A Review on (Hydro)Porphyrin-Loaded Polymer Micelles: Interesting and Valuable Platforms for Enhanced Cancer Nanotheranostics

Abstract

Porphyrins are known therapeutic agents for photodynamic therapy of cancer and also imaging agents for NIR fluorescence imaging, MRI, or PET. A combination of interesting features makes tetrapyrrolic macrocycles suitable for use as theranostic agents whose full potential can be achieved using nanocarriers. This review provides an overview on nanotheranostic agents based on polymeric micelles and porphyrins developed so far.

Keywords: micelles; nanoparticles; nanotheranostics; photodynamic therapy; porphyrin.

Figure 1

Schematic illustration of the core–shell micelle self-assembled from Gal-APP-PAEMA-PCL.

Figure 2

Schematic illustration of the micellization and demicellization processes of protoporphyrin IX (PpIX)-pH-responsive polymeric micelles (pH-PMs) and simultaneous tumor photodiagnosis and photodynamic therapy in vivo.

Figure 3

Non-invasive fluorescence imaging and photodynamic therapy (PDT) with PpIX-pH-PMs in live SCC7 tumor-bearing mice. In vivo time-dependent whole body imaging after injection (a); in vivo quantification of tumor target specificity of free PpIX and PpIX-pH-PMs (b); ex vivo images of organs (liver, lung, spleen, kidney, heart) and tumors (c). (d) H&E staining of tumor tissues 10 days after treatment. (e) Tumor growth of SCC7 tumor-bearing mice treated with drug injection and irradiation. Results represent means ± SDs. (n = 2). Reproduced from Reference [37] with permission from the Royal Society of Chemistry, 2010.

Figure 4

PEG-PLA and photosensitizer (a) and PEG-PLA-photosensitizer (b) structures used for the preparation of encapsulated and conjugated micelles, respectively.

Figure 5

Synthetic strategy for folate-conjugated PEOz-PLA copolymer used to prepare pH-responsive micelles to encapsulate m-THPC.

Figure 6

Structure of PLL-g-PEG/DPA/TPS/PheA (probe 1) and schematic illustration of the pH-activable probe 1.

Figure 7

Schematic illustration of glutathione (GSH)-activable PS-conjugated pseudopolyrotaxane nanocarriers for photodynamic theranostics. Reproduced from Reference [42] with permission from Small, 2016.

Figure 8

(A) Human oral epidermoid carcinoma (KB) tumor-bearing nude mice and (B) excised KB tumor images after 14 days of treatment with (a) phosphate-buffered saline (PBS), (b) α-CD-ss-Ce6 NPs without laser, (c) free Ce6 with laser, and (d) α-CD-ss-Ce6 NPs with laser. Reproduced from Reference [42] with permission from Small, 2016.

Figure 9

Schematic illustration of the synthesis, (A) transmission electron microscopy (TEM) and (B) atomic force microscopy (AFM) images of a Mn(III)-labeled nanobialy. 1. nanobialys and 4. Sensitizers numbered in the original figure. Reproduced from [44] with permission from Journal of the American Chemical Society, 2008.

Figure 10

Schematic illustration of Ce6-loaded MPEG-b-PAspDA micelles incorporating cypate for dual-mode tumor photoacoustic (PA)/near-infrared fluorescence (NIRF) imaging and synergistic cancer photothermal therapy (PTT)/PDT through enhanced cytoplasmic delivery of the photosensitizer. Reproduced from Reference [48] with permission from Biomaterials, 2014.

Figure 11

Schematic illustration of IR825@C18PMH-PEG-Ce6-Gd nanomicelles; Ce6 is attached on the backbone of C18PMH-PEG polymer via a short PEG linker; Gd³⁺ forms a chelate complex with Ce6; IR825 is encapsulated inside the formed micellar system.

Figure 12

(a) In vivo fluorescence imaging and (b) MRI of mice bearing 4T1 tumor cells taken at different time points post-injection with IR825@C18PMH-PEG-Ce6-Gd (200 μL, [Ce6] = 0.5 mg/mL, [IR825] = 1.3 mg/mL); dashed circles in (a) and (b) highlight the tumor, while arrows in (b) point to the heart; (c) quantification of tumor signals and tumor-to-normal tissue signal (T/N) ratios from fluorescence images shown in (a) at different post-injection times; (d) quantification of average T1-MRI signals in the tumor by manual drawn region of interest at different post-injection times; (e) in vivo PA imaging of mice bearing 4T1 tumor cells taken at different time points post-injection of IR825@C18PMH-PEG-Ce6-Gd. Reproduced from Reference [49] with permission from Advanced Functional Materials, 2014.

Figure 13

(a) Schematic illustration of a multifunctional NPor self-assembled by a representative porphyrin-telodendrimer system, PEG_5k-Por₄-CA₄, comprised of four Por molecules and four CA moieties, attached to the terminal end of a linear PEG chain and (b) its use as a “all-in-one” nanomedicine platform against cancer; (c) TEM image of NPors; (d) absorbance spectra of NPors before and after chelating different metallic ions; (e) fluorescence emission spectra of NPs in the presence of PBS and SDS using a 405 nm excitation; (f) NIRF imaging of a NPor solution in the presence and absence of SDS with an excitation bandpass filter at 625/20 nm and an emission filter at 700/35 nm; (g) single oxygen generation of NPs in PBS and SDS after light irradiation (690 nm at 0.25 W/cm² for 60 s); concentration-dependent photothermal transduction of NPors—(h) thermal images and (i) quantitative temperature change curve; the temperature of the NPor solution in the presence and absence of SDS was monitored by a thermal camera after irradiation with NIR light (690 nm at 1.25 W/cm² for 20 s). Reproduced from Reference [50] with permission from Nature Communications, 2014.

Figure 14

NPor-mediated MRI and PET imaging in animal models. (a) MRI signal of Gd-NPors in the presence and absence of SDS obtained in vitro by T₁-weighted MRI; (b) representative coronal and axial MRI images of transgenic mice with mammary cancer (FVB/n Tg(MMTV-PyVmT)) at pre-injection and post-injection of 0.15 mL Gd-NPors (Gd dose = 0.015 mmol/kg); red arrows point to the tumor site; (c) PET image of nude mice bearing SKOV3 ovarian cancer xenografts at 4, 8, 16, 24, and 48 h post-injection of ⁶⁴Cu-NPors (150–200 µL, ⁶⁴Cu dose = 0.6–0.8 mCi); white arrows point to the tumor site; (d) 3D coronal MRI images of nude mice bearing A549 lung cancer xenografts at 4 or 24 h post-injection with 0.15 mL of ⁶⁴Cu and Gd dual-labeled NPors (150–200 µL, ⁶⁴Cu dose = 0.6–0.8 mCi, Gd dose = 0.015 mmol/kg); white arrows point to the tumor site; (e) PET-MRI images of tumor slices of nude mice bearing A549 lung cancer xenografts at 4 or 24 h post-injection of dual-labeled NPors; white arrows point to the necrotic area in the center of the tumor. Reproduced from Reference [50] with permission from Nature Communications, 2014.

Figure 15

Imaging-guided drug delivery of NP-AAG in both mouse models bearing (a) subcutaneous and (b) orthotopic PC3 xenograft. In vivo and ex vivo white light (WL) and NIRF imaging of nude mice bearing subcutaneous PC3 xenograft (a) or orthotopic PC3 xenograft (b) 72 h post-injection of NP-AAG. Arrows: tumor site. (c) Analysis of NIRF imaging on each tumor and organs after normalization to the fluorescence of muscle. Reproduced from Reference [52] (Theranostics 06: 1324 image No. 006, open access policy).

Figure 16

In vivo therapeutic response to PPNs-mediated chemotherapy combined with phototherapy. (A) In vivo antitumor efficacy after the intravenous treatment of various DOX formulations combined with PPNs-mediated phototherapy (n = 6). The SKOV3 tumor-bearing mice were intravenously injected with PBS (control), free DOX (2.5 mg/kg), PPNs (2 mg/kg calculated on porphyrin), and PPNs–DOX (PPNs 2 mg/kg, DOX 2.5 mg/kg) on day 0, 5, 10, and 15, followed by various light irradiations for 2 min on tumors, 24 h post-injection. (B) Kaplan–Meier survival curves of SKOV3 tumor-bearing mice treated with the above indicated conditions, where tumor volume reached 500 mm³ and was considered as the end point of survival data. (C) Photographs showing therapeutic response to PPNs-mediated phototherapy with irradiation at 0.5 W/cm² for 2 min and 1.25 W/cm² for 2 min, respectively. (D) H&E staining of tumor sections collected from control mice and PPNs-injected (2 mg/kg) and variously irradiated mice (0.5 W for 2 min and 1.25 W for 2 min, respectively), 24 h post-injection. Reproduced from Reference [54] (Theranostics 07:3901 image No. 005, open access policy).