Current Limitations and Recent Progress in Nanomedicine for Clinically Available Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) using oxygen, light, and photosensitizers has been receiving great attention, because it has potential for making up for the weakness of the existing therapies such as surgery, radiation therapy, and chemotherapy. It has been mainly used to treat cancer, and clinical tests for second-generation photosensitizers with improved physicochemical properties, pharmacokinetic profiles, or singlet oxygen quantum yield have been conducted. Progress is also being made in cancer theranostics by using fluorescent signals generated by photosensitizers. In order to obtain the effective cytotoxic effects on the target cells and prevent off-target side effects, photosensitizers need to be localized to the target tissue. The use of nanocarriers combined with photosensitizers can enhance accumulation of photosensitizers in the tumor site, owing to preferential extravasation of nanoparticles into the tumor vasculature by the enhanced permeability and retention effect. Self-assembly of amphiphilic polymers provide good loading efficiency and sustained release of hydrophobic photosensitizers. In addition, prodrug nanomedicines for PDT can be activated by stimuli in the tumor site. In this review, we introduce current limitations and recent progress in nanomedicine for PDT and discuss the expected future direction of research.

Keywords: nanocarrier; nanomedicine; photodynamic therapy; photosensitizer; prodrug; self-assembly.

Figure 1

Schematic representation of nanomedicine for photodynamic therapy (PDT). Accumulation of photosensitizers in the tumor site can be enhanced by nanocarriers. In addition, prodrug nanomedicines for PDT can be activated by such stimuli as enzymes in the tumor site. Self-assembly of amphiphilic polymers may provide good loading efficiency and sustained release of hydrophobic photosensitizers.

Figure 2

(A) A scheme for fabrication of photosensitive nanoparticles by amphiphilic dipeptide- or amino acid-tuned self-assembly. (B) (a) Scanning electron microscopy (SEM) image and (b) transmission electron microscopy (TEM) image of assembled Fmoc-_L-Lys/Ce6 nanoparticles using Fmoc-_L-Lys (2.0 mg mL⁻¹) and chlorin e6 (Ce6) (0.5 mg mL⁻¹) as building blocks. (c) SEM image and (d) TEM image of assembled cationic diphenylalanine (CDP)/Ce6 nanoparticles using CDP (2.0 mg mL⁻¹) and Ce6 (0.5 mg mL⁻¹) as building blocks (reproduced with permission from [59]).

Figure 3

(a) Synthesis of the C36–fucoidan theranostic nanogel (CFN-gel). (b) schematic illustration of the CFN-gel and its mode of action. EDC: 1-ethyl-3-(3-dimethylamino) propyl carbodiimide; NHS: N-hydroxysuccinimide; GSH: glutathione (reproduced with permission from Cho, M.H.; Li, Y.; Lo, P.C.; Lee, H.R.; Choi, Y. Fucoidan-Based Theranostic Nanogel for Enhancing Imaging and Photodynamic Therapy of Cancer. Nano Micro. Lett. 2020, 12).

Figure 4

Schematic representation of visible light-induced apoptosis activatable nanoparticles of chlorin e6 (Ce6)–Asp–Glu–Val–Asp (DEVD) –monomethyl auristatin E (MMAE) for targeted cancer therapy. (a) The molecular structure of Ce6–DEVD–MMAE consisting of Ce6 (green), DEVD (black), p-amino-benzyl carbamate linker (blue), and MMAE moieties (red). (b) The Ce6–DEVD–MMAE can form stable nanoparticles via self-assembly of an amphiphilic prodrug-based structure. (c) The self-assembly of Ce6–DEVD–MMAE nanoparticles may enhance drug delivery to targeted tumors via enhanced permeation and retention effect. (d) The cytotoxicity of nanoparticles at the targeted tumors can be continuously induced with caspase 3 following exposure to visible light irradiation and it can be further amplified by activating MMAE from Ce6–DEVD–MMAE nanoparticles without visible light irradiation, resulting in sequential, repetitive, and amplified cell death of targeted tumor tissues (reproduced with permission from Um, W.; Park, J.; Ko, H.; Lim, S.; Yoon, H.Y.; Shim, M.K.; Lee, S.; Ko, Y.J.; Kim, M.J.; Park, J.H.; Lim, D.K.; Byun, Y.; Kwon, I.C.; Kim, K. Visible light-induced apoptosis activatable nanoparticles of photosensitizer-DEVD-anticancer drug conjugate for targeted cancer therapy. Biomaterials 2019, 224, 119494).

Figure 5

Schematic illustration of the components of the activatable prodrug nanoparticle and its light-boosted hypoxia-activated self-immolative drug release for synergistic tumor inhibition. A light-boosted hypoxia-activated self-immolative paclitaxel (PTX) prodrug nanosystem was designed for synergistic photodynamic therapy and chemotherapy. After intravenous administration, the nanoparticle could gather at the tumor site. Upon irradiation, severe hypoxia occurred and amplified the specific release of paclitaxel from the prodrug bridged with azobenzene. The nanoparticle showed superior antitumor efficacy with little toxicity to other organs (reproduced with permission from Zhou, S.; Hu, X.; Xia, R.; Liu, S.; Pei, Q.; Chen, G.; Xie, Z; Jing, X. A paclitaxel prodrug activatable by irradiation in a hypoxic microenvironment. Angew. Chem. Int. Ed. Engl. 2020, 59, 23198–23205).