Patenting Activities Related to Biomedical ...

Recent Patents on Nanomedicine, 2011, 1, 1-6

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Patenting Activities Related to Biomedical Applications of Fullerenes Tarek Baati1,2, Henri Szwarc3 and Fathi Moussa*,3 1

UMR CNRS 8612, Faculté De Pharmacie, Université Paris Sud XI, Rue J-B Clement-F92296 Chatenay-Malabry, France 2

Unité Elements Trace et Antioxydants, Laboratoire De Biophysique And Service D'anatomie et De Cytologie Pathologiques, CHU de Médecine De Monastir, 5000, France 3

Laboratoire d’Etude des Techniques et Instruments d’Analyse Moléculaire, EA 4041, IUT d’Orsay, Université Paris Sud XI, Plateau de Moulon, 91400 Orsay, France Received: 09 June 2011; Revised: 21 July 2011; Accepted: 31 July 2011

Abstract: Fullerene patents take advantage of the many very interesting biological properties of C60 and its derivatives to encompass a wide range of biomedical applications, including antiviral and anti-cancer ones. Some cosmetic applications have already reached the commercial area, but the main industrial potential of fullerenes in the medical field is still to be exploited. It is to be expected that certified toxicity data of each active derivative must be provided in order to boost this promising field.

Keywords: [60]fullerene, C60, patents, free radicals, antioxidant, imaging, drug delivery, targeting, photodynamic therapy, miscellaneous, HIV, fungal, cell death, aging. INTRODUCTION Since their discovery in 1985, fullerenes [1] (Fig. 1) attracted considerable attention in many areas of research including biology and medicine. After the development of a method of efficient synthesis [2] and the exploration of their physico-chemical properties [3], a number of studies showed that [60] fullerene or C60, the most abundant fullerene, and some of its derivatives have many very interesting biological properties including anti HIV protease activity, specific DNA cleavage, enzyme inhibition, free-radical scavenging, etc. [4, 5]. Furthermore the discovery of endohedral compounds opened the perspective towards their potential applications in imaging and radiotherapy [6]. All these potentialities can be attributed to some well described intrinsic properties of this molecule mainly including its geometry, its ability to scavenge a large number of free radicals [7] and its ability to sensitize singlet oxygen 1O2 formation after UV-Visible irradiation [2]. Preliminary investigations raised the hope that this molecule will lead to a large panel of new drug candidates and medical devices [4, 5]. A number of patents were filled in this area indeed. Combining Patentscope [8] and IFA databases [9], 124 out of 550 patents relate to biomedical applications, which are the subject of this review. Fig. (2) represents the comparison between the evolutions of patenting activities related to biomedical applications and total applications ranging from cosmetics to displays of solar cells.

*Address correspondence to this author at the Laboratoire d’Etude des Techniques et Instruments d’Analyse Moléculaire, EA 4041, IUT d’Orsay, Université Paris Sud XI, Plateau de Moulon, 91400 Orsay, France; Tel: +33 (0)1 69 33 61 31; Fax: +33 (0)1 69 33 60 48; E-mail: [email protected]

1877-9123/11 $100.00+.00

The first patents related to potential biomedical applications involve the synthesis of C60-derivatives with antiviral activity or photo-induced DNA specific cleavage. Then emerged those devoted the free-radical scavenging properties together with those for imaging and radiotherapy. Besides, some other applications were tackled from cosmetics to health water. In this review we will first summarize the patent activity related to C60-derivative synthesis before focusing on patents related to the prevention and treatment of free-radical related diseases as well as imaging and radiotherapy. A section will be devoted to miscellaneous applications before discussing the problems inherent to the use of these patents, including toxicological and environmental aspects. Our purpose is not to make an exhaustive survey of all existing patents. We shall only try to point out the general trends and the possible future evolution of the patenting activity related to fullerenes in the biomedical field. We are quite aware that there are also Russian and Asiatic patents but for language reasons they will not be considered in this review. PATENTS RELATED TO PURIFICATION, FUNCTIONALIZATION, AND SOLUBILIZATION OF FULLERENES [60] Fullerene is soluble only in a limited number of nonbiocompatible solvents, such as toluene, benzene, chloronaphtalène and dichlorobenzene [3-5]. Since fullerenes were macroscopically produced [2], the chemical functionalization of their surfaces, mainly through addition reactions [3], led to the production of a large variety of soluble derivatives with promising biological activities [4, 5]. As fullerenes are electrophilic, most reported derivatization reactions involve the addition of nucleophilic reagents [3]. First patents filed describe some processes of forming polysubstituted fullerenes. The most widely © 2011 Bentham Science Publishers Ltd.

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Baati et al.

(a)

R1

M

O OH

OH O

N H

HN HN

OHO O HO

O HO

O

O O

O O

O

O

O

OHO

N H

O

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OH O OH O HO O

HN

O HO O HO

O

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O OH

OH O OH O

O

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(c)

(b)

HN

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O HO

HO O

OH O

Fig. (1). (a) [60]Fullerene or C60, (b) [70]fullerene or C70, (c) a C60-derivative, (d) a endohedralfullerene (M@fullerene) and DF a dendrofullerene derivative.

recognized process of C60 functionalization is the nucleophilic addition, the so-called "Bingel" cyclopropanation reaction [10-21]. A patent related to the improvement of the cyclopropanation reaction was also filed in 2003 [11]. This invention provides improved methods for the derivatization, solubilization and purification of insoluble

fullerenes in general, from C60 to giant fullerenes and also endohedral fullerenes, carbon nanotubes and metal-carbon nano-encapsulates. One year later, another patent describing the synthesis of water-soluble dendrimeric fullerene derivatives was filed [22].

Biomedical Applications of Fullerenes

Recent Patents on Nanomedicine, 2011, Volume 1, No. 2 3

Fig. (2). Comparison between total patenting (NTot) activities evolution and patenting activities related to biomedical applications (N Bio).

The synthesis of a number of other derivatives with specific biomedical applications have also been patented (cf. List of Patents ). They will be considered together with their uses in the following sections. PATENTS RELATED TO THE FREE RADICALSCAVENGING PROPERTIES Due to its 30 carbon double-bonds, C60 is probably the most efficient free radical scavenger among all known chemical compounds [7]. A number of studies demonstrated the potential of water-soluble fullerene derivatives as freeradical scavenger in vitro as well as in vivo [4-5]. Since then fullerene derivatives have been proposed as antioxidants in a

large variety of free-radical related disorders from cell death to aging. Patenting related to free-radical scavenging properties represent the highest activities in the field [22-70]. It represents more than 38 % of total patenting activities related to biomedical applications of fullerenes (Fig. 3). Potential applications range from inhibiting cell death to prolonging life. Patenting activities in this field can be separated in two individualised sections. The first section [22-52] includes patents related to freeradical related diseases, mainly neuro-protection and lifeextension, treating neurodegenerative disorders including parkinsonism, and central nervous system (CNS)

Fig. (3). Patenting activities related to biomedical applications (PDT = photodynamic therapy).


Baati et al.

inflammation, psychosis, delirium, post-traumatic stress disorder or syndrome (PTSD/PTSS). This section also includes patents related to treating shock, wounds, inflammation and priritus, to inhibiting arterial plaque buildup and allergic response, and to ameliorating hearing loss, collateral damage of chemotherapy, or mucositis. Finally, some fullerene derivativatives were proposed to modulate nitric oxide synthase and calmodulin activity [27]. The second section [53-67] includes patents related to external compositions proposed as hair growth agents [66] and hair growth tonics [62] as well as cosmetics. Cosmetic compositions are proposed mainly as external antioxidant agents for preventing free-radical damages and as skin antiwrinkle [67], cellulite-controlling [58], and melanincontrolling [59] agents as well as anti-allergy fragrance agents [60]. Finally, fullerenes were also proposed as oil stabilizers [64]. Most of these patents are related to soluble fullerene derivatives. According to the authors, the antioxidant properties of these derivatives are mainly due to the freeradical scavenging activity of the C60-moiety. The freeradical scavenging effect remains valid for a number of C60derivatives with different addends, which indicates that this property is related to the C60 moiety [5]. Indeed C60 itself is a powerful anti-oxidant as demonstrated in different experimental models [71, 72]. A first patent related to using pristine C60 as antioxidant in vivo was filed in 2005 [68]. Since, some patents related to pristine C60 were filed, namely external compositions containing liposomes as fullerene carriers for in vivo delivery of fullerenes [69]. Although several experiments showed that C60 can efficiently scavenge a large variety of free radicals in vitro, the mechanism of the antioxidant action has never been demonstrated in vivo. C60 can act in vivo as a free-radical scavenger, however resulting C60 by-products have not been characterized yet in biological media [71]. Alternatively, C60 can act as a decomposition catalyst for O2-/H2O2, as it has been postulated for its tris-malonic acid derivatives [73]. PATENTS RELATED SPECTROSCOPY

TO

IMAGING

AND

Patenting activities related to imaging and NMR spectroscopy represent more than 12 % of total patenting activities (Fig. 3) [74-88]. Fullerene derivatives with internal (Endohedrals, Fig. 1) and external addends were proposed for X-Ray and MR imaging and NMR spectroscopy, respectively. Endohedral fullerenes (M@Fullerene) consist of fullerene cages that encapsulate atoms, clusters, or small molecules [89]. Typically, the encapsulated metal atom is an alkali metal, alkaline earth metal, Sc, Y, U, or a lanthanide metal. As the lanthanide elements play a dominant role in diagnostic and therapeutic medicine, several patents related to lanthanometallofullerenes applications in medicine were filed early [76-88]. Fullerenes that contain a paramagnetic lanthanide ion such as Gd3+ are believed to have a number of important advantages as MRI contrast agents. The paramagnetic lanthanide ion provides the unpaired electron density needed

to decrease the relaxation time of nearby H2O proton nuclei, while the fullerene cage, which is highly stable with respect to cage opening reactions in even the most extreme chemical environments, protects the lanthanide from chemical attack or dissociation and sequesters the toxicity of a naked lanthanide ion [89]. For all these reasons compositions for enhancing MRI and spectroscopy which involve perfluorinated fullerenes were proposed since 1992 for fluorine-19 imaging [74]. Incorporating paramagnetic metal species into the carbon cluster cage improves fluorine and proton imaging [74]. Iodinated empty or endohedral fullerenes were also proposed for X-ray imaging in 2001 [77]. Since then several patents related to MRI contrast agent-based fullerenes were filed including some derivatives devoted to imaging and targeting [88]. Finally, fullerenes were also proposed for molecular imaging including the detection, identification and/or sequencing of biomolecules such as nucleic acids or proteins by scanning probe microscopy [80-81]. PATENTS THERAPY

RELATED

TO

PHOTODYNAMIC

Fullerenes absorb strongly in the UV and moderately in the visible regions of the spectrum [4]. In general, the UV absorption of C60 derivatives is similar to that of C60. Singlet excited states of C60 (1C60) are initially formed upon light excitation. Very little fluorescence is observed for C60 and the lifetime of 1C60 is 1.3 ns. The predominant decay mode is an intersystem crossing to triplets. Quantum yield of triplet formation for 3C60 is almost unity [4]. This is explained by the relatively large spin orbit coupling of C60 due to its spherical geometry. The triplet lifetime of 3C60 in solution is 130 ps. Additionally, fullerene triplets can be formed indirectly using triplet sensitizers such as acridine and anthracene, and are quenched by triplet quenchers such as rubrene, tetracene, and ground state triplet oxygen (302) [4]. 3 C60 efficiently (almost 100%) sensitizes formation of 102, which makes fullerenes candidates for DNA cleavage and photodynamic therapy (PDT) [4]. The first patent related to DNA specific photo-induced cleavage was filed in 1996 [90]. Six years later, although fullerenes moderately absorb light in the visible spectrum, several patents related to using fullerenes for PDT were filed [91-102]. They represent about 10 % of the total patenting activity (Fig. 3). PATENTS RELATED TO TREATING INFECTIOUS AGENTS Based on molecular modeling, it was anticipated that a C60 molecule should fit into the hydrophobic cavity of the HIV-1 protease [103]. Since then, several patents related to inhibiting viral infection were filed [104-107]. Some other patents related to fungal treatment, removing environmental contamination as well as degrading chemical and biological contaminations were also filed [108-110]. These biological activities are, however, related to 1O2 sensitization.

Biomedical Applications of Fullerenes

Recent Patents on Nanomedicine, 2011, Volume 1, No. 2 5

Fig. (4). Patenting activities in the world (Local Russian and Asiatic patenting activities are not taken into account).

Patenting activities related to treating infectious agents represent about 6.5 % of the total patenting activities (Fig. 3). PATENTS RELATED TO DRUG DELIVERY AND TARGETING As fullerenes are electrophilic, they can be functionalized by reactions involving the addition of nucleophilic reagents. Possible poly-adduct formation together with their spherical geometry makes fullerenes suitable candidates for drug delivery and targeting. Patent activities in this field, including targeting cancer cells with endohedrals for radiotherapy, represent less than 7 % of total patenting activities (Fig. 3) [111-118]. MISCELLANEOUS In addition to patent activities related to the general physic-chemical properties of fullerenes, a number of patents related to some sometimes unexpected properties were also filed [119-138]. These activities are not negligible as they represent more than 16 % of the total activities (Fig. 3). Among the unexpected properties the most intriguing are the use of fullerenes to preparing nanoparticle-based anticoagulants [137] or for condensing DNA for gene therapy [120]. Due to their high absorption in the UV region, endohedral fullerenes having enclosed one or more ozone molecules were patented as UV absorbing agents for a wide range of applications [138]. Other patents include enzyme inhibition [135], fullerene based nanomaterials for bioremediation [136], fullerene based particles for determining the local temperature [131], fullerene based resin for medical equipment [133], low friction coatings for use in dental and medical devices [134]. Fullerenes were also patented as deodorant [132] as well as for producing light-polymerizable dental composition [125],

polymer for biocompatibility [122], catheter system having fullerenes [121], fullerene coated surfaces for cell culture [119], coating that promotes endothelial cell [123] adherence and light emitting film coated fullerene for in vivo light emission and as well as fullerene-based MALDI matrices for peptides and proteins [129]. Finally, patents related to producing antibodies specific for fullerenes were also filed in 2001 and 2003 [124, 126-128]. CURRENT AND FUTURE DEVELOPMENT Fullerene patents encompass a wide range of interesting biomedical applications. The strongest patenting activities occurred in the late 2000 and most patents were filed in USA (Fig. 4). This seems to be related to the National Nanotechnology Initiative (NNI) [139], but the industrial potential of fullerenes in the medical field is still to be exploited. The main hurdle arises from the alleged danger of C60 and nanotechnologies, probably due to the NNI itself, which initially neglected the toxicological and the environmental aspects of nanomaterials [140]. Although several academic studies confirmed the safety of pristine C60 itself [141-143], some papers continue to fuel doubt [144]. To cross this hurdle, certified toxicological data are needed for each new compound as new safety rules demand [145]. For the time being fullerene patenting activities follow the same trends as was described in 2008 [146]. As fullerenes and some derivatives have moderate to null toxicity together with interesting biomedical properties [4, 5, 141], we can predict that when certified toxicity data is provided patenting and industrial activities for these unique materials will start and develop. For 2011 eleven patents, which are obviously not taken into account in the presented statistics, were filed [147-157]. Compared to previous years (Fig. 2), this seems to indicate a renewal of the patenting activity, but the general trend remains nearly the same than previously including, cancer targeting [147], imaging [149-


151], cosmetics [152], drug delivery [154, 155], and bioremediation [156]. One of these patents copes with a new application, namely beta-blocking activity [148]. Although it does not concern the biomedical field a recent patent on genetic plant transformation deserves to be quoted here because of its potential implication [157]. CONFLICT OF INTEREST The authors, who are academic teacher-researchers (French government employees); certify that they have no conflict of interest.

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