Mitochondria‐Targeted Water‐Soluble Organic Nanoparticles of Chlorin Derivatives for Biocompatible Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) is a promising non‐invasive cancer therapy without any side‐effects. The photosensitizers (PSs) used in PDT are usually hydrophobic and not soluble in water. Water‐soluble PSs have been rarely studied in PDT research. Therefore, preparing water‐soluble PSs for clinical trials in PDT remains challenging. Here, we prepared water‐soluble organic nanoparticles (WSONs) using the following three chlorin derivatives: methyl pyropheophorbide a (MPPa), zinc metal‐introduced MPPa, and purpurin‐18 methyl ester. We used a very simple co‐precipitation method to develop WSONs through nanoprecipitation (solvent‐exchange) from THF to water. In this method, WSONs were developed in 87–112 nm sizes, based on TEM, with good water solubility and high water stability for more than a month. We evaluated intracellular accumulation and cell viability of these WSONs, exhibiting PDT results comparable to that of free PSs using HeLa cells. All WSONs were accumulated in mitochondria to induce mitochondria‐mediated apoptosis via effective PDT activity. This result is important not only for preparing WSONs with hydrophobic PSs to form highly water‐soluble PSs having good water stability in nanometre size, but also for retaining PDT activity with reduced dark toxicity, enabling potential applications for biocompatible PDT.

Mitochondrial Targeting Cationic Purpurinimide–Polyoxometalate Supramolecular Complexes for Enhanced Photodynamic Therapy with Reduced Dark Toxicity

“… [58,59] Fluorescence of the purpurinimide or CPI molecules (red colour) of all compounds was detected inside the cells, indicating successful cellular uptake of purpurinimide or CPI in the cytoplasm of the tumour cells. In particular, all the purpurinimide or CPI molecules showed mitochondrial targeting (orange colour in merged images) inducing mitochondria‐mediated apoptosis to destroy the tumour cells after photoirradiation [50–54] …”

“…To overcome these limitations, we herein report the design and synthesis of new CPIs and the preparation of their POM complexes (CPI–POMs), that show long wavelength absorption ( λ max 707 nm in CH 2 Cl 2 ), and therefore permit deeper light penetration at tumour sites and high photodynamic activity. Purpurinimides, CPIs, and CPI–POMs accumulated in A549 and HeLa cells, and exhibited mitochondrial targeting, inducing mitochondria‐mediated apoptosis to destroy the tumour cells [50–54] . The CPIs and CPI–POM complexes exhibited significantly enhanced (highly decreased) IC 50 values compared to the corresponding free neutral purpurinimides.…”

PEGylated Water‐Soluble Organic Nanoparticles with Chlorin Derivative for Biocompatible Photodynamic Therapy In Vitro and In Vivo

“…PEGylated WSONs (WSON‐PEGs) with various molecular weight PEGs (200, 2000, 3400, and 8000) were prepared using a modified nanoprecipitation method via a solvent‐exchange preparation method of WSON, as reported in our previous study (Figure 2a) [37] . Briefly, PPa was dissolved in THF solvent (5 mg/mL) and added to a PEG aqueous solution (50 mg/5 mL) with vigorous stirring.…”

“…Most of the PSs in WSON‐PEG 3400 and WSON‐PEG 2000 were located in the cytoplasm of the tumour cells. In particular, WSON‐PEG 3400 and WSON‐PEG 2000 displayed a mitochondria‐targeted accumulation (orange‐colour in merged images) of PSs, inducing mitochondria‐mediated apoptosis to destroy the tumour cells [22,37,47–51] …”

“…As one example of biocompatible PSs, we recently developed self‐assembly‐based water‐soluble organic nanoparticles (WSONs) using a highly simple co‐precipitation (nanoprecipitation via solvent‐exchange from tetrahydrofuran (THF) to water) method with non‐ionic and organic water‐insoluble PS molecules [37] . To overcome the limitations of PDT in in vivo applications, we prepared PEGylated WSONs (WSON‐PEGs) with a one‐pot preparation process using a water‐insoluble organic PS molecule (a chlorin derivative, pyropheophorbide a (PPa, λ max 705 nm)) [27,32] with PEG (Scheme 1).…”