Alkyl Chain Length in Poly(2-oxazoline)-Based Amphiphilic Gradient Copolymers Regulates the Delivery of Hydrophobic Molecules: A Case of the Biodistribution and the Photodynamic Activity of the Photosensitizer Hypericin

Abstract

Self-assembled nanostructures of amphiphilic gradient copoly(2-oxazoline)s have recently attracted attention as promising delivery systems for the effective delivery of hydrophobic anticancer drugs. In this study, we have investigated the effects of increasing hydrophobic side chain length on the selfassembly of gradient copolymers composed of 2-ethyl-2-oxazoline as the hydrophilic comonomer and various 2-(4-alkyloxyphenyl)-2oxazolines as hydrophobic comonomers. We show that the size of the formed polymeric nanoparticles depends on the structure of the copolymers. Moreover, the stability and properties of the polymeric assembly can be affected by the loading of hypericin, a promising compound for photodiagnostics and photodynamic therapy (PDT). We have found the limitation that allows rapid or late release of hypericin from polymeric nanoparticles. The nanoparticles entering the cells by endocytosis decreased the hypericininduced PDT, and the contribution of the passive process (diffusion) increased the probability of a stronger photoeffect. A study of fluorescence pharmacokinetics and biodistribution revealed differences in the release of hypericin from nanoparticles toward the quail chorioallantoic membrane, a preclinical model for in vivo studies, depending on the composition of polymeric nanoparticles. Photodamage induced by PDT in vivo well correlated with the in vitro results. All formulations studied succeeded in targeting hypericin at cancer cells. In conclusion, we demonstrated the promising potential of poly(2-oxazoline)-based gradient copolymers for effective drug delivery and sequential drug release needed for successful photodiagnostics and PDT in cancer therapy.

Spheroidal Model of SKBR3 and U87MG Cancer Cells for Live Imaging of Caspase-3 during Apoptosis Induced by Singlet Oxygen in Photodynamic Therapy

“…This specificity can persist over a longer period of up to several hours (24 h). Therefore, this model is suitable for the specific administration of hypericin, as has been shown previously with non-spheroidal cells grafted to CAM [ 5 , 6 ]. The application of cancer cell spheroids to quail CAM may affect their vasculature and especially angiogenesis after PDT, as reported by Majernik et al [ 41 ].…”

“…In the present study, hypericin was used as a model molecule for a hydrophobic photosensitizer. It has very interesting photodynamic and photodiagnostic properties [ 5 ]. Moreover, it has a dual character.…”

Nanomedicine in Clinical Photodynamic Therapy for the Treatment of Brain Tumors

“…The process can include mechanical agitation, mild heating or sonication. As an alternative to amphiphilic PS derivatives with low solubility in aqueous media, dialysis has been the most reported method [ 116 , 117 ]. On this basis, the PS derivative can be dissolved in an organic solvent such as dimethyl sulfoxide, dimethyl formamide, or methanol mixed with water and dialyzed against an aqueous solution to remove the solvent.…”

Influence of Hydrophobic Side-Chain Length in Amphiphilic Gradient Copoly(2-oxazoline)s on the Therapeutics Loading, Stability, Cellular Uptake and Pharmacokinetics of Nano-Formulation with Curcumin

“…The gradient copolymers contained 2-phenyl-2-oxazoline (PhOx), 2-(4-butylphenyl)-2-oxazoline (BuPhOx), or 2-(4-butoxyphenyl)-2-oxazoline (BuOPhOx) as the hydrophobic monomer [33]. Recently, we synthesized a small library of gradient copoly(2-oxazoline)s with different hydrophobic side-chain lengths containing 2-ethyl-2-oxazoline (EtOx) as a hydrophilic monomer and 2-(4-methoxyphenyl)-2-oxazoline (MeOPhOx), 2-(4-ethoxyphenyl)-2-oxazoline (EtOPhOx), 2-(4-hexyloxyphenyl)-2-oxazoline (HexOPhOx), or 2-(4-dodecyloxyphenyl)-2-oxazoline (DOPhOx) as a hydrophobic monomer [35,36]. The self-assembly of these gradient copoly(2-oxazoline)s has been used to formulate hypericin, a promising compound for photodiagnostics and photodynamic therapy [35].…”

“…Recently, we synthesized a small library of gradient copoly(2-oxazoline)s with different hydrophobic side-chain lengths containing 2-ethyl-2-oxazoline (EtOx) as a hydrophilic monomer and 2-(4-methoxyphenyl)-2-oxazoline (MeOPhOx), 2-(4-ethoxyphenyl)-2-oxazoline (EtOPhOx), 2-(4-hexyloxyphenyl)-2-oxazoline (HexOPhOx), or 2-(4-dodecyloxyphenyl)-2-oxazoline (DOPhOx) as a hydrophobic monomer [35,36]. The self-assembly of these gradient copoly(2-oxazoline)s has been used to formulate hypericin, a promising compound for photodiagnostics and photodynamic therapy [35]. The hypericin's loading capacity and entrapment efficiency did not change significantly with the increase in the length of the hydrophobic side-chain in the synthesized gradient copoly(2-oxazoline)s [35].…”