Journal
JOURNAL OF CONTROLLED RELEASE
Volume 352, Issue -, Pages 1093-1103Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2022.11.007
Keywords
EPR effect; Extracellular matrix; Cancer stroma; Triple -negative breast cancer; Collagen type IV; Bromelain
Funding
- John A Paulson School of Engineering & Applied Science at Harvard University
- JSPS Overseas Research Fellowships [202060159]
- Astellas Foundation
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This study reports a method of targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The results showed that the conjugate significantly increased tumor accumulation and improved the distribution of therapeutic drugs within the tumor, while minimizing side effects.
Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention ef-fect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted de-livery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide con-jugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumor ex vivo. The HA-C4BP conjugate showed a significant increase in tumor accumulation in 4T1 -bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral de-livery of therapeutics.
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