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Protein Encapsulation of Experimental Anticancer Agents 5F 203 and Phortress: Towards Precision Drug Delivery
Alastair F Breen1, David Scurr1, Maria Letizia Cassioli1
1Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
Introduction:
Advancement of novel anticancer drugs into clinical use is frequently halted by their lack of solubility, reduced stability under physiological conditions, and non-specific uptake by normal tissues, causing systemic toxicity. Their progress to use in the clinic could be accelerated by the development of new formulations employing suitable and complementary drug delivery vehicles.
Methods:
A robust method for apoferritin (AFt)-encapsulation of antitumour benzothiazoles has been developed for enhanced activity against and drug delivery to benzothiazole-sensitive cancers.
Results:
More than 70 molecules of benzothiazole 5F 203 were encapsulated per AFt cage. Post-encapsulation, the size and integrity of the protein cages were retained as evidenced by dynamic light scattering. ToF-SIMS depth profiling using an argon cluster beam confirmed 5F 203 exclusively within the AFt cavity. Improved encapsulation of benzothiazole lysyl-amide prodrugs was achieved (~130 molecules of Phortress per AFt cage). Transferrin receptor 1, TfR1, was detected in lysates prepared from most cancer cell lines studied, contributing to enhanced anticancer potency of the AFt-encapsulated benzothiazoles (5F 203, Phortress, GW 610, GW 608-Lys). Nanomolar activity was demonstrated by AFt-formulations in breast, ovarian, renal and gastric carcinoma cell lines, whereas GI50 >50 µM was observed in non-tumourigenic MRC-5 fibroblasts. Intracellular 5F 203, a potent aryl hydrocarbon receptor (AhR) ligand, and inducible expression of cytochrome P450 (CYP) 1A1 were detected following exposure of sensitive cells to AFt-5F 203, confirming that the activity of benzothiazoles was not compromised following encapsulation.
Conclusion:
Our results show enhanced potency and selectivity of AFt-encapsulated 5F 203 against carcinomas derived from breast, ovarian, renal, colorectal as well as gastric cancer models, and offer realistic prospects for potential refinement of tumour-targeting and treatment, and merit further in vivo investigations.
Insights
Apoferritin (AFt) encapsulation enhances benzothiazole anticancer drug delivery and potency. This novel formulation shows high selectivity for cancer cells, offering improved tumor targeting and treatment prospects.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Novel anticancer drugs often face challenges like poor solubility and systemic toxicity.
- Drug delivery vehicles are crucial for accelerating the clinical advancement of these therapies.
- Apoferritin (AFt) offers a promising protein cage for drug encapsulation.
Purpose of the Study:
- To develop a robust method for encapsulating antitumour benzothiazoles into apoferritin (AFt).
- To enhance the anticancer activity and targeted delivery of benzothiazole drugs.
- To evaluate the efficacy and selectivity of AFt-encapsulated benzothiazoles against various cancer cell lines.
Main Methods:
- Developed AFt-encapsulation of benzothiazole compounds (5F 203 and lysyl-amide prodrugs).
- Utilized dynamic light scattering to confirm protein cage integrity post-encapsulation.
- Employed ToF-SIMS depth profiling with an argon cluster beam to verify drug localization within the AFt cavity.
- Assessed anticancer potency via GI50 values in cancer and non-tumourigenic cell lines.
- Detected intracellular drug presence and downstream biological effects (AhR ligand, CYP1A1 induction).
Main Results:
- Successfully encapsulated over 70 molecules of 5F 203 and ~130 molecules of Phortress per AFt cage.
- AFt cage size and integrity were maintained after drug encapsulation.
- AFt-encapsulated benzothiazoles demonstrated nanomolar activity against breast, ovarian, renal, and gastric carcinoma cell lines.
- High selectivity was observed, with minimal toxicity to non-tumourigenic MRC-5 fibroblasts (GI50 >50 µM).
- Confirmed that encapsulation did not compromise the intrinsic activity of benzothiazoles, evidenced by intracellular drug detection and biological response.
Conclusions:
- AFt-encapsulated benzothiazoles exhibit enhanced potency and selectivity against a range of carcinoma models.
- This formulation strategy shows realistic prospects for refining tumor targeting and cancer treatment.
- Further in vivo investigations are warranted to explore the therapeutic potential of AFt-drug conjugates.
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