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Novel protein-based nanomaterial for active targeted drug delivery to human hepatocyte carcinoma cells
This work addressed the potential applicability of maize protein as an example of plant-derived proteins in drug delivery. Herein, zein, a well-established biomaterial in drug and food applications, was invested to create innovative formulations using the α -zein fraction. Such green-based designs w...
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| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2023
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| Subjects: | |
| Online Access: | PDF Full Text |
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| Summary: | This work addressed the potential applicability of maize protein as an example of plant-derived proteins in drug delivery. Herein, zein, a well-established biomaterial in drug and food applications, was invested to create innovative formulations using the α -zein fraction. Such green-based designs were used to enhance the delivery of the naturally derived photosensitizers hypericin and parietin in the context of PDT. The design, optimization, and application of zein-based carrier systems in the treatment of hepatocellular carcinoma (HepG2 cells) were addressed in two sections throughout the current study.
The first section considered the tailoring of the surface of zein with polyethylene glycol to serve for the encapsulation of hypericin. PEGylated zein was assembled as micelles in aqueous buffers. The developed micelles showed reduced size, high encapsulation competence, and enhanced stability upon dilution. The in vitro outcomes on HepG2 cells disclosed an escalated cytotoxic effect of hypericin after micellization,
coupled with a higher uptake profile in hepatocellular carcinoma cells. Moreover, a lower toxic effect was recorded in non-cancerous fibroblasts indicating the relative safety profile of the developed system on normal cells. Furthermore, the chemically modified zein influenced the high level of intracellular ROS and mitochondrial damage in HepG2 cells which induced pronounced apoptotic events in cells treated with the
encapsulated hypericin.
The second section focused on the use of zein NPs decorated with glycyrrhetinic acid for targeting hepatocellular carcinoma. NPs were loaded with parietin, a green hydrophobic photosensitizer, which possesses a promising photodynamic potential for several types of cancer. The obtained NPs were monodisperse and stable when exposed to serum. Further to that, zein NPs successfully solubilized parietin and retained its photodynamic activity in aqueous buffers. The system's direct targeting capability towards HepG2 cells manifested an enhanced in vitro phototoxicity. As compared to non-targeted zein, the higher cytotoxicity of encapsulated parietin was credited to the glycyrrhetinic acid- NPs' tethering which influenced increased uptake and improved ROS production in liver cancer cells. As proof of concept, the accumulation of zein
NPs was tracked in live mice. The obtained in vivo data revealed an efficient accumulation of zein NPs in the liver of living mice as indicated by the fluorescence signals that persisted for an extended period of time suggesting that zein NPs tailored with glycyrrhetinic acid could be employed as a potential targeted delivery system to the liver. It is worth mentioning that zein surface engineering with biocompatible shells
represents an effective method to convey diverse drug substances for the treatment of hepatocellular carcinoma and other liver-related pathological conditions. Furthermore, the employment of targeting probes like glycyrrhetinic acid serves as an extra tool for delivering hydrophobic photosensitizers to liver cancer cells in vitro and to achieve a site-specific accumulation of the loaded cargo in vivo. Furthermore, because of the
surface inertness conferred by the hydrophilic PEG shells, PEGylated zein would be dependable in the in vivo application for the efficient delivery of photosensitizers in cancer PDT.
Future research should investigate the antigenicity of PEGylated zein in vivo after multiple IV administrations. In addition, the assessment of zein loaded with photosensitizers on the in vitro three-dimensional cancer models and in the in vivo tumor models is planned to confirm the better anticancer activity of our platform. We anticipate that our findings will pave the way for synthesizing more green-based nanomaterials to tackle the toxicity challenges associated with current nanomaterials and broaden the clinical application of PDT. |
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| DOI: | 10.17192/z2023.0244 |