PEGylated Composite Nanoparticles for Photodynamic Therapy

Photodynamic Therapy (PDT) is an approved treatment for non-small cell lung cancers. The therapy relies on activation of a photosensitizer by visible light to produce cytotoxic singlet oxygen. The current method has significant limitations. Most photosensitizers (PS) have limited water solubility and thus non-deliverable to target tumors, the visible light used to excite these photosensitizers has a limited penetration distance in tissue and the mode of singlet oxygen delivery is not targeted specifically to cancer cells.

This paper presents a composite nanoparticle design where upconverting nanophosphors (UCNP) and a photosensitizer (PS) are simultaneously packaged in a biodegradable nanoparticle compartment. The UCNP, composed of NaY4:Yb3+, Er3+, emits visible light, when it is exposed to near infra-red light (λ=980 nm). The visible light emitted can be used to excite the PS. The near infra red light, with a greater tissue penetration distance compared to visible light, will answer the tissue penetration distance problem, hence making our formulation accessible to deep-seated tumors.

The UCNP and the photosensitizer (meso-tetraphenyl porphine (mTPP)) are packaged in a single compartment using biocompatible, FDA-approved polymeric materials. Candidate block-copolymers include PEG-PCL (poly(ethylene glycol)-block-poly(caprolactone), PEG-PLGA (poly(ethylene glycol)-block-poly(lactide-co-glycolide) acid) and PEG-PLA (poly(ethylene glycol)-block-poly(lactide)) of varying molecular weights. The CNPs are manufactured using Flash NanoPrecipitation technology which provides homogenous mixing, resulting in good control over nanoparticle size with high reproducibility.

We found that PEG-PLGA and PEG-PLA provides better particle stabilization in water and in physiological conditions compared to PEG-PCL. We further found that PEG-PLA with molecular weights 5000-b-5000 Da and 5000-b-10,000 Da formed superior nanoparticle vehicle, while PEG-PLA with molecular weights of 5000-b-20,000 Da did not form stable nanoparticles. With a high ratio of photosensitizer to drug (1:3, by weight) in the composite, these composite nanoparticles are capable of producing cytotoxic singlet oxygen. Functionalization of PEG for active targeting ligand attachment on the surface of nanoparticles is underway.