Site-specific in situ growth of an interferon-polymer conjugate that outperforms PEGASYS in cancer therapy

Hu, Jin; Wang, Guilin; Zhao, Wenxiang; Liu, Xinyu; Zhang, Libin; Gao, Wanzhen

doi:10.1016/j.biomaterials.2016.04.035

Biomaterials

2016

DOI: 10.1016/j.biomaterials.2016.04.035

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Site-specific in situ growth of an interferon-polymer conjugate that outperforms PEGASYS in cancer therapy

Jin Hu

Guilin Wang

Wenxiang Zhao

et al.

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Cited by 43 publications

(45 citation statements)

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“…Inspired by this work, we chose to synthesize C-terminal IFN-α conjugates of POEGMA with three high molecular weights of ca. 20, 60 and 100 kDa by using the SIG method that has recently been developed by us [18][19][20][21][22]. We found that increasing the molecular weight of POEGMA decreased the in vitro activity of IFN-α but increased the in vitro stability of IFN-α.…”

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confidence: 86%

“…Most recently, we have demonstrated site-specific in situ growth (SIG) of a C-terminal IFN-α conjugate of POEGMA that outperforms PEGASYS in antitumor efficacy [18]. Inspired by this work, we chose to synthesize C-terminal IFN-α conjugates of POEGMA with three high molecular weights of ca.…”

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confidence: 99%

“…To synthesize C-terminal IFN-POEGMA conjugates, a triglycine-functionalized initiator for atom transfer radical polymerization (ATRP) was solely attached to the C-terminus of recombinant IFN-α by sortase A mediated ligation to yield a C-terminal IFN-α-initiator conjugate (IFN-Br) [18]. Subsequently, in situ ATRP of OEGMA from IFN-Br was performed to yield C-terminal IFN-POEGMA conjugates (Fig.…”

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confidence: 99%

“…1a). Based on our previous work in which a C-terminal IFN-POEGMA conjugate with the POEGMA molecular weight of 66.2 kDa outperforms PEGASYS in antitumor efficacy [18], we chose to synthesize three C-terminal IFN-POEGMA conjugates with POEGMA molecular weights that were below, near and above 66.2 kDa. The molecular weight of POEGMA was controlled by adjusting the feeding molar ratio of OEGMA to IFN-Br.…”

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confidence: 99%

“…1e). The CD spectra of them showed a similar doublet at 208/222 nm that matched with that of IFN-α, suggesting that the in situ growth of POEGMA with different molecular weights from IFN did IFN-α is a highly pleiotropic cytokine, which is widely used to treat a variety of viral diseases and cancers [18,[23][24][25]. We investigated the antiproliferative activity of the conjugates using Daudi B cells (Fig.…”

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Tuning the molecular size of site-specific interferon-polymer conjugate for optimized antitumor efficacy

Wang

Gao

2017

Sci. China Mater.

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The covalent attachment of protein-resistant polymers to therapeutic proteins is a widely used method for extending their in vivo half-lives; however, the effect of molecular weight of polymer on the in vitro and in vivo functions of protein-polymer conjugates has not been well elucidated. Herein we report the effect of molecular weight of poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) on the in vitro and in vivo properties of C-terminal interferon-alpha (IFN)-POEGMA conjugates. Increasing the molecular weight of POEGMA decreased the in vitro activity of IFN-α but increased its thermal stability and in vivo pharmacokinetics. Intriguingly, the in vivo antitumor efficacy of IFN-α was increased by increasing the POEGMA molecular weight from ca. 20 to 60 kDa, but was not further increased by increasing the molecular weight of POEGMA from ca. 60 to 100 kDa due to the neutralization of the improved pharmacokinetics and the reduced in vitro activity. This finding offers a new viewpoint on the molecular size rationale for designing next-generation protein-polymer conjugates, which may benefit patients by reducing administration frequency and adverse reactions, and improving therapeutic efficacy.

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confidence: 86%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Tuning the molecular size of site-specific interferon-polymer conjugate for optimized antitumor efficacy

Wang

Gao

2017

Sci. China Mater.

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Weaving Enzymes with Polymeric Shells for Biomedical Applications

Blum

et al. 2021

Advanced Materials

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the most common administration method. However, the sizes of most enzymes are smaller than the kidney filtration threshold (50-60 kDa), resulting in fast renal clearance and short half-lives. [5] Also, limited by its hydrophilicity and large molecular weight, it is difficult for exogenous enzyme macromolecules to pass through the cell membrane to effectively catalyze intracellular target reactions. [6] To date, most of the clinical protein therapeutics were explored toward extracellular targets owing to the low translocation efficiency. [7] However, for enzyme therapeutics, especially for the enzyme replacement therapy, intracellular delivery is considered critical for effective therapy. [8] Typically, even if a number of enzymes are transfected into

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Thermo‐pH‐Sensitive Polymer Conjugated Glucose Oxidase for Tumor‐Selective Starvation‐Oxidation‐Immune Therapy

et al. 2023

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Protein drugs are increasingly used as therapeutics for the treatment of cancer. However, their inherent drawbacks, such as poor stability, low cell membrane and tissue permeability, lack of tumor selectivity, and severe side effects, limit their wide applications in cancer therapy. Herein, screening of a thermo‐pH‐sensitive polymer–glucose oxidase conjugate that can controllably self‐assemble into nanoparticles with improved stability is reported. The size, surface charge, and bioactivity of the conjugate can be tuned by adjustment of the solution temperature and pH. The cellular uptake, intracellular hydrogen peroxide generation, and tumor cell spheroid penetration of the conjugate are greatly enhanced under the acidic tumor microenvironment, leading to increased cytotoxicity to tumor cells. Upon a single intratumoural injection, the conjugate penetrates into the whole tumor tissue but hardly diffuses into the normal tissues, resulting in the eradication of the tumors in mice without perceivable side effects. Simultaneously, the conjugate induces a robust antitumor immunity to efficiently inhibit the growth of distant tumors, especially in combination with an immune checkpoint inhibitor. These findings provide a novel and general strategy to make multifunctional protein‐polymer conjugates with responsiveness to the acidic tumor microenvironment for selective tumor therapy.

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Site-specific in situ growth of an interferon-polymer conjugate that outperforms PEGASYS in cancer therapy

Cited by 43 publications

References 29 publications

Tuning the molecular size of site-specific interferon-polymer conjugate for optimized antitumor efficacy

Tuning the molecular size of site-specific interferon-polymer conjugate for optimized antitumor efficacy

Weaving Enzymes with Polymeric Shells for Biomedical Applications

Thermo‐pH‐Sensitive Polymer Conjugated Glucose Oxidase for Tumor‐Selective Starvation‐Oxidation‐Immune Therapy

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