Recent Advances in Photosensitizers as Multifunctional Theranostic Agents for Imaging-Guided Photodynamic Therapy of Cancer

Abstract

In recent years tremendous effort has been invested in the field of cancer diagnosis and treatment with an overall goal of improving cancer management, therapeutic outcome, patient survival, and quality of life. Photodynamic Therapy (PDT), which works on the principle of light-induced activation of photosensitizers (PS) leading to Reactive Oxygen Species (ROS) mediated cancer cell killing has received increased attention as a promising alternative to overcome several limitations of conventional cancer therapies. Compared to conventional therapies, PDT offers the advantages of selectivity, minimal invasiveness, localized treatment, and spatio-temporal control which minimizes the overall therapeutic side effects and can be repeated as needed without interfering with other treatments and inducing treatment resistance. Overall PDT efficacy requires proper planning of various parameters like localization and concentration of PS at the tumor site, light dose, oxygen concentration and heterogeneity of the tumor microenvironment, which can be achieved with advanced imaging techniques. Consequently, there has been tremendous interest in the rationale design of PS formulations to exploit their theranostic potential to unleash the imperative contribution of medical imaging in the context of successful PDT outcomes. Further, recent advances in PS formulations as activatable phototheranostic agents have shown promising potential for finely controlled imaging-guided PDT due to their propensity to specifically turning on diagnostic signals simultaneously with photodynamic effects in response to the tumor-specific stimuli. In this review, we have summarized the recent progress in the development of PS-based multifunctional theranostic agents for biomedical applications in multimodal imaging combined with PDT. We also present the role of different imaging modalities; magnetic resonance, optical, nuclear, acoustic, and photoacoustic in improving the pre-and post-PDT effects. We anticipate that the information presented in this review will encourage future development and design of PSs for improved image-guided PDT for cancer treatment.

Keywords: Cancer diagnosis; Molecular imaging; Photodynamic therapy; Photosensitizers; Theranostics.

Figure 1

General schematic representation of Photodynamic Therapy (PDT): A. Illustration of PDT where photosensitizer (PS) serves as both an imaging agent and a therapeutic agent. Advantages, disadvantages, and different strategies to enhance PDT of cancer. B. Modified Jablonski diagram showing the principle of PDT: Absorption of light energy by ground state PS (S₀) results into its excitation to singlet ¹PS^* (S₁). Intersystem crossing (ISC) transforms the S₁ to excited triplet ³PS^* (T₁). T₁ either through electron transfer to cellular biomolecules (Type I) and/or via direct energy transfer to ³O₂ (Type II) results in the production of Reactive Oxygen Species (ROS) to induce cell death.

Figure 2

Photodynamic Therapy (PDT) induced cellular effects and immune responses: Generation of reactive oxygen species induces (a) direct tumor cell killing predominantly via apoptosis and necrosis, and (b) damages tumor vasculature. In addition, PDT effect is further potentiated by activating both (c) innate and (d) adaptive immune responses against tumor, further eliminating the residual tumor cells. PS: Photosensitizer.

Figure 3

A schematic illustration depicting the roles of structural, functional and molecular imaging in guiding pre-treatment planning, therapy monitoring, and outcome assessment in Photodynamic Therapy.

Figure 4

Chemical modifications of photosensitizer molecules with resulting photophysical and photochemical changes: (a) reduction of main macrocyclic porphyrin ring results in red shift of Q band of tetrapyrrole photosensitizer, (b) peripheral modification and (c) central metal coordination of tetrapyrrole ring induce changes in singlet oxygen quantum yield (φ∆), triplet quantum yield (Φ_T) and triplet state lifetime (τ_T) depending on the type of side groups and central metal (diamagnetic or paramagnetic). Soret band: The strong absorption band of PS in the blue wavelength region of the visible spectrum due to the S₀ to S₂ transition. Q band: The weak absorption band of PS in longer wavelength region i.e red or far red, due to S₀ to S₁ transition.φ∆: Quantitative measure of PS efficiency to convert O₂ into ¹O₂ upon photoexcitation. Φ_T: Number of PS molecules that undergoes singlet to triplet state transition with per photon absorption. PS: Photosensitizer

Figure 5

The structural designing of photosensitizer for therapy and imaging: Non metallated and metallated (radioactive or nonradioactive isotope) in the form of conjugates, linked with targeting moiety and nanoparticles for application in image-guided Photodynamic Therapy.

Figure 6

Schematic illustration of principle of upconverting nanoparticles (UCNPs) mediated Upconversion Luminescence (UCL) imaging and Photodynamic Therapy (PDT): A. Upconversion process in the UCNPs under Near Infrared Radiation (NIR) excitation, and the Luminescence resonance energy transfer (LRET) between UCNP and photosensitizer (PS). B. Deeper penetration of NIR compared to visible light excites UCNPs and converts NIR to visible wavelength emission for activation of the PS producing Reactive Oxygen Species (ROS) to induce PDT mediated tumor damage with simultaneous imaging with UCL.

Figure 7

Schematic design and illustration of Surface-Enhanced Raman Scattering (SERS) probes for in vivo imaging: A. Structure of SERS probe consisting of a metal nanoparticle as plasmonic core, adsorbed Raman reporter molecule on the metal surface, a biocompatible surface coating layer loaded with photosensitizer (PS), B. Depiction of energy transitions of photons during different types of light scattering upon absorption of light by plasmonic nanoparticle. Representation of SERS image and SERS spectra of tumor.

Figure 8

Schematic illustration of microbubble mediated ultrasound-assisted imaging and guided Photodynamic Therapy (PDT): A. Ultrasound (US) targeted microbubble destruction (UTMD) followed by (a) induced transformation of microbubbles to nanoparticles, (b) CO₂ generation and photosensitizer (PS) release, resulting in tumoral uptake and in vivo PDT; B. Illustration of US induced Contrast Enhanced Ultrasound (CEUS) imaging, PDT and Sonodynamic Therapy (SDT).

Figure 9

Theranostic Photosensitizers: Applications of theranostic photosensitizers (PS) in various imaging modalities: Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Optical Imaging (OI), X-ray computerized tomography (CT), Ultrasound Imaging (US), Photoacoustic Imaging (PAI).