Liposomes Boost Photodynamic Therapy Effectiveness

By encapsulating PS within liposomal nanocarriers, their systemic circulation time can be significantly extended. This altered pharmacokinetic profile allows for greater accumulation at target sites, such as tumors, through mechanisms like the Enhanced Permeability and Retention (EPR) effect, a phenomenon where nanoparticles preferentially accumulate in leaky tumor vasculature.

Liposomes facilitate both passive and active targeting. Passive targeting leverages the EPR effect, while active targeting involves conjugating specific ligands (e.g., antibodies, peptides, aptamers) to the liposome surface. These ligands bind to overexpressed receptors on diseased cells, ensuring precise delivery of the PS. This targeted approach minimizes exposure to healthy tissues, drastically reducing systemic side effects like skin photosensitivity, a common issue with free PS.

Liposomes offer the unique advantage of co-delivering PS with other therapeutic agents, such as chemotherapeutics, gene therapy agents, or immunomodulators. This enables combination therapies that can achieve synergistic effects, overcoming drug resistance and enhancing overall treatment outcomes, as extensively discussed in the scientific community.

Liposomal encapsulation can optimize the delivery of PS, allowing for more precise control over their release and accumulation in deeper tissues. This is crucial for treating tumors located beneath the skin surface or within organs, where light penetration is a limiting factor for conventional PDT. By improving PS delivery and localization, liposomes indirectly enhance the effective depth of light penetration by maximizing the PS concentration at the desired site.

The tumor microenvironment (TME) often presents significant barriers to effective drug delivery, including hypoxia, abnormal vasculature, and dense extracellular matrix. Liposomes can be engineered to respond to specific TME cues (e.g., low pH, high enzyme activity) to release their cargo, or to carry agents that can modulate the TME, thereby improving PS penetration and PDT efficacy within the complex tumor environment.

Fig. 2 Proposed mechanism of PLNA for enhanced PDT via NIR remote -controlled BSO release for the inhibition of GSH biosynthesis.^1,3

Liposomes integrating both therapeutic and diagnostic capabilities by serving as carriers for imaging agents. This allows for real-time monitoring of imaging agents delivery and accumulation, assisting in diagnosis, as well as the assessment of the diagnostic process and disease progression. Common imaging modalities that can be integrated with liposomal PDT include photoacoustic (PA) imaging, magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, ultrasonic imaging (USI), computed tomography (CT), and fluorescence imaging (FLI). This image-guided approach enables precise diagnostic planning and accurate localization of the PS.

Liposomes offer the unique advantage of co-delivering PS with other therapeutic agents, such as chemotherapeutics, gene therapy agents, or immunomodulators. This enables combination therapies that can achieve synergistic effects, overcoming drug resistance and enhancing overall treatment outcomes, as extensively discussed in the scientific community.

Beyond co-delivery of cytotoxic agents, liposome-based PDT can be effectively combined with a range of other therapeutic modalities to achieve superior outcomes. This includes combining PDT with photothermal therapy (PTT) or magnetic hyperthermia (MHT) for enhanced tumor ablation, integrating different PDT approaches (e.g., using multiple PS or light wavelengths), or combining with chemodynamic therapy (CDT) to amplify reactive oxygen species generation and cell death.

Fig. 3 The mechanism of release of capsulated PSs and drugs for combined therapies.^1,3

• Porphyrin Derivatives: Porphyrins and their derivatives were among the first PS to be clinically used. Liposomal formulations of porphyrins aim to reduce their skin photosensitivity and improve tumor accumulation.

Fig. 4 The mechanism of release of capsulated PSs and drugs for combined therapies.^1,3

• Phthalocyanines and Naphthalocyanines: These PS absorb light in the red and near-infrared regions, which allows for deeper tissue penetration. Liposomal encapsulation of hydrophobic phthalocyanines, like aluminum phthalocyanine (AlPcS4), significantly enhances their solubility and circulation time, leading to improved PDT efficacy.
• Chlorins: Chlorin-based PS, such as chlorin e6 (Ce6), m-tetrahydroxyphenylchlorin (mTHPC), purpurin 18 (P18), are potent PS.

Building upon classic approaches, modern liposomal PS systems incorporate advanced functionalities through surface modification and stimuli-responsive designs, enabling more precise targeting and controlled release:

• Surface-Modified Liposomes: To achieve highly specific delivery, ligands are conjugated to the liposome surface. These ligands (e.g., antibodies, peptides like RGD, folate, hyaluronic acid, aptamers) specifically recognize and bind to receptors overexpressed on cancer cells or within the tumor microenvironment. This active targeting mechanism leads to increased PS accumulation in diseased tissues and enhanced cellular uptake while minimizing off-target effects.

Fig. 5 Typical models of active-targeted liposomes.^1,3

• Stimuli-Responsive Liposomes: These "smart" liposomes are engineered to release their encapsulated PS in response to specific internal or external triggers (e.g., light, temperature, enzyme, pH, and X-ray), ensuring localized PS release at the target site.

Fig. 6 Liposomal collapse induced by various stimuli.^1,2