang; Lu, Hua

doi:10.1016/j.giant.2020.100040

Cited by 17 publications

(16 citation statements)

References 43 publications

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“…Synthetic polypeptides have been used for protein conjugation, i.e. protein PEPylation, for improved pharmacological properties [ 43 , 51 , 54 , 57–61 ]. But the function of PLP for protein modification is yet to be fully exploited.…”

Section: Discussionmentioning

confidence: 99%

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Tian

Xiong

et al. 2022

National Science Review

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The production of polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is usually conducted under stringent anhydrous conditions. The ROP of proline NCA (ProNCA) for the synthesis of poly-L-proline (PLP) is particularly challenging due to the premature product precipitation as polyproline type I helices, leading to slow reactions up to one week, poor control of the molar mass, and laborious workup. Here, we report the unexpected water-assisted controlled ROP of ProNCA, which affords well-defined PLP as polyproline II helices in 2-5 minutes and almost quantitative yields. Experimental and theoretical studies together suggest an as-yet-unreported role of water in facilitating proton shift, which significantly lowers the energy barrier of the chain propagation. The scope of initiators can be expanded from hydrophobic amines to also encompass hydrophilic amines and thiol-bearing nucleophiles, including complex biomacromolecules such as proteins. Protein-mediated ROP of ProNCA conveniently affords various protein-PLP conjugates via a grafting-from approach. PLP modification not only preserves the biological activities of the native proteins, but also enhances their resistance to extreme conditions. Moreover, PLP modification extends the elimination half-life of asparaginase (ASNase), a first-line anticancer drug for lymphoma treatment, by 18 folds and mitigates the immunogenicity of wt ASNase by more than 250 folds. Together, this work provides a simple solution to a longstanding problem in PLP synthesis, and offers valuable guidance for the development of water-resistant ROP of other proline-like NCAs. The facile access of PLP can greatly boost the application potential of PLP-based functional materials for engineering industry enzymes and therapeutic proteins.

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Section: Discussionmentioning

confidence: 99%

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Tian

Xiong

et al. 2022

National Science Review

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“…8,39 Encouraged by the robustness of the ROP at various pH and salt concentrations (Figure S4&7), we further examined whether amine-bearing proteins could be utilized as macroinitiator to generate protein-PLP conjugates in situ (Figure 5A). [40][41][42][43][44][45][46][47] The protein-initiated ROP of various NCAs, including ProNCA, was previously tested in 1950-1960s but later discontinued. [48][49] Here, we decided to revisit this topic using the fast ROP in mixed ACN/H 2 O. Gratifyingly, 10-min ROP of ProNCA at 10 o C in ACN/PBS (v/v = 1/1, pH 7.4) in EGFP solution led to the efficient formation of EGFP-PLP conjugates based on SDS-PAGE analysis.…”

Section: Resultsmentioning

confidence: 99%

Water-Assisted and Protein-Initiated Ring-Opening Polymerization of Proline N-Carboxyanhydride

Hu¹,

Tian²,

Xiong³

et al. 2021

Preprint

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The production of poly-L-proline (PLP) via the ring-opening polymerization (ROP) of L-proline N-carboxyanhydride (ProNCA) is challenging due to a combination of factors, including the stringent requirement of moisture-free conditions, slow monomer conversion, poor control of the molar mass, and premature precipitation of the product in the form of polyproline type I helix. Here, we report water-assisted ROP of ProNCA, which affords well-defined PLP in polyproline II helix in 2-5 minutes. Density functional theory reveals an as-yet-unreported role of water in facilitating proton shift that significantly lowered the energy barrier of the chain propagation. Protein-mediated ROP of ProNCA conveniently affords various protein-PLP conjugates via a grafting-from approach. PLP conjugation not only preserves the biological activities of the native proteins, but also enhances the stability of proteins against extreme conditions. This work provides a simple means and new mechanistic insight to solve a longstanding problem in PLP synthesis and will offer valuable guidance for the development of water-resistant ROP of other NCAs. The facile access of PLP can greatly boost the application potentials of PLP-based functional materials.

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“…[114] Followed by this work, in 2021, Lu and co-workers produced IFN-PolyDox-PEP with IFN-PDS-PEP, a multifunctional and stimuliresponsive protein-drug-polymer (PDP), realizing the synergistic co-delivery of IFN and doxorubicin (Dox) (Scheme 14d). [115] These studies clearly demonstrate the strong potential of highly efficient chemistry to construct well-defined PEPylations which are promising and powerful macromolecules for various chemo-protein combination therapies. [116]…”

Section: Modification Of Other Species Of Side Chainsmentioning

confidence: 86%

“…Using this method, Lu's group prepared interferon (IFN) modified with the helical polypeptide, which displayed stronger binding affinity as well as higher antiproliferative activity and efficacy in vitro compared to IFN modified by PEG (Scheme 14d) [114] . Followed by this work, in 2021, Lu and co‐workers produced IFN‐PolyDox‐PEP with IFN‐PDS‐PEP, a multifunctional and stimuli‐responsive protein‐drug‐polymer (PDP), realizing the synergistic co‐delivery of IFN and doxorubicin (Dox) (Scheme 14d) [115] . These studies clearly demonstrate the strong potential of highly efficient chemistry to construct well‐defined PEPylations which are promising and powerful macromolecules for various chemo‐protein combination therapies [116] …”

Section: Post‐polymerization Reactions On Different Side‐chains Of Po...mentioning

confidence: 99%

Recent Advances in Post‐polymerization Modifications on Polypeptides: Synthesis and Applications

Chang

Chen

2022

Chemistry An Asian Journal

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Polypeptides, a kind of very promising biomaterial, have shown a wide range of applications due to their excellent biocompatibility, easy accessibility, and structural variability. To synthesize polypeptides with desired functions, post-polymerization modification (PPM) plays an important role in introducing novel chemical structure on their sidechains. The key to PPM strategy is to develop highly selective and efficient reactions that can couple the additional func-tional moieties with pre-installed side-chain functionalities on polypeptides. In this minireview, classic PPM approaches and their recent progresses are summarized and categorized into five sections, including various reactions on unsaturated alkyl, oxygen-, nitrogen-, sulfur-containing and other special functional groups. In addition, we also highlight the applications of the resultant structure-diversified polypeptides in the field of biomaterial.

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Doxorubicin@ PEPylated interferon-polydisulfide: A multi-responsive nanoparticle for enhanced chemo–protein combination therapy

Cited by 17 publications

References 43 publications

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Water-Assisted and Protein-Initiated Ring-Opening Polymerization of Proline N-Carboxyanhydride

Recent Advances in Post‐polymerization Modifications on Polypeptides: Synthesis and Applications

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