Rational molecular design of two-photon activated temoporfin: a computational study for advanced photodynamic therapy

Area of Science:

• Photochemistry and Photophysics
• Medicinal Chemistry
• Computational Chemistry

Background:

• Photodynamic therapy (PDT) is a non-invasive cancer treatment using photosensitizers (PSs) activated by light to generate reactive oxygen species.
• Current PDT limitations include poor light penetration in deep tissues and photosensitizer aggregation/solubility issues, hindering bioavailability and efficacy.
• Temoporin (mTHPC), a clinically used PS, requires modification for improved deep-tissue PDT applications.

Purpose of the Study:

• To enhance the efficacy of temoporin (mTHPC) for deep-tissue photodynamic therapy (PDT) by functionalizing it with two-photon absorption (TPA) chromophores.
• To investigate the photophysical properties, solubility, aggregation behavior, and biological membrane interactions of novel TPA-temoporin conjugates.
• To assess the potential of rational molecular design in improving both optical properties and drug delivery for advanced PDT agents.

Main Methods:

• Design and synthesis of three TPA-temoporin conjugates (DTP1-mTHPC, DTP2-mTHPC, and DPP-mTHPC).
• Investigation of properties using quantum mechanics (QM), molecular dynamics (MD), and hybrid QM/MM simulations.
• Encapsulation studies with β-cyclodextrins (β-CDs) to assess solubility and aggregation.
• Simulations of candidate agents within a biological membrane model.

Main Results:

• TPA cross-section (σ) of the DTP moieties significantly increased upon conjugation to mTHPC, enabling efficient near-infrared (NIR) absorption.
• Encapsulation with β-cyclodextrins (β-CDs) successfully improved solubility and prevented aggregation without compromising optical properties.
• Simulations demonstrated favorable interactions and localization of the TPA-temoporin conjugates within lipid bilayers, indicating good membrane compatibility.

Conclusions:

• Rational molecular design of temoporin conjugates with TPA chromophores effectively enhances NIR absorption for deep-tissue PDT.
• β-cyclodextrin encapsulation provides a viable strategy to overcome solubility and aggregation challenges, improving drug delivery potential.
• The developed TPA-temoporin conjugates show promise for more effective deep-tissue PDT treatments due to improved optical properties and bioavailability.