Elsevier

Journal of Controlled Release

Volume 156, Issue 3, 20 December 2011, Pages 276-280
Journal of Controlled Release

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

https://doi.org/10.1016/j.jconrel.2011.08.019Get rights and content

Abstract

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 O2radical dot through the electron transfer pathway over 1O2 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.

Graphical abstract

Table of Content Graphics: The electron-rich mTHPP-PDPA micelles resulted in the increase of type I photoactivation reactions and higher phototoxicity in multiple cancer cells under hypoxic conditions.

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Section snippets

Concept and hypothesis

Photodynamic therapy (PDT) is an emerging clinical modality that has received considerable attention for the treatment of cancer, cardiovascular, dermatological, and ophthalmic diseases [1], [2], [3]. PDT has three essential elements: a photosensitizer (PS), light and oxygen. New photosensitizing drugs based on porphyrins and chemically related compounds such as chlorins and phthalocyanines have been under extensive investigations [4], [5]. Most photosensitizers are hydrophobic and poorly

Preparation of mTHPP-loaded micelles

PEG-b-PDPA and PEG-b-PLA copolymers were synthesized using atom transfer radical polymerization (ATRP) [23] and ring-opening polymerization [24] methods, respectively. The PEG segments in both copolymers were controlled at 5 kD. The PDPA and PLA segments were controlled at 10 kD. mTHPP-loaded PEG-b-PLA (mTHPP-PLA) and PEG-b-PDPA (mTHPP-PDPA) micelles were produced using a solvent evaporation method [25]. Briefly, a proper amount of the copolymer was first dissolved in tetrahydrofuran (THF) with

Conclusions

In summary, we report the development of a novel PS nanoparticle formulation that confers greater PDT cytotoxicity against cancer cells under hypoxic conditions. The photophysical and photodynamic properties of mTHPP are highly dependent on the micelle core environment. With the electron-donating PDPA segment, the generation of O2radical dot through the electron transfer pathway competes with 1O2 production through the energy transfer process under aerobic environments, and becomes dominant under hypoxic

Acknowledgement

This research is supported by the National Cancer Institute to JG (R01CA122994 and R01CA129011) and to DAB (R01CA102792) and the National Center for Research Resources to BDS (5 UL1 RR024982-02). This is manuscript CSCN060 from the Program of Cell Stress and Cancer Nanomedicine in the Simmons Cancer Center. We thank Yanhong Liu at Technical Institute of Physics and Chemistry, CAS for assistance with ESR studies, Kejin Zhou for helpful discussions, and Vikram Kodibagkar and Praveen Gulaka for

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