In situ chemically crosslinked injectable hydrogels for the subcutaneous delivery of trastuzumab to treat breast cancer

Autor: Ming Hsi Wu, Hsiu O. Ho, Ming Thau Sheu, Yu Cheng Wang, Wen Yu Wang, Ya Ling Chiu, Maggie Lu, Wen-Hsuan Chiang, Yu Wen Lo, Chia Mu Tu
Rok vydání: 2019
Předmět:
Mice
SCID
02 engineering and technology
Pharmacology
Biochemistry
Maleimides
Rats
Sprague-Dawley
chemistry.chemical_compound
Drug Delivery Systems
Trastuzumab
skin and connective tissue diseases
Chemistry
Hydrogels
General Medicine
021001 nanoscience & nanotechnology
Controlled release
Cross-Linking Reagents
Polyglutamic Acid
Female
Rheology
0210 nano-technology
Biotechnology
medicine.drug
Cell Survival
0206 medical engineering
Biomedical Engineering
Cmax
Injectable hydrogels
Antineoplastic Agents
Breast Neoplasms
macromolecular substances
Injections
Biomaterials
Breast cancer
Pharmacokinetics
In vivo
Cell Line
Tumor
medicine
Animals
Humans
neoplasms
Molecular Biology
Cell Proliferation
Body Weight
technology
industry
and agriculture
medicine.disease
Xenograft Model Antitumor Assays
020601 biomedical engineering
Drug Liberation
Ethylene glycol
Zdroj: Acta Biomaterialia. 86:280-290
ISSN: 1742-7061
DOI: 10.1016/j.actbio.2019.01.003
Popis: Recently, novel approaches for the delivery of therapeutic antibodies have attracted much attention, especially sustained release formulations. However, sustained release formulations capable of carrying a high antibody load remain a challenge for practical use. In this study, a novel injectable hydrogel composed of maleimide-modified γ-polyglutamic acid (γ-PGA-MA) and thiol end-functionalized 4-arm poly(ethylene glycol) (4-arm PEG-SH) was developed for the subcutaneous delivery of trastuzumab. γ-PGA-MA and 4-arm PEG-SH formed a hydrogel through thiol-maleimide reactions, which had shear-thinning properties and reversible rheological behaviors. Moreover, a high content of trastuzumab (>100 mg/mL) could be loaded into this hydrogel, and trastuzumab demonstrated a sustained release over several weeks through electrostatic attraction. In addition, trastuzumab released from the hydrogel had adequate stability in terms of its structural integrity, binding bioactivity, and antiproliferative effect on BT-474 cells. Pharmacokinetic studies demonstrated that trastuzumab-loaded hydrogel (Her-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, and 10 mg/mL trastuzumab) and trastuzumab/Zn-loaded hydrogel (Her/Zn-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, 5 mM ZnCl2, and 10 mg/mL trastuzumab) could lower the maximum plasma concentration (Cmax) than the trastuzumab solution. Furthermore, Her/Zn-hydrogel-10 was better able to release trastuzumab in a controlled manner, which was ascribed to electrostatic attraction and formation of trastuzumab/Zn nanocomplexes. In a BT-474 xenograft tumor model, Her-hydrogel-10 had a similar tumor growth-inhibitory effect as that of the trastuzumab solution. By contrast, Her/Zn-hydrogel-10 exhibited a superior tumor growth-inhibitory capability due to the functionality of Zn. This study demonstrated that this hydrogel has potential as a carrier for the local and systemic delivery of proteins and antibodies. Statement of Significance Recently, novel sustained-release formulations of therapeutic antibodies have attracted much attention. However, these formulations should be able to carry a high antibody load owing to the required high dose, and these formulations remain a challenge for practical use. In this study, a novel injectable chemically cross-linked hydrogel was developed for the subcutaneous delivery of trastuzumab. This novel hydrogel possessed ideal characteristics of loading high content of trastuzumab (>100 mg/mL), sustained release of trastuzumab over several weeks, and maintaining adequate stability of trastuzumab. In vivo studies demonstrated that a trastuzumab-loaded hydrogel possessed the ability of controlled release of trastuzumab and maintained antitumor efficacy same as that of trastuzumab. These results implied that a γ-PGA-MA and 4-arm PEG-SH-based hydrogel has great potential in serving as a carrier for the local or systemic delivery of therapeutic proteins or antibodies.
Databáze: OpenAIRE
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