Multi-Functional Liposome: A Powerful Theranostic Nano-Platform Enhancing Photodynamic Therapy

Abstract

Although photodynamic therapy (PDT) has promising advantages in almost non-invasion, low drug resistance, and low dark toxicity, it still suffers from limitations in the lipophilic nature of most photosensitizers (PSs), short half-life of PS in plasma, poor tissue penetration, and low tumor specificity. To overcome these limitations and enhance PDT, liposomes, as excellent multi-functional nano-carriers for drug delivery, have been extensively studied in multi-functional theranostics, including liposomal PS, targeted drug delivery, controllable drug release, image-guided therapy, and combined therapy. This review provides researchers with a useful reference in liposome-based drug delivery.

Keywords: combined therapy; drug delivery; liposomes; photodynamic therapy; theranostics.

Figure 1

A) In the cell, liposomal PS is activated from the ground state (S₀) to the excited state (S₁) by light irradiation. Then, the singlet PS* is transferred to the triplet state PS* by ISC, the latter induced radicals and ROS (type I) and singlet oxygen (¹O₂) from triplet oxygen (³O₂) (type II), which may cause cell damage. B) Development of multi‐functional liposomes. C) Typical liposome structure consist of the lipid bilayer, aqueous core, hydrophobic drugs imbedded in lipid bilayer, hydrophilic drug inside the aqueous core, recognition moieties and PEG linker on the liposome surface. D,E) Typical preparation encapsulation methods of PS and drugs: D) hydrophobic and E) hydrophilic.

Figure 2

Representative parent porphyrinoids and liposomal porphyrinoids.

Figure 3

Liposomal porphyrinoids with metal chelation.

Figure 4

Other types of liposomal PSs.

Figure 5

Lipid‐conjugated PSs.

Figure 6

A) Upon the liposomes were collapsed in acidic lysosome, due to the degradation of acid‐sensitive lipid DOPE, liposomal DiBDP was activated by NTR under hypoxia. Confocal fluorescence microscopy imaging of HeLa cells which were pre‐cultured under hypoxic (1% pO₂) conditions for 6 h and then incubated with Ab‐DiBDP NPs (50 mg mL⁻¹) for 20 min. λ _ex = 543 nm, Scale bar = 40 µm. Reproduced with permission.^{[ 83 ]} Copyright 2018, Royal Society of Chemistry. B) Schematic illustration of combined therapy by liposomal system: Lip(Ce6+ICG). Reproduced with permission.^{[ 101 ]} Copyright 2015, Royal Society of Chemistry.

Figure 7

Typical models of active‐targeted liposomes. Specific recognitions includes: A) antibody‐antigen interactions, B) aptamer‐receptor interactions and C) ligand‐receptor interactions.

Figure 8

Biomimic liposomes made from A) cancer cell membrane, B) red blood cell membrane.

Figure 9

A) Liposomal collapse induced by various stimuli, such as light, photothermal effect, enzyme, pH, and X‐ray. B) Typical modification sites on lipid backbone for liposomal activation.

Figure 10

The structures of ROS‐sensitive lipids with C═C bond.

Figure 11

A) NIR irradiation was converted to visible light (540 nm) by NaYF₄ UCN to activate liposomal PS (MC540) for B) PDT and FLI. Reproduced with permission.^{[ 137 ]} Copyright 2014, American Chemical Society.

Figure 12

Three ways to enhance the supply of cellular oxygen to PS: A) delivery of extracellular oxygen by oxygen carriers (PTF and Hb); B,C) delivery of oxygen‐generating materials (CaO₂) to PS; D) transformation of other endogenous molecules (H₂O₂) to oxygen; E,F) suppression of other pathways that consuming intracellular oxygen by inhibitors (metformin, Au nanoclusters).

Figure 13

Proposed mechanism of PLNA for enhanced PDT via NIR remote ‐controlled BSO release for the inhibition of GSH biosynthesis.

Figure 14

A schematic illustration of the components of CLG@NCP‐PEG and the mechanism of its pH‐sensitive degradation and collagen degradation to enhance PDT.

Figure 15

A) Liposomes encapsulating various imaging agents for visualization of tumor‐bearing mice. Tumors are indicated by yellow arrows. B) FLI after i.v. injection of AIEsomes. Reproduced with permission.^{[ 93 ]} Copyright 2018, WILEY VCH GmbH & Co. KGaA. C) PA images after i.v. injection of free ICG and DOX@GdMSNs‐ICG‐TSLs. D) PA intensity of tumor sites after treatment with free ICG and DOX@GdMSNs‐ICG‐TSLs. E) T1‐weighted MR images of DOX@GdMSNs‐ICG‐TSLs nanoparticles at various Gd concentrations (top). T1‐weighted MR images before and after injection with DOX@GdMSNs‐ICG‐TSLs (bottom). F) Relative MR intensities before and after the injection of DOX@GdMSNs‐ICG‐TSLs. C‐F) Reproduced with permission.^{[ 30 ]} Copyright 2018, American Chemical Society. G) 3D volume‐rendered images after injection with NL‐co‐encapsulated iodixanol and TPPS₄ (LIT). Reproducedunder the terms of the Creative Commons CC‐BY license.^{[ 58 ]} Copyright 2019, Ivyspring International Publisher. H) In vivo PET images after i.v. injection of ⁶⁴Cu²⁺‐labeled AQ4N‐hCe6‐liposome. Reproduced with permission.^{[ 160 ]} Copyright 2017, American Chemical Society. I) Infrared photothermal images after i.v. injection of liposomal ICG followed by laser irradiation. Reproduced with permission.^{[ 161 ]} Copyright 2015, Elsevier. J) In vivo SPECT imaging after i.v. injection of Liposome@Ce6‐^99mTc. Mice with (right) and without (left) pretreatment of CLG@NCP‐PEG were visualized. Reproduced with permission.^{[ 154 ]} Copyright 2018, American Chemical Society.

Figure 16

The mechanism of release of capsulated PSs and drugs for combined therapies.

Figure 17

Combination of PDT and hypoxia‐activated chemotherapy. A) Prodrug liposomal TPZ and AQ4N were activated to toxic BTZ and AQ4 under hypoxia, respectively. B) Mechanism of transformation of TPZ and AQ4N under hypoxia. The relative tumor volume changes of mice treated with liposomes containing prodrug D) TPZ and E) AQ4N. D) Reproduced with permission.^{[ 178b ]} Copyright 2018 Elsevier. E) Reproduced with permission.^{[ 160 ]} Copyright 2017 American Chemical Society.

Figure 18

Combination of PDT with A) PTT excited by light or B) MHT excited by magnetic field. The therapeutic effects of C) Ce6‐CuS‐TSL liposomes. Reproduced with permission.^{[ 188 ]} Copyright 2016, Elsevier. D) Plasmonic liposomes (PLs). Reproduced with permission.^{[ 189 ]} Copyright 2014, Royal Society of Chemistry. E) Ultramagnetic photosensitive liposomes (UMPL). Reproduced with permission.^{[ 191 ]} Copyright 2015, American Chemical Society.

Figure 19

A) Structure of liposome co‐encapsulated with ZnPC and Ru(NO) and the activation modes via two photosensitive mechanisms. B) In vitro phototoxicity against B16‐F10 cells. Reproduced with permission^{[ 192 ]} Copyright 2017, Elsevier.

Figure 20

Schematic illustration of targeted PDT to three organelles (lysosome, mitochondria and ER) by lipid‐anchored BPD liposome and Visudyne. Reproduced with permission.^{[ 61 ]} Copyright 2019, Wiley‐VCH.

Figure 21

Schematic illustration of the synthesis of RALP@HOC@Fe₃O₄ liposome and i.v. injection. The collapse of ROS‐sensitive liposome induced the release of photo/chemodynamic therapeutic agents which were then activated by TME.

Figure 22

Schematic illustration of the multi‐diagnoses (MRI, FLI and PAI) and multi‐therapies (PDT, chemotherapy and PTT) based on multi‐functional theranostic liposomes. Reproduced with permission.^{[ 194 ]} Copyright 2019, American Chemical Society.

Figure 23

Schematic illustration of the preparation of multi‐functional theranostic nanocomposite DOX@GdMSNs‐ICG‐TSLs for fluorescence/photoacoustic/magnetic resonance imaging‐guided chemo‐ and phototherapies. Reproduced with permission.^{[ 30 ]} Copyright 2018, American Chemical Society.

Figure 24

Schematic illustration of components of AQ4N‐hCe6‐liposome and its applications in tumor theranostic. Reproduced with permission.^{[ 160 ]} Copyright 2017, American Chemical Society.

Figure 25

Schematic illustration of components and preparation of EGFR‐CPIG and its application of theranostic in vivo. Reproduced with permission.^{[ 156 ]} Copyright 2018, Royal Society of Chemistry.