Scientists develop a colorectal cancer cell-activated nanoconjugate-in-alginate drug delivery system for precise, localized antitumor effects

BUSAN, South Korea, Feb. 19, 2025 /PRNewswire/ -- Colorectal cancer (CRC) is one of the most prevalent types of cancer and has a high mortality rate globally. Oral administration of anticancer drugs that pass through the gastrointestinal (GI) tract into the colorectum is a common strategy to deliver drugs in CRC treatment. However, this approach presents distinct challenges: most of these drugs lack target-specificity, leading to off-target side effects; these drugs get easily adsorbed onto the microvilli structure of the small intestinal epithelium, resulting in premature drug loss; and systemic drug absorption reduces CRC-targeted drug delivery. These challenges result in insufficient drug accumulation in the tumor cells and reduce the therapeutic efficiency of CRC treatment. Therefore, an innovative drug delivery strategy is urgently needed to ensure localized, precise CRC therapy.

To address these challenges, a team of researchers led by Prof. Jin-Wook Yoo from Pusan National University, Republic of Korea, developed a unique drug delivery strategy for CRC therapy. In their exciting work, they proposed a drug delivery strategy by enclosing CRC cell-activated nanoconjugates (CTNCs) inside an alginate (Alg) matrix for highly specific and localized drug release. Prof. Yoo explains, "The main aim of this study is to develop CTNCs-in-alginate (Alg/ CTNCs) by synthesizing a hyaluronic acid (HA)-Poly (D, L-lactide-co-glycolide) (PLGA)-irinotecan (IRI) copolymer (HPI), followed by self-assembly for nanoconjugate formation and incorporation into an alginate matrix for highly CRC-specific oral drug delivery that bypasses the systemic circulation". This paper was made available online on 3rd January 2025 and to be published in Volume 505 of the Chemical Engineering Journal on 1st February 2025.

The alginate matrix transitions from a solution-like form to a gel-like form when exposed to the harsh acidic environment of the stomach and intestine, and shields the nanoconjugates, thus suppressing premature drug loss. Upon exposure to the basic pH in the colorectum, it converts back to the solution-like form, and deshields the nanoconjugates, thus delivering the CTNCs to the target tumor cells. The deshielded CTNCs readily interact with the CD44 receptor on the tumor cells via the HA ligand of CTNCs. Once the CTNCs are selectively internalized by CRC cells, the intracellular esterase of the tumor cells cleaves irinotecan from the HPI copolymer, ensuring highly target-specific drug release in vitro and in vivo. Prof. Yoo further explains their results, "The sol-gel transition in the stomach aids in shielding the CTNCs from unwanted interactions with the small intestine epithelium, resulting in facilitated passage and minimized IRI loss before reaching the colorectum. Additionally, completely deshielded CTNCs can be selectively internalized by CRC cells, followed by cancer esterase-triggered drug release within CRC cells, resulting in potent local anticancer effects without systemic side effects".

This study presents the successful development of a potential orally administrable drug delivery system that can bypass systemic circulation and precisely target CRC by leveraging the sol-gel-sol transition of alginate in the GI tract. "These findings highlight the potential of reversible shielding/deshielding and target cell-activated drug releasing strategies for the highly selective oral delivery of various therapeutics, such as small molecules, antibodies, and nucleic acid-based drugs, to disease sites in the colorectum", Prof. Yoo adds. The proposed drug delivery strategy can also be extended to treat other colorectum-specific diseases, such as ulcerative colitis.

Reference
Title of original paper: On-site sol-gel-sol transition of alginate enables reversible shielding/ deshielding of tumor cell-activated nanoconjugates for precise local colorectal cancer therapy
Journal: Chemical Engineering Journal
DOI: https://doi.org/10.1016/j.cej.2024.158935 

About Pusan National University
Website: https://www.pusan.ac.kr/eng/Main.do 

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SOURCE Pusan National University