Organic molecule-based photothermal agents: an expanding photothermal therapy universe

Abstract

Over the last decade, organic photothermal therapy (PTT) agents have attracted increasing attention as a potential complement for, or alternative to, classical drugs and sensitizers involving inorganic nanomaterials. In this tutorial review, we provide a structured description of the main classes of organic photothermal agents and their characteristics. Representative agents that have been studied in the context of photothermal therapy since 2000 are summarized and recent advances in using PTT agents to address various cancers indications are highlighted.

Jonathan L. Sessler (left), Hyo Sung Jung (right)

Peter Verwilst, Jong Seung Kim, Amit Sharma, Jinwoo Shin (from left to right)

Fig. 1

(A) Molecular structure of free ICG and its modified forms: (B) ICG/DMPC based liposome 1, (C) ICG/PL-PEG aggregates 2 conjugated with FA 3 and mAb 4, (D) ICG/PLGA cancer cell membrane coated biomimetic agent 5, and (E)ICG/DOX encapsulated lipid-polymer material 6. DMPC: 1,2-dimyristoyl-sn-glycero-3-phosphocholine; PL: phospholipid; PEG: polyethylene glycol; FA: folate receptor; mAb: monoclonal antibody; DSPE=1,2-distearoyl-sn-glycero-3-phosphoethanolamine; PLGA: poly(lactic-co-glycolic acid); DOX: doxorubicin.

Fig. 2

(A) Molecular structures of the heptamethine cyanines: IR825, IR780, IR808, and IR2 and associated PTT systems: (B) IR825/PEGylated micelle 7, (C) IR780/heparine-folic acid system 8, (D) mitochondria-targetedheptamethine 9, and (E) pH-switchable theranostic heptamethine dyes10 and 10-H⁺.

Fig. 3

(A) Molecular structures of phthalocyanines: metallonaphthalocyanines, GdSand, PcBu₄, SiNcOH and SiNc2 and constructs containing these dyes: (B) GdSand/HDL/Tat nanoparticle 11, (C) PcBu₄/Pluronic F-68/glycol chitosan/heparin nanoparticle 12, (D) PEG-phospholipids encapsulated SiNcOH nanoparticle 13, and (E) dendrimer-encapsulated SiNc 2 nanoparticle 14. GdSand: gadolinium-bisnapthalocyanine sandwich complex; PcBu₄: tetra-t-butylphthalocyanine; HDL: high-density lipoprotein; Tat=transactivator of transcription; SiNcOH: silicon 2,3-naphthalocyanine dihydroxide; SiNc2: silicon 2,3-naphthalocyanine bis(trihexylsilyloxide).

Fig. 4

(A) Molecular structures of RC and cryptocyanine and constructs prepared from these particular dyes: (B) RC/BSA 15 and (C) TPP-functionalized cryptocyanine 16. RC: hemicyanine-rhodamine; BSA: bovine serum albumin; TPP:triphenylphosphonium.

Fig. 5

(A)Molecular structure of diketopyrrolopyrroles: DPP-TPA, SDPP, SP2, SP3, SP4, and PDPP, and selected derivatives: (B) Diketopyrrolopyrrole triphenylamine nanoparticle 17, (C) small-molecule diketopyrrolopyrrole-based therapeutic nanoparticles 18, (D) semiconducting polymeric nanoparticles 19–21, and (E) PDPP-containing nanoparticles 22. DPP-TPA: dithienyldiketopyrrolopyrrole-triphenylamine; SDPP: 5-bis(6-bromo-hexyl)-3,6-bis[5-[4-(4-dimethylaminobenzoyl)-phenyl]-thiophen-2-yl]-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione; SP: semiconducting polymer; PDPP: poly(dithienyldiketopyrrolopyrrole).

Fig. 6

(A) Molecular structure of croconaines: Croc, CrocRot I, Dumbbell Croc, CrocRot II, Bis(guanidinium) Croc, CrocRot III, and CrocRot IV. (B) Preparation of Dumbbell Croc-based silicate nanoparticle 23 and CrocRot II-based silicate nanoparticle 24. (C) Preparation of Dumbbell Croc-based nanoparticles 25 and liposomes 26, respectively. (D) DOX-containing nanoparticles constructed using Dumbbell Croc and ICG. (E) Dumbbell Croc-containing liposomes loaded with carboxyfluorescein. (F) Unlike ICG, Dumbbell Croc retains its potential to cause a photothermal effect over multiple cycles when incorporated in PLGA/mPEG2000-DSPE nanoparticles 25. Adapted with permission from Ref. . Copyright 2015 American Chemical Society. (G) pH dependent absorbance and PTT effect of CrocRot IV. Adapted from Ref. with permission from The Royal Society of Chemistry. Croc: croconaine dye; CrocRot: pseudorotaxane croconaine.

Fig. 7

(A) Molecular structure of porphyrins: phosphatidylcholine-pyropheophorbide, TPP-G-FF, and PorCp, and (B) phosphatidylcholine-pyropheophorbide’s modified porphysome 27. (C) Transmission electron microscopy images of 27. Reprinted by permission from Macmillan Publishers Ltd: Nature Materials (Ref. 32), Copyright 2011. (D) TPP-G-FF self-assembled porphyrins 28 and (E) PorCP polymeric nanoprecipitates 29. TPP-G-FF: tetraphenylporphyrin conjugate; PorCp: porphyrin conjugated polymer.

Fig. 8

(A) Molecular structure of polymers explored in the context of PTT: Polyaniline, PEDOT:PSS, polypyrrole (PPy), and poly(BIBDF-BT). (B) Systematic process for polyaniline (emeraldine) base nanoparticle 30 and polyaniline (emeraldine) salt nanoparticle 31. (C) Structure of PEDOT:PSS-PEG nanoparticle 32. (D) Systematic illustration of PVA-coated PPy nanoparticles 33, (E) Fe₃O₄-PPy-PEG nanoparticles 34, (F) PPy nanoparticles by a simple one-step aqueous dispersion polymerization method, (G) IONP@PPy-PEG nanoparticles 35, (H) multifunctional PPy@MIL-100-DOX nanoparticle 36, (I) PEG-POA PPy nanoparticle 37, and (J) poly(BIBDF-BT) nanoparticles 38. PEDOT:PSS: poly(3,4-ethylenedioxythiophen):poly(4-styrene-sulfonate); PVA: poly(vinylalcohol); IONP: iron-oxide nanoparticles.

Fig. 9

(A) Molecular structure of other agents studied in the context of PTT: Squaraine, BBTEHT, and BPDI. (B) Temperature elevation of water and aqueous melanin-dopamine CNSs at different concentrations seen upon NIR light illumination (808 nm laser, power 2 W/cm²). Reproduced from Ref. with permission from Wiley. (C) Molecular structure of squaraine with BSA adduct. Reproduced from Ref. with permission from Elsevier. (D) Molecular structure of BBTEHT and its self-assembled nanoparticles 39. (E) Molecular structure of BPDI 40a, BPDI radical species 40b, CB[7]-based molecular assembly. Also shown is the chemical reduction and corresponding photothermal conversion seen upon NIR irradiation. BBTEHT: benzo[1,2-c;4,5-c′]bis[1,2,5]thiadiazole-4,7-bis(5-(2-ethylhexyl)thiophene); BPDI: 1:2 bola-type amphiphilicperylene diimide.

Scheme 1

Working principle underlying organic PTT agents as illustrated using a modified Jablonski diagram.