Bispecific T-cell engagers non-covalently decorated drug-loaded PEGylated nanocarriers for cancer immunochemotherapy

Cheng, Wei-Jie; Chuang, Kuo-Hsiang; Lo, Yu-Ju; Chen, Michael; Chen, Yi-Jou; Roffler, Steve R.; Ho, Hsiu O.; Lin, Shyr-Yi; Sheu, Ming Thau

doi:10.1016/j.jconrel.2022.03.015

Cited by 7 publications

(6 citation statements)

References 47 publications

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“… 80 The CMC results indicated that the addition of soy lecithin increased the colloidal stability, which was consistent with a previous report. 51 D/P_NCs decorated with BsAbs groups revealed higher cytotoxicity profile than the D/P_NCs alone, which was attributed to the higher cellular uptake of NCs with BsAbs. Nevertheless, the statistical difference of IC 50 values of each nanocarriers with the combination of DTX and PIC were insignificant, which could be attributed to the reason that the IC 50 values were below the CMC value.…”

Section: Discussionmentioning

confidence: 92%

“…To assess the stability of the NCs, the D/P_NCs and Dual-D/P_NCs were diluted in pH 7.4 PBS buffer and stored at 4 °C. The particle size and drug content were monitored with a Zetasizer ZSP (Malvern Instruments, Malvern, UK) and HPLC system to observe colloidal stability of nanocarriers and degradation of the drugs at 0, 24, and 48 h. The critical micelle concentration (CMC) was evaluated using the Zetasizer ZSP (Malvern Instruments, Malvern, UK), which was equipped with a 10 mW He-Ne laser operating at a wavelength of 633 nm, and the detection angle was set at 173° as described in previous reports 50 , 51 at 25 °C. The D/P_NCs stock solutions were serially diluted to the concentration range of 0.0073~1.875 μg/mL.…”

Section: Methodsmentioning

confidence: 99%

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Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer

Cheng¹,

Lin²,

Chuang³

et al. 2022

IJN

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Introduction: Approximately 15%~30% of breast cancers have gene amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), resulting in the chemotherapy resistance, a more-aggressive phenotype and poor prognosis. Methods: We propose a strategy of nanocarriers co-loaded with docetaxel (DTX) and pictilisib (PIC) at a synergistic ratio and noncovalently bound with dual anti-HER2 epitopes bispecific antibodies (BsAbs: anti-HER2-IV/methoxy-polyethylene glycol (mPEG) and anti-HER2-II/methoxy-PEG) for synergistic targeting to overcome the therapeutic dilemmas of the resistance for HER2-targetable chemodrugs. DTX/PIC-loaded nanocarriers (D/P_NCs) were prepared with single emulsion methods and characterized using dynamic light scattering analysis, and the drug content was assayed by high-performance liquid chromatographic method. The integrity and function of BsABs were evaluated using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). The in vitro cell studies and in vivo breast tumor-bearing mice model were used to evaluate the anticancer effect and biosafety of formulations. Results: D/P_NCs optimally prepared exhibited a spherical morphology with small particle sizes (~140 nm), high drug loading (~5.5%), and good colloidal stability. The synergistic tumor cytotoxicity of loading DTX and PIC at 2:1 ratio in D/P_NCs was discovered. The BsAbs are successfully decorated on mPEGylated DTX/PIC-loaded nanocarriers via anti-mPEG moiety. In vitro studies revealed that non-covalent decoration with dual BsAbs on D_P-NCs significantly and synergistically increased cellular uptake, while with loading DTX and PIC at a synergistic ratio of 2:1 in D/P_NCs further resulted in synergistic cytotoxicity. In vivo tumor inhibition studies showed the comparable results for synergistic antitumor efficacy while minimizing systemic toxicity of chemodrugs. Conclusion: Non-covalent modification with dual distinct epitopes BsAbs on the nanocarriers loaded with dual chemodrugs at a synergistic ratio was expected to be a promising therapeutic platform to overcome the chemoresistance of various cancers and warrants further development for future therapy in the clinical.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer

Cheng¹,

Lin²,

Chuang³

et al. 2022

IJN

Self Cite

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“…157 In addition, bispecific T-cell engagers (BiTEs) were nano-engineered with two single-chain variable fragments (scFvs) that targeted T cells and tumor cells, respectively. 158,159 Similarly, synthetic nanoparticle antibodies were prepared from a Janus nanoplatform with a cell-targeting ligand on one ''face'' and a Fc-mimicking ligand on the opposite ''face''. 160 Both BiTEs and synthetic nanoparticle antibodies were engineered onto the surface of the nanomedicine with multivalent contact.…”

Section: Design Strategies Of Nanomedicines For Radioimmunotherapymentioning

confidence: 99%

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

Luo

Zhang

et al. 2023

Chem. Soc. Rev.

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“…Cheng et al. [ 183 ] developed CD3/PD-L1/mPEG trispecific antibodies as BiTEs to non-covalently bind chemodrug ganetespib-loaded PEGylated nanocarriers via anti-mPEG fragment in order to achieve synergistic antitumor effects through activating T cells to eliminate malignant cells, blocking the PD-1-suppression pathway, and boosting the antitumor efficacy of ganetespib.…”

Section: Lipid-based Nanoparticles For Dcs and T Cells Associated Tum...mentioning

confidence: 99%

Lipid-based nanoparticles for cancer immunotherapy

Fan,

Han,

Yan

et al. 2023

Medical Review

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As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicit durable antitumor effects in the clinic by leveraging the patient’s own immune system to eradicate the cancer cells. However, the limited population of patients who benefit from the current immunotherapies and the immune related adverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure, which leads to cancer immune evasion and immunity cycle blockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicity of their therapeutic cargos by spatiotemporally controlling the biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to make clinical translation, which are now established platforms for diverse areas. In this perspective, we discuss the available lipid-based nanoparticles in research and market here, then describe their application in cancer immunotherapy, with special emphasis on the T cells-activated and macrophages-targeted delivery system. Through perpetuating each step of cancer immunity cycle, lipid-based nanoparticles can reduce immunosuppression and promote drug delivery to trigger robust antitumor response.

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Bispecific T-cell engagers non-covalently decorated drug-loaded PEGylated nanocarriers for cancer immunochemotherapy

Cited by 7 publications

References 47 publications

Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer

Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

Lipid-based nanoparticles for cancer immunotherapy

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