Shining light on nanotechnology to help repair and regeneration

Abstract

Phototherapy can be used in two completely different but complementary therapeutic applications. While low level laser (or light) therapy (LLLT) uses red or near-infrared light alone to reduce inflammation, pain and stimulate tissue repair and regeneration, photodynamic therapy (PDT) uses the combination of light plus non-toxic dyes (called photosensitizers) to produce reactive oxygen species that can kill infectious microorganisms and cancer cells or destroy unwanted tissue (neo-vascularization in the choroid, atherosclerotic plaques in the arteries). The recent development of nanotechnology applied to medicine (nanomedicine) has opened a new front of advancement in the field of phototherapy and has provided hope for the development of nanoscale drug delivery platforms for effective killing of pathological cells and to promote repair and regeneration. Despite the well-known beneficial effects of phototherapy and nanomaterials in producing the killing of unwanted cells and promoting repair and regeneration, there are few reports that combine all three elements i.e. phototherapy, nanotechnology and, tissue repair and regeneration. However, these areas in all possible binary combinations have been addressed by many workers. The present review aims at highlighting the combined multi-model applications of phototherapy, nanotechnology and, reparative and regeneration medicine and outlines current strategies, future applications and limitations of nanoscale-assisted phototherapy for the management of cancers, microbial infections and other diseases, and to promote tissue repair and regeneration.

Fig. 1. Schematic illustration of photodynamic action (Jablonski diagram)

The PS initially absorbs a photon that excites it to the short-lived excited singlet state. This can lose energy by fluorescence, internal conversion to heat, or by intersystem crossing to the long-lived triplet state. This triplet PS can interact with molecular oxygen in two pathways, type 1 and type 2, leading to the formation of reactive oxygen species (ROS) and singlet oxygen (¹O₂) respectively.

Fig. 2. Schematic representation of various nanoparticles with photosensitizer (PS) used in photodynamic therapy

(A) Liposome containing lipid soluble PS in hydrophobic lipid bilayer. (B) Polymeric dendrimer with PS. (C) Silica nanoparticle (SiNP) doped with PS. (D) Gold nanoshell encapsulated with PS. (E) Typical quantum dot (QD) with core shell, followed by a biocompatible polymer coating. PS is covalently attached to the QD that can take part in FRET with the emission of the QD being used to excite the PS.

Fig. 3. Combined applications of phototherapy, nanotechnology and, reparative and regenerative medicine

ECM, extra cellular matrix.

Fig. 4. Fullerene photodynamic therapy for disseminated peritoneal cancer in mice

(A) Novel skin flap model to allow illumination of the abdominal cavity with white light. (B) Skin flap can be readily closed after illumination. (C) Non-invasive bioluminescence imaging of mouse colon carcinoma engineered to express luciferase after no treatment or after BF4 fullerene-mediated PDT. (D) Quantification of bioluminescence signals from (C). (E) Kaplan–Meier survival plot of mice treated with white, green, or red light (100 J/cm²) 24 h after injection of 5 mg/kg BF4. (F) mono-pyrrolidinium fullerene (BF4). (Reproduced with permission from reference (Mroz et al., 2011). Copyright 2011 Elsevier).

Fig. 5

(A) Schematic representation showing near-infrared irradiation on nanoparticle (NP) induces upconversion (UC) which emits visible light activating the coated photosensitizer (PS) to generate singlet oxygen (¹O₂). (B) Multi-functional NP with magnetite core (Fe₃O₄) coated with biocompatible layer and PS is covalently attached by linker. (C) Lipoprotein NP consists of hydrophobic PS, specific apoprotein, cholesterol esters, triglycerides and cholesterol used as a drug carrier for photodynamic therapy.

Figure 6

Historical timeline of clinical approvals of photosensitizers used for photodynamic therapy

Figure 7. A possible mechanism of action of low-level laser (or light) therapy (LLLT) mediated repair and regeneration

Light is initially absorbed by mitochondrial chromophore (cytochrome c oxidase) and causes increase production of ATP, reactive oxygen species (ROS) and nitric oxide (NO), which in turn cause changes in cellular redox potential, Ca²⁺, K⁺, cAMP and pH levels and induce several transcription factors (Ref-1, AP-1, NFkB, HIF-1α). The photosignal transduction and amplification chain induced by light leads to an increase of cell proliferation (stimulation of DNA and RNA synthesis), cell motility, production of growth factors and extra cellular matrix accumulation.