Photoactivation switch from Type II to Type I reactions by electron-rich micelles for improved photodynamic therapy of cancer cells under hypoxia

Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States.
Journal of Controlled Release (Impact Factor: 7.71). 08/2011; 156(3):276-80. DOI: 10.1016/j.jconrel.2011.08.019
Source: PubMed


Photodynamic therapy (PDT) is an emerging clinical modality for the treatment of a variety of diseases. Most photosensitizers are hydrophobic and poorly soluble in water. Many new nanoplatforms have been successfully established to improve the delivery efficiency of PS drugs. However, few reported studies have investigated how the carrier microenvironment may affect the photophysical properties of photosensitizer (PS) drugs and subsequently, their biological efficacy in killing malignant cells. In this study, we describe the modulation of type I and II photoactivation processes of the photosensitizer, 5,10,15,20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP), by the micelle core environment. Electron-rich poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) micelles increased photoactivations from type II to type I mechanisms, which significantly increased the generation of O(2)(-) through the electron transfer pathway over (1)O(2) production through energy transfer process. The PDPA micelles led to enhanced phototoxicity over the electron-deficient poly(D,L-lactide) control in multiple cancer cell lines under argon-saturated conditions. These data suggest that micelle carriers may not only improve the bioavailability of photosensitizer drugs, but also modulate photophysical properties for improved PDT efficacy.

Download full-text


Available from: Ying Dong
  • Source
    • "It is preferred over surgical resection because it is noninvasive , as is the case for radiotherapy. PDT, established in the 1970s, is based on the interaction of light with photosensitive agents known as photosensitizers that preferentially accumulate in target cells and produce energy transfer and a local chemical effect (Ding et al. 2011). After exposure to specific wavelengths of light, the photosensitizer is excited from the ground state to the singlet state, then undergoes type I (electron transfer) and/or type II (energy transfer) reactions to produce reactive oxygen species (ROS), resulting in necrosis and/or apoptosis of exposed cells Pass (1993). "
    [Show abstract] [Hide abstract]
    ABSTRACT: 5-Aminolevulinic acid (ALA) is a photosensitizer used in photodynamic therapy (PDT) because it causes preferential accumulation of protoporphyrin IX (PpIX) in tumor cells, where it forms singlet oxygen upon light irradiation and kills the tumor cells. Our previous study demonstrated that PpIX enhances generation of reactive oxygen species by physicochemical interaction with X-rays. We investigated the effect of ALA administration with X-ray irradiation of mouse B16-BL6 melanoma cells in vitro and in vivo. ALA facilitates PpIX accumulation in tumor cells and enhances ROS generation in vitro. Tumor suppression significantly improved in animals treated with fractionated doses of radiation (3 Gy × 10; total, 30 Gy) with local administration of 50 mg/kg ALA at 24 h prior to fractional irradiation. These results suggest ALA may improve the efficacy of cancer radiotherapy by acting as a radiomediator.
    Full-text · Article · Nov 2013 · SpringerPlus
  • Source
    • "Further, Zhou et al. 44 synthesized micellar nanocarriers containing pH-sensitive tetramethyl rhodamine dye which gives increased fluorescence emission within 5 minutes of pH activation, due to increased fluorophore release. Interestingly, PEG-based electron-rich micelles containing the photosensitizer 5,10,15,20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP) synthesized by Ding et al. 45 can generate increasing amounts of O2·− by the energy transfer process, thereby competing with 1O2 production under hypoxic conditions. This results in increased photoactivation, resulting in greater phototoxicity when exposed to hypoxic cancer cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Photo-based diagnosis and treatment methods are gaining prominence due to increased spatial imaging resolution, minimally invasive modalities involved as well as localized treatment. Recently, nanoparticles (NPs) have been developed and used in photo-based therapeutic applications. While some nanomaterials have inherent photo-based imaging capabilities, others including polymeric NPs act as nanocarriers to deliver various fluorescent dyes or photosensitizers for photoimaging and therapeutic applications. These applications can vary from Magnetic Resonance Imaging (MRI) and optical imaging to photothermal therapy (PTT) and chemotherapy. Materials commonly used for development of photo-based NPs ranges from metal-based (gold, silver and silica) to polymer-based (chitosan, dextran, poly ethylene glycol (PEG) and poly lactic-co-glycolic acid (PLGA)). Recent research has paved the way for multi-modal 'theranostic' (a combination of therapy and diagnosis) nano-carriers capable of active targeting using cell-specific ligands and carrying multiple therapeutic and imaging agents for accurate diagnosis and controlled drug delivery. This review summarizes the different materials used today to synthesize photo-based NPs, their diagnostic and therapeutic applications as well as the current challenges faced in bringing these novel nano-carriers into clinical practices.
    Full-text · Article · Feb 2013 · Theranostics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer caused human death. In this work, we selected oncogene mouse double minute 2 (MDM2) as a therapeutic target for NSCLC treatment and proposed that sufficient MDM2 knockdown could inhibit tumor growth via induction of cell cycle arrest and cancer cell apoptosis. On this regard, a new pH-responsive diblock copolymer of poly(methacryloyloxy ethyl phosphorylcholine)-block-poly(diisopropanolamine ethyl methacrylate) (PMPC-b-PDPA)/siRNA-MDM2 complex nanoparticle with minimized surface charge and suitable particle size was designed and developed for siRNA-MDM2 delivery in vitro and in vivo. The experimental results showed that the nanoparticles were spherical with particle size around 50 nm. MDM2 knockdown in p53 mutant NSCLC H2009 cells induced significant cell cycle arrest, apoptosis and growth inhibition through upregulation of p21 and activation of caspase-3. Furthermore, the growth of H2009 xenograft tumor in nude mice was inhibited via repeated injection of PMPC-b-PDPA/siRNA-MDM2 complex nanoparticles. These results suggested that PMPC-b-PDPA/siRNA complex nanoparticles targeting a unique set of oncogenes could be developed into a new therapeutic approach for NSCLC treatment.
    No preview · Article · Jan 2013 · Biomaterials
Show more