Targeted photodynamic therapy via receptor mediated delivery systems

Sharman, Wesley M.; Lier, Johan E. van; Allen, Cynthia M.

doi:10.1016/j.addr.2003.08.015

Cited by 348 publications

(259 citation statements)

References 101 publications

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“…12 To improve specificity, PSs have been coupled to targeting elements such as monoclonal antibodies 13 or other ligands. 14 Photosensitizers conjugated to whole antibodies can target a range of cancers 12 or pathogens 15 ; however, experiences so far has shown that many technical problems exist in coupling high numbers of PS to whole antibodies. These include impaired antibody binding, reduced solubility [16][17][18][19] and unfavorable pharmacokinetics due to the resulting high molecular weight of such photoimmunoconjugates (PICs).…”

mentioning

confidence: 99%

Targeted photodynamic therapy with multiply‐loaded recombinant antibody fragments

Bhatti

Yahioglu

Milgrom

et al. 2007

Intl Journal of Cancer

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Current photodynamic therapy (PDT) of cancer is limited by inefficiencies involved in specifically targeting photosensitizers to tumors. Although antibodies are being explored as targeting vehicles, they present significant challenges, particularly in terms of pharmacokinetics and drug-coupling. We describe here a novel and effective system to covalently attach multiple photosensitizer molecules (both preclinical, pyropheophorbide-a and clinically approved, verteporfin photosensitizers) to single-chain Fvs. Further, we demonstrate that not only do the resulting photoimmunoconjugates retain photophysical functionality, they are more potent than either free photosensitizer, effectively killing tumor cells in vitro and in vivo. For example, treatment of human breast cancer xenografts with a photoimmunoconjugate comprising an anti-HER-2 scFv linked to 8-10 molecules of pyropheophorbide-a leads to significant tumor regression. These results give an insight into the important features that make scFvs good carriers for PDT drugs and provide proof of concept of our unique approach to targeted photodynamic therapy (tPDT). This promises to significantly improve on current photodynamic therapies for the treatment of cancer. ' 2007 Wiley-Liss, Inc.Key words: photodynamic therapy; single chain Fv; pyropheophorbide-a; verteporfin Photodynamic therapy (PDT) is a minimally invasive procedure used in a range of conditions where superficially localized lesions such as age-related macular degeneration (AMD) or tumors need to be treated. 1 PDT is typically a 2-step process that involves the administration of a photosensitizer (PS) leading to marginal accumulation in the tumor. Following this, the PS is activated by exposure to light of an appropriate wavelength. This ultimately leads to the conversion of molecular oxygen into reactive oxygen species (ROS), primarily singlet oxygen, leading to tumor cell death via irreversible damage to cellular components such as proteins, lipids and DNA. 2 Current clinical use of PDT achieves efficacies similar to conventional therapies but with lower morbidity, simplicity of use and improved functional and cosmetic outcome. 3,4 PDT has mainly been used where conventional approaches have failed or were unsuitable. These include premalignant dysplastic lesions and noninvasive cancers, which are commonly found in the mucosa of the aerodigestive 5 and urinary tracts. 6 Success in treating these types of cancers has been achieved using Photofrin 1 , 7 Levulan 18 and Foscan 1 . 9 The most successful application of PDT has been for wet age-related macular degeneration (AMD) for which the photosensitizer verteporfin (Visudyne 1 ) has been used to destroy ocular neovasculature. 10 PDT has also had great successes in dermatology because of its impressive cosmetic outcome. Methyl 5-aminolaevulinate (Metvix 1 ) has been used to treat actinic keratosis with up to 90% cure. 11 Although PSs accumulate in cancer cells, the tumor specificity ratios are low and their inherent hydrophobicity, causes them to persist...

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confidence: 99%

Targeted photodynamic therapy with multiply‐loaded recombinant antibody fragments

Bhatti

Yahioglu

Milgrom

et al. 2007

Intl Journal of Cancer

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“…The first concerns the development of PDT systems to enhance the efficiency of delivery to target cells. Most (Hamblin and Newman, 1994;Klyashchitsky et al, 1994;Dolmans et al, 2003), but not all (Gijsens et al, 2002;Sharman et al, 2004) targeted PDT studies have used monoclonal antibodies as the address moiety. As the use of antibodies poses several practical limitations (Rihova, 1998), an alternate approach is to target a Tf -Ps conjugate to Tf receptors that are overexpressed on tumour cells (Faulk et al, 1980;Cavanaugh, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Photodynamic therapy is believed to mediate tumour cell destruction by at least two additional mechanisms: destruction of tumour vascular cells and the induction of both inflammatory and immune antitumour reactions (Dougherty et al, 1998;van Duijnhoven et al, 2003). The history, mechanism of action and biomedical applications of PDT have been the subject of several comprehensive reviews (Ceburkov and Gollnick, 2000;Dolmans et al, 2003;Brown et al, 2004;Sharman et al, 2004).…”

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confidence: 99%

“…First, whereas Pss tend to accumulate in tumour tissue, their clinical use is often associated with side effects such as cutaneous photosensitivity (Vrouenraets et al, 2003;Sharman et al, 2004). To overcome this problem investigators have covalently linked the Ps to carrier molecules so as to localise the PDT effect (Klyashchitsky et al, 1994;Vrouenraets et al, 2003).…”

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Intracellular chemiluminescence activates targeted photodynamic destruction of leukaemic cells

et al. 2006

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Photodynamic therapy (PDT) involves a two-stage process. A light-absorbing photosensitiser (Ps) is endocytosed and then stimulated by light, inducing transfer of energy to a cytoplasmic acceptor molecule and the generation of reactive oxygen species that initiate damage to cellular membrane components and cytolysis. The expanded use of PDT in the clinic is hindered by the lack of Ps targetcell specificity and the limited tissue penetration by external light radiation. This study demonstrates that bioconjugates composed of transferrin and haematoporphyrin (Tf -Hp), significantly improve the specificity and efficiency of PDT for erythroleukemic cells by a factor of almost seven-fold. Fluorescence microscopy showed that the conjugates accumulate in intracellular vesicles whereas free Hp was mostly membrane bound. Experiments with cells deliberately exposed to Tf -Hp at oLD 100 doses showed that surviving cells did not develop resistance to subsequent treatments with the conjugate. Furthermore, we show that the compound luminol induces intracellular chemiluminescence. This strategy was then used to obviate the use of external radiation for Ps activation by incubating the cells with luminol either before or together with Tf -Hp. This novel chemical means of PDT activation induced cytotoxicity in 95% of cells. These combined approaches provide an opportunity to develop broader and more effective applications of PDT.

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“…These conjugates named third generation PS are being the subject of extensive studies that have been reviewed recently (Sharman et al 2004). Photosensitizer conjugates with ligands selective to various cellular receptors, mostly over-expressed by tumor cells, have been prepared.…”

Section: Targeting With Photosensitizer Conjugatesmentioning

confidence: 99%

ROS: Reactive Oxygen Species

김윤미¹,

김영찬²,

정신교³

2013

Encyclopedia of Metalloproteins

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New therapies have been developed using reactive oxygen species produced by light-activation of photosensitizers (PS). Since the lifetime of these species is extremely short and their diVusion in space is limited, the photo-induced reactions primarily aVect the cell organelles labeled by the PS. In addition to the development of molecules with the best optical and photosensitizing properties, considerable research has been done to understand the physico-chemical parameters governing their subcellular localization. In this review, we examine these parameters to establish the structure/eYcacy relationships, which allow speciWc targeting of PS. We examine the eVect of subcellular localization on the cellular response to photosensitization processes. We discuss the determinants of subcellular localization, including the hydrophobic/hydrophilic balance, the speciWc charge eVects and the dynamics of PS' transfer through membranes. SpeciWc targeting can also be achieved with molecular structures able to recognize cellular or intracellular receptors, and this is also dealt with in this paper.

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Targeted photodynamic therapy via receptor mediated delivery systems

Cited by 348 publications

References 101 publications

Targeted photodynamic therapy with multiply‐loaded recombinant antibody fragments

Targeted photodynamic therapy with multiply‐loaded recombinant antibody fragments

Intracellular chemiluminescence activates targeted photodynamic destruction of leukaemic cells

ROS: Reactive Oxygen Species

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