π-π-Stacked Poly(ε-caprolactone)-b-poly(ethylene glycol) Micelles Loaded with a Photosensitizer for Photodynamic Therapy

Abstract

To improve the in vivo stability of poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-PEG)-based micelles and cargo retention by π-π stacking interactions, pendant aromatic rings were introduced by copolymerization of ε-caprolactone with benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (TMC-Bz). It was shown that the incorporation of aromatic rings yielded smaller micelles (18-30 nm) with better colloidal stability in PBS than micelles without aromatic groups. The circulation time of i.v. injected micelles containing multiple pendant aromatic groups was longer (t 1 /2-α:~0.7 h; t 1 /2-β: 2.9 h) than that of micelles with a single terminal aromatic group (t 1 /2 < 0.3 h). In addition, the in vitro partitioning of the encapsulated photosensitizer (meta-tetra(hydroxyphenyl)chlorin, mTHPC) between micelles and human plasma was favored towards micelles for those that contained the pendant aromatic groups. However, this was not sufficient to fully retain mTHPC in the micelles in vivo, as indicated by similar biodistribution patterns of micellar mTHPC compared to free mTHPC, and unequal biodistribution patterns of mTHPC and the host micelles. Our study points out that more detailed in vitro methods are necessary to more reliably predict in vivo outcomes. Furthermore, additional measures beyond π-π stacking are needed to stably incorporate mTHPC in micelles in order to benefit from the use of micelles as targeted delivery systems.Pharmaceutics 2020, 12, 338 2 of 26 and can subsequently transfer its energy to molecular oxygen to yield singlet oxygen species (ROS), which are highly reactive with biomolecules present in cytoplasma or cell membranes, leading to cell death [5,6]. Effective cancer PDT is, however, hindered by some undesired properties in PS. Most PS molecules-including the clinically approved second generation PS, meta-tetra(hydroxyphenyl)chlorin (mTHPC)-are highly hydrophobic due to the extended delocalized aromatic π electron system. This promotes non-specific binding to cells, resulting in unspecific distribution of PS in healthy tissues (i.e., no selective accumulation of the PS in tumorous tissues), which can cause skin toxicity [7][8][9]. Moreover, the poor water solubility caused by the high hydrophobicity makes PS prone to aggregation in aqueous solutions, leading to lower ROS generation and decreased therapeutic efficacy [9][10][11].Loading of PS in polymeric micelles is a promising approach to address these challenges [12]. Polymeric micelles are self-assembled nanostructures based on amphiphilic block copolymers formed in an aqueous solution and have been extensively investigated as drug delivery systems, particularly for the targeted delivery of hydrophobic drugs [13][14][15][16]. Polymeric micelles are characterized by a well-defined structure, containing a hydrophobic core and a hydrophilic shell. The micellar core has a high capacity to accommodate hydrophobic compounds, including photosensitizers, while the hydrophilic shell, which is mostly composed of poly(ethylene glycol) (PEG), can result in...

In Vitro and Circulation Kinetic Studies on π-π-stacked Poly (ɛ-caprolactone)-based Micelles Loaded with Olaparib

“…The poly (ε-caprolactone)-co-poly (benzyl-5-methyl-2-oxo-1,3dioxane-5-carboxylate)-b-poly (ethylene glycol) (P(CL-co-TMC-Bz)-PEG) was synthesized, as previously described. 14…”

“…The average degree of polymerization (DP) of CL or TMC-Bz was determined by 1 H-NMR, as previously described. 14 Briefly, DP was calculated using the ratio of the integral of the CH 2 protons of CL at 1.38 ppm, or the CH 2 protons of benzyl groups in the poly (TMC-Bz) at 5.16 ppm, to the CH 3 protons of mPEG-OH at 3.36 ppm. The average molecular weight (M n ) of the polymer was calculated based on the molecular weight of the DP of each unit.…”

“…12, 13 We previously reported that polymeric micelles constituted of poly (ε-caprolactone)-co-poly (benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate, i.e., benzyl-functionalized trimethylene carbonate-bpoly (ethylene glycol) (P(CL-co-TMC-Bz)-PEG), was not only an excellent and safe solubilizer of a hydrophobic photosensitizer but also displayed prolonged circulation times in mice, as a result of the π-π stacking interactions of the micellar core. 14 In the present study, π-π stacked P(CL-co-TMC-Bz)-PEG micelles were used to investigate its capability as a solubilizer of olaparib to improve the solubility, while ensuring its safety to different organs. Meanwhile, the micelles were evaluated as a drug delivery system for the prolonged circulation time of olaparib responsible for the improvement of its tumor site accumulation through the EPR effect.…”

Nanoparticle-Based Combination Therapy for Ovarian Cancer

“…17 Nanoparticulate drug delivery systems can encapsulate hydrophobic therapeutic agent(s), such as PTX to yield aqueous dispersions facilitating its administration and/or to accommodate hydrophilic agent(s) such as RNA facilitating its access to cells. 15,[17][18][19] Nanoparticle-based therapeutics typically consist of nanosized particles with a diameter in the range of 10 to 200 nm, favorable for increasing accumulation of delivered cargoes in the tumor via passive targeting, ie, enhanced permeability and retention (EPR) effect (Figure 1). 20,21 Nanoparticles can also be modified with targeting molecules such as growth factors, antibodies, antibody fragments, or peptides, which can specifically bind to receptors overexpressed by tumor cells, leading to enhanced internalization of drug loaded nanoparticles by targeted cells and thus improved selectivity and therapeutic response by so-called active targeting (Figure 1).…”

The Photosensitizer Temoporfin (mTHPC) – Chemical, Pre‐clinical and Clinical Developments in the Last Decade†‡

“…However, as the temoporfin was found to be rapidly released from the micelles in plasma this selectivity could not be exploited in vivo . ε‐Caprolactone micelles loaded with temoporfin were also tested in two other in vivo investigations in mice investigating the effect of aromatic groups on the polymer (101) as well as that of dithiolane‐crosslinking and pegylation (280). The presence of aromatic groups in the polymer and non‐crosslinked micelles resulted in higher temoporfin retention.…”