(W1330-01-02) Poloxamer 188 and Propylene Glycol Loaded with Novel Pyridine-Based 1,2,4-Triazolo-Tethered Indole Conjugate as Rectal Suppository to Treat Colorectal Cancer

Purpose: Colorectal cancer (CRC) poses a substantial global health challenge, demanding innovative solutions for effective treatment. This study strives to advance therapeutic options for CRC, addressing the limitations of conventional treatments. The rectal suppository formulation, integrating a groundbreaking pyridine-based conjugate, holds the promise to transform CRC therapy by providing a precise and efficient delivery method for the therapeutic agent to the colorectal region. The potential impact of this research lies in its capacity to usher in a new era of targeted and effective treatments, overcoming challenges inherent in traditional modalities for CRC.

Methods: A novel series of pyridine-based 1,2,4-triazolo-tethered indole conjugates (14a−q) has exhibited robust anti-proliferative activity across six human cancer cell lines, with remarkable efficacy against HT-29 (IC₅₀=1.0μM for 14a, contrasting with 5.31μM for 5-fluorouracil). The selected pyridine-based conjugate, synthesized through meticulous chemical reactions, has demonstrated promising anticancer properties. The formulation strategy utilizes Poloxamer 188, known for its thermosensitive gelation properties, and Propylene Glycol as key excipients to optimize drug release and enhance bioavailability.The rectal suppository, comprising 70% P188 and 30% PG, exhibited solidification at room temperature and rapid melting at physiological temperature. These characteristics position it as a viable and efficient option for anticancer rectal administration in murine models, showcasing the potential for translation into clinical applications.

Results: The combination of P188and PG in varying ratios (80/20, 70/30, 50/50) yielded suppository bases with distinct melting points, indicating a homogeneous phase. The 70/30 mixture, solidifying at room temperature and transitioning to a liquid state near body temperature, emerged as the optimal suppository base, supported by favorable properties for drug delivery. The novel conjugate suppository effectively addressed rectal cancer in rats, with significantly higher survival rates than oral 5-fluorouracil. These novel conjugates anticancer efficacy was notably enhanced through rectal suppository administration. These findings underscore the 70/30 P188 and PG suppository bases significance, demonstrating promising potential for rectal cancer therapy

Conclusion: Collectively, our findings affirm the efficacy of the poloxamer gel system (suppository bases) incorporating novel conjugate loaded with P188 and PG as a potent rectal dosage form for treating rectal cancers. The newly formulated rectal suppository which contains novel conjugate (manufactured using 70% P188, 30% PG) demonstrated significant tumor reduction and enhanced survival in rats with rectal cancer. This study underscores its potential not only for rectal cancer but also for diverse cancer types, attributed to its unique attributes of solidification at room temperature and swift liquefaction at body temperature. The demonstrated effectiveness positions this suppository as a highly promising rectal dosage form with broad therapeutic applications

References: 1. Yakkala, P.A.; Panda, S.R.; Naidu, V.G.M.; Shafi, S.; Kamal, A. Pyridine-Based 1,2,4-Triazolo-Tethered Indole Conjugates Potentially Affecting TNKS and PI3K in Colorectal Cancer. ACS Med. Chem. Lett.2023, 14, 260–269.
2. Paek SH, Xuan JJ, Choi HG, Park BC, Lee YS, Jeong TC, Jin CH, Oh YK, Kim JA. Poloxamer 188 and propylene glycol-based rectal suppository enhance the anticancer effect of 5-fluorouracil in mice. Biological and Pharmaceutical Bulletin. 2006;29(5):1060-3.

Acknowledgements: The authors are thankful to Jamia Hamdard University (New Delhi, India) for providing the novelsynthesized compound.

Funding: No external fundingSources. Conflict of interest: The authors have no conflicts of interest to declare.

Graphical abstract of our research work