Preparation and characterization of enzyme-responsive zwitterionic nanoparticles for monoclonal antibody delivery

Abstract

Monoclonal antibodies have been used in many diseases, but how to improve their delivery efficiency is still a key issue. As the modification of zwitterionic polymers can maintain the stability and biological activity of monoclonal antibodies, in this study, zwitterionic monomers, sulfobetaine methacrylate (SBMA), and 3-[[2-(methacryloyloxy) ethyl] dimethylammonio] propionate (CBMA) were used to prepare monoclonal antibody-loaded zwitterionic nanoparticles with the aid of the crosslinker of MMP-2 enzyme-responsive peptide which was a rapid synthesis process under mild conditions. The results from dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) indicated that a series of zwitterionic nanoparticles had been successfully prepared by the in situ free radical polymerization using the MMP-2 enzyme-responsive peptide as the cross-linking agent. These nanoparticles were spherical with the sizes of (18.7±1.9) nm (SBMA nanoparticle) and (18.2±2.1) nm (CBMA nanoparticle), and the surface contained zwitterionic polymers. It was revealed that they had no cytotoxicity, could be released in tumor microenvironment by enzyme to inhibit the growth of tumor cells, and was able to effectively penetrate endothelial cells (> 2%) by transwell. Therefore, the development of this strategy has a great prospect for the delivery of monoclonal antibodies.

Graphical abstract

Keywords

zwitterionic polymer / monoclonal antibody delivery / enzyme responsive release / penetration of endothelial cell

References

[1] Pandit R, Chen L, Götz J . The blood–brain barrier: physiology and strategies for drug delivery.Advanced Drug Delivery Reviews, 2020, 165–166: 1–14

[2] Lin M, You R, Liu Y P, . Beneficial effects of anti-EGFR agents, Cetuximab or Nimotuzumab, in combination with concurrent chemoradiotherapy in advanced nasopharyngeal carcinoma.Oral Oncology, 2018, 80: 1–8

[3] McDaid W J, Greene M K, Johnston M C, . Repurposing of Cetuximab in antibody-directed chemotherapy-loaded nanoparticles in EGFR therapy-resistant pancreatic tumours.Nanoscale, 2019, 11(42): 20261–20273

[4] Abbott N J, Rönnbäck L, Hansson E . Astrocyte–endothelial interactions at the blood–brain barrier.Nature Reviews Neuroscience, 2006, 7(1): 41–53

[5] Abbott N J, Romero I A . Transporting therapeutics across the blood–brain barrier.Molecular Medicine Today, 1996, 2(3): 106–113

[6] Vermonden T, Censi R, Hennink W E . Hydrogels for protein delivery.Chemical Reviews, 2012, 112(5): 2853–2888

[7] Gu Z, Biswas A, Zhao M, . Tailoring nanocarriers for intracellular protein delivery.Chemical Society Reviews, 2011, 40(7): 3638–3655

[8] Cui Y, Cui P, Chen B, . Monoclonal antibody: formulations of marketed products and recent advances in novel delivery system.Drug Development and Industrial Pharmacy, 2017, 43(4): 519–530

[9] Rizvi S A A, Saleh A M . Applications of nanoparticle systems in drug delivery technology.Saudi Pharmaceutical Journal, 2018, 26(1): 64–70

[10] Duncan R, Gaspar R . Nanomedicine(s) under the microscope.Molecular Pharmaceutics, 2011, 8(6): 2101–2141

[11] Kumar Khanna V. Targeted delivery of nanomedicines. International Scholarly Research Notices, 2012, 2012

[12] Zhao Z, Nelson A R, Betsholtz C, . Establishment and dysfunction of the blood–brain barrier.Cell, 2015, 163(5): 1064–1078

[13] Li J, Guo Y, Kuang Y, . Choline transporter-targeting and co-delivery system for glioma therapy.Biomaterials, 2013, 34(36): 9142–9148

[14] Tian H, Du J, Wen J, . Growth-factor nanocapsules that enable tunable controlled release for bone regeneration.ACS Nano, 2016, 10(8): 7362–7369

[15] Li S, Chen L, Huang K, . Tumor microenvironment-tailored weakly cell-interacted extracellular delivery platform enables precise antibody release and function.Advanced Functional Materials, 2019, 29(43): 1903296

[16] Mikitsh J L, Chacko A M. Pathways for small molecule delivery to the central nervous system across the blood–brain barrier. Perspectives in Medicinal Chemistry, 2014, 6: doi:10.4137/PMC.S13384

[17] Leeson P D, Springthorpe B . The influence of drug-like concepts on decision-making in medicinal chemistry.Nature Reviews. Drug Discovery, 2007, 6(11): 881–890

[18] He Q, Liu J, Liang J, . Towards improvements for penetrating the blood–brain barrier ― recent progress from a material and pharmaceutical perspective.Cells, 2018, 7(4): 24

[19] Jones A R, Shusta E V . Blood–brain barrier transport of therapeutics via receptor-mediation.Pharmaceutical Research, 2007, 24(9): 1759–1771

[20] Chen Y, Dalwadi G, Benson H A E . Drug delivery across the blood–brain barrier.Current Drug Delivery, 2004, 1(4): 361–376

[21] Alves C G, de Melo-Diogo D, Lima-Sousa R, . IR780 loaded sulfobetaine methacrylate-functionalized albumin nanoparticles aimed for enhanced breast cancer phototherapy.International Journal of Pharmaceutics, 2020, 582: 119346

[22] Men Y, Peng S, Yang P, . Biodegradable zwitterionic nanogels with long circulation for antitumor drug delivery.ACS Applied Materials & Interfaces, 2018, 10(28): 23509–23521

[23] Wang Y, He L, Yu B, . ZnO quantum dots modified by pH-activated charge-reversal polymer for tumor targeted drug delivery.Polymers, 2018, 10(11): 1272

[24] Han X, Li S, Li X, . The effect of zwitterionic surface content on blood circulation time of nanocapsule.Journal of Biomaterials Applications, 2020, 35(3): 371–384

[25] Han L, Liu C, Qi H, . Systemic delivery of monoclonal antibody to the central nervous system for brain tumor therapy.Advanced Materials, 2019, 31(19): 1805697

[26] Anderson N M, Simon M C . The tumor microenvironment.Current Biology, 2020, 30(16): R921–R925

[27] Cabral-Pacheco G A, Garza-Veloz I, Castruita-De la Rosa C, . The roles of matrix metalloproteinases and their inhibitors in human diseases.International Journal of Molecular Sciences, 2020, 21(24): 9739

[28] Chen N, Li S, Li X, . Construction of enzymatic nanoreactors with high catalytic activity in millifluidic systems for cancer therapy.Chemical Engineering Journal, 2022, 429: 132305

[29] Li X, Li S, Qi H, . Early healing of alveolar bone promoted by microRNA-21-loaded nanoparticles combined with Bio-Oss particles.Chemical Engineering Journal, 2020, 401: 126026

[30] Liang S, Liu Y, Jin X, . Phosphorylcholine polymer nanocapsules prolong the circulation time and reduce the immunogenicity of therapeutic proteins.Nano Research, 2016, 9(4): 1022–1031

[31] Qi H, Yang L, Li X, . Systemic administration of enzyme-responsive growth factor nanocapsules for promoting bone repair.Biomaterials Science, 2019, 7(4): 1675–1685

[32] Liu C, Wen J, Meng Y, . Efficient delivery of therapeutic miRNA nanocapsules for tumor suppression.Advanced Materials, 2015, 27(2): 292–297

[33] Del Vecchio C A, Giacomini C P, Vogel H, . EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms.Oncogene, 2013, 32(21): 2670–2681

[34] Mazorra Z, Chao L, Lavastida A, . Nimotuzumab: beyond the EGFR signaling cascade inhibition.Seminars in Oncology, 2018, 45(1–2): 18–26

[35] Wen J, Wu D, Qin M, . Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice.Nature Biomedical Engineering, 2019, 3(9): 706–716

[36] Xu D, Wu D, Qin M, . Efficient delivery of nerve growth factors to the central nervous system for neural regeneration.Advanced Materials, 2019, 31(33): 1900727

[37] Meng X, Zhao Y, Han B, . Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways.Nature Communications, 2020, 11(1): 594

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant No. 51773151) and the Tianjin Applied Basic Research Multi-Input Fund (21JCYBJC01560). Thank Miss Yiou Lyu for her help in article writing and editing.

Electronic supplementary information

Supplementary materials can be found in the online version at https://doi.org/10.1007/s11706-023-0667-3 and https://journal.hep.com.cn/foms/EN/10.1007/s11706-023-0667-3, which include Fig. S1 and Tables S1‒S2.

RIGHTS & PERMISSIONS

2023 Higher Education Press