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Host-Guest Adduct as a Stimuli-Responsive Prodrug: Enzyme-Triggered Self-Assembly Process of a Short Peptide Within

Sandip Sarkar1, Atin Chatterjee1, Dohyun Kim2

  • 1Department of Chemical Sciences and Center for Advanced Functional Material, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur, 741246, India.

Advanced Healthcare Materials
|November 7, 2024
PubMed

Insights

This study introduces novel supramolecular adducts for targeted cancer therapy. These complexes deliver chemotherapy drugs specifically to cancer cells, inducing apoptosis without harming healthy cells.

Area of Science:

  • Supramolecular Chemistry
  • Nanomedicine
  • Cancer Therapeutics

Background:

  • Nonspecific biodistribution of chemotherapeutic drugs limits treatment efficacy and increases side effects.
  • Targeted drug delivery systems are crucial for improving cancer treatment outcomes.
  • Mitochondrial membrane localization offers a promising strategy for selective cancer cell targeting.

Purpose of the Study:

  • To develop stable [2]pseudorotaxane complexes for targeted cancer therapy.
  • To demonstrate the selective delivery and release of therapeutic agents in cancer cells.
  • To evaluate the efficacy of supramolecular adducts in inducing cancer cell death and in vivo tumor reduction.

Main Methods:

  • Synthesis of stable [2]pseudorotaxane complexes (PK@CAOPP and PR@CAOPP) with specific targeting moieties.
  • Utilizing electrostatic interactions for targeted localization to the mitochondrial membrane (MM).
  • Investigating ALP-induced hydrolytic cleavage for drug release and subsequent apoptosis induction in cancer cells (MCF7) versus normal cells (HEK293).
  • In vivo efficacy studies using MCF7 tumor xenograft models in Balb/c nude mice.

Main Results:

  • PK@CAOPP and PR@CAOPP complexes demonstrated specific localization to the mitochondrial membrane via electrostatic interactions.
  • Alkaline phosphatase (ALP) in cancer cells triggered the release of active moieties (PK/PR), leading to fibril formation, MM dysfunction, ROS generation, and apoptosis.
  • No significant effects were observed in ALP-negative normal cells, confirming selectivity.
  • In vivo studies showed significant reduction in tumor volume in the xenograft model.

Conclusions:

  • Supramolecular adducts offer a viable strategy for targeted cancer chemotherapy, minimizing off-target effects.
  • The developed pseudorotaxane system enables selective drug release and potent induction of cancer cell apoptosis.
  • This approach holds potential for developing safer and more effective cancer therapeutics.
Keywords:
enzyme‐triggered self‐assemblyhost–guest adductsserum stabilityshort peptide therapeuticstumor growth inhibition

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