PLASMON PHOTOTHERMAL TREATMENT OF SKIN CANCERS WITH EXTENSIVE LESIONS USING GOLD NANOPARTICLES

Abstract

The invention relates to the field of skin tumor treatment. More specifically, the invention concerns the use of gold nanoparticles to treat skin tumors with a volume greater than or equal to 500 mm³. The invention is based on the administration of gold nanoparticles directly into the tumor followed by near-infrared laser irradiation. The combination of gold nanoparticles and plasmonic phototherapy, in repeated treatments at 11- to 17-day intervals, allows for the complete disappearance of a skin tumor with extensive lesions, without recurrence.

Description

Title of the invention: PLASMONIC PHOTOTHERMAL TREATMENT OF SKIN CANCERS WITH EXTENSIVE LESIONS USING GOLD NANOPARTICLES

[0001] The invention relates to the field of skin tumor treatment. More particularly, the invention concerns the use of gold nanoparticles to treat skin tumors with a volume greater than or equal to 500 mm³. The invention is based on the administration of gold nanoparticles directly into the tumor followed by near-infrared laser irradiation. The combination of gold nanoparticles and plasmonic phototherapy, in repeated treatment at 11- to 17-day intervals, allows for the complete disappearance of a skin tumor with extensive lesions, without recurrence. Scope of the invention

[0002] Skin cancers, particularly multi-lesional basal cell carcinomas (BCCs), are prevalent on sun-exposed areas of skin, especially the arms, face, and back. Currently, the first-line treatment remains surgical resection or Mohs surgery. Despite its complexity, Mohs surgery is well-practiced in the United States and Germany and yields very good results in terms of both therapeutic efficacy and cosmetic outcome.

[0003] This type of lesion can also be treated by photodynamic therapy, but large lesions of more than 2 cm remain difficult to eliminate with the topical cream used in photodynamic therapy (PDT).

[0004] A recent study demonstrated the efficacy of near-infrared (NIR) laser photothermal therapy using gold nanoparticles to treat small basal cell carcinomas, specifically those with a volume of 50 mm³. The nanoparticles used in this study were obtained through a green chemistry process using an extract of the plant Hubertia ambavilla. This treatment consisted of two injections of nanoparticles three days apart, with the volume of solution injected during the first administration being equivalent to 20% of the tumor volume and that of the second administration being equivalent to 100% of the tumor volume. This treatment resulted in complete tumor regression without recurrence (S. Pesnel, JEADV Clin. Pract. 2013;1-9).

[0005] Hubertia ambavilla is an endemic plant native to Réunion Island in the Indian Ocean, traditionally used both internally and externally. The main compounds of Hubertia ambavilla are flavonoids, tannins, proanthocyanidins, and a carbohydrate complex, leading to therapeutic activities for the skin such as anti-inflammatory and healing properties, as well as other therapeutic activities used to treat kidney infections, asthma, and diabetes. Disadvantages of the state of the art

[0006] Surgical resection has the disadvantage of leaving unsightly scars, especially when the tumor is extensive. It is not suitable for treating inaccessible, unresectable lesions. Furthermore, it requires a high level of expertise on the part of the surgeon for proper execution of the surgical procedure and successful treatment, expertise that is not available to many patients.

[0007] Photodynamic therapy is a topical application, acting on the surface, and does not allow for the effective deep treatment of large lesions larger than 2 cm. The risk of tumor recurrence is high.

[0008] The treatment of extensive tumor lesions is a function of the initial tumor volume, and correlated with the angiogenic control of the tumor (Hahndeldt P. Cancer research 59, 4770-4775, October 1, 1999).

[0009] There is an unmet medical need for a reliable and widely accessible treatment for extensive skin tumors, which are particularly difficult to treat. Description of the invention

[0010] The objective of the present invention is to provide an alternative treatment to surgery that allows for the complete regression of large skin lesions in less than one month and without recurrence. This is the first non-invasive treatment for such tumors.

[0011] The proof of concept of the proposed treatment was validated by the inventors through a detailed study in the experimental part of this text and summarized below.

[0012] Methods: Tumor induction in a murine model by injection of human skin tumor cells. Treatment of mice bearing a 500 mm³ subcutaneous tumor by administration of an increasing dose of gold nanoparticles at a fixed initial concentration C0 = 0.3 mg / mL, perfused into the tumor, followed by exposure of the region of interest to a NIR medical laser to evaluate the therapy. One or two intratumoral administrations were compared to surgery and to the control, i.e., no treatment, laser alone, or nanoparticles alone.

[0013] Results: Gold nanoparticles alone or the NIR laser alone did not induce tumor regression. The combination of the laser and nanoparticles, called plasmonic nanophotothermal therapy (PPTT), induced apoptosis. The dermis and The hypodermis treated in this way did not show any visible gold nanoparticles and showed good healing.

[0014] Conclusion: Plasmonic nanophotothermal therapy using two doses of gold nanoparticles was the only treatment method for the disease that proved effective on large lesions, i.e. 500 mm3, on a murine model bearing a basal cell carcinoma of human origin, and this in 14 days.

[0015] On this basis, the present invention relates to the use of a gold nanoparticle coated with glucose for the treatment of a skin tumor with a volume greater than or equal to 500 mm3.

[0016] This treatment represents a significant advance in the treatment of large skin tumors since it allows the definitive regression of the tumor through the administration of gold nanoparticles into the tumor followed by NIR irradiation of the tumor area, this sequence being repeated 10 to 17 days after the first irradiation. Advantages of the invention

[0017] As defined and validated in a preclinical model, this treatment allows complete regression of skin tumors with a volume of 500 mm3 in 2 weeks by implementing a photothermal therapy protocol involving at least two injections of gold nanoparticles.

[0018] The efficacy and originality of the treatment lie in the deep physical destruction of the cells constituting the tumor mass, through a combination of nanoparticles administered directly into the tumor followed by irradiation of these nanoparticles with a NIR laser. The invention relates to a new therapeutic approach for large skin tumors, which present a particular therapeutic challenge. Indeed, this type of extensive lesion (tumor volume of 500 mm³ and more) is difficult to treat, and the solution proposed by the inventors allows for the physical destruction of tumor cells by heat induction. When tumors are aggressive, this approach makes it possible to act quickly and effectively to stop tumor growth and limit the risk of metastasis.When the tumor is extensive but not very aggressive, plasmonic photothermal therapy according to the present invention can be used alone or as neoadjuvant therapy to surgery.

[0019] Following treatment, an improvement in skin microrelief is observed compared to the scars remaining after surgical resection, which is particularly interesting from an aesthetic point of view due to the extent of the treated lesions. DETAILED DESCRIPTION OF THE INVENTION

[0020] The invention relates to the use of a glucose-coated gold nanoparticle in the treatment of a skin tumor with a volume greater than or equal to 500 mm3

[0021] The use of gold nanoparticles (AuNPs) in medicine is well known and their safety has been demonstrated. The gold nanoparticles according to the invention are coated with glucose and accumulate in tumor cells due to the overexpression of GLUT1 and GLUT3 receptors in these cells. The surface of the AuNPs is coated with glucose by simple contact with a glucose solution.

[0022] The NPAu according to the invention preferably have a diameter less than or equal to 20 nm as measured by transmission electron microscopy (TEM) and are spherical. Most preferably, the NPAu have a diameter of 15 nm.

[0023] In a particular embodiment of the invention, the NPAu are obtained by mixing gold with a flavonoid-rich plant extract. Preferably, the plant extract is derived from Hubertia ambavilla. Advantageously, the processes used to obtain the NPAu comply with the principles of green chemistry; they are environmentally friendly and eco-responsible.

[0024] For use, NPAu must be suspended in an aqueous solution. This solution may be physiological saline, a 0.9% NaCl solution, or PBS (phosphate-buffered saline). The NPAu concentration in the solution is between 0.2 and 0.6 mg / ml, preferably between 0.3 and 0.5 mg / ml, or even between 0.3 and 0.4 mg / ml.

[0025] The treatment of skin tumors with NPAu according to the invention is achieved by photothermal ablation, preferably by exposing said tumor to plasmonic phototherapy. Such phototherapy consists of continuous NIR laser irradiation at a wavelength between 755 and 1064 nm, at a power between 0.5 and 2 W / cm² for a duration of 5 to 20 min. In a particular embodiment of the invention, the irradiation is carried out at a wavelength of 808 nm at a power of 1 W / cm² for 10 min. NIR irradiation makes it possible to reach the hypodermis where the tumor cells are located. As this type of laser is well tolerated by the skin, this treatment does not cause surface lesions.The inventors have validated the fact that, after treatment, the skin surface at the site of the tumor has a less pronounced microrelief than after surgery, and scarring is less visible, which is of interest in the case of large lesions, generally located on visible and exposed areas of the skin.

[0026] In order to induce the destruction of tumor cells, the administration of NPAu is carried out intradermally, more precisely into the tumor mass, i.e., intratumorally. This protocol, implemented by the inventors, is the only A method exists to obtain a sufficient quantity of NPAu at the tumor site, thus enabling the thermal effect of over 10°C required for the physical destruction of cells by heat. The cells are destroyed by apoptosis. The intravenous route conventionally used in phototherapy would prove ineffective because the NPAu would be too diluted and the concentration insufficient at the intratumoral site.

[0027] The volume of NPAu solution to be injected into the tumor mass is also an important parameter for the success of the therapy. It has been determined that the volume of NPAu solution should be between 5% and 40% of the tumor volume, preferably between 15% and 30%. In a preferred embodiment, the injected volume is equivalent to 20% of the tumor volume.

[0028] Furthermore, in order to achieve definitive tumor eradication, it is necessary to repeat the treatment sequence, namely (i) administration of the NPAu solution followed by plasmonic phototherapy (NIR irradiation), at least twice. Indeed, after a single treatment sequence, tumor growth resumes. This repetition of the treatment must occur when the tumor mass is visible (to allow for intratumoral injection). This repetition takes place between 11 and 17 days after the first treatment sequence. The volume of NPAu solution is between 5% and 40% of the tumor volume for each NPAu administration.

[0029] The treatment according to the invention therefore consists of the administration of at least two doses of NPAu; these administrations being separated by 11 to 17 days.

[0030] In practice, when a skin tumor is detected and its volume is greater than or equal to 500 mm3, the photothermal treatment according to the invention can be applied, namely: - Step 1: Intratumoral administration of NPAu covered with glucose, in particular with an NPAu solution having an NPAu concentration between 0.2 and 0.6 mg / ml - Step 2: Photothermal treatment, for example by continuous NIR laser irradiation at a wavelength between 755-1064 nm, at a power between 0.5 and 2 W / cm² for a duration of 5 to 20 min, administering an amount of NPAu solution between 5% and 40% of the tumor volume - Step 3: Repeat steps 1 and 2 between 11 and 17 days after completing said steps 1 and 2.

[0031] The treatment according to the invention makes it possible to treat skin tumors with a volume greater than or equal to 500 mm³, and in particular melanomas, basal cell carcinomas, and squamous cell carcinomas. This treatment aims to treat, in particular, tumors having a volume between 500 mm3 and 2 cm2. It can be considered as the main treatment of the tumor or as a neoadjuvant, for example, to surgery or immunotherapy.

[0032] Depending on national patent legislation and in particular before patent offices for which therapeutic or surgical treatment methods are excluded from the scope of patentability, it is understood that references to therapeutic or surgical treatment methods or to in vivo diagnostic methods in this description should be interpreted as references to the compounds, pharmaceutical compositions and drugs which are the subject of the present invention for the implementation of one of these methods. DESCRIPTION OF THE FIGURES

[0033] [Fig. 1] [Fig. 1]: Protocol for administering plasmonic photothermal therapy (PPTT)

[0034] [Fig.2][Fig.2]: Effects of NPAu@G administration in the tumor and of laser irradiation on the body weight of mice bearing subcutaneous xenografts of human CBC.

[0035] [Fig.3] [Fig.3]: Mean ± SEM quantity of NPAu@G in the spleen, liver, kidneys, quadriceps, brain, heart, lungs, tumor, tissue around the tumor on the skin side, tissue around the tumor on the peritoneal side and blood as a percentage of the total amount injected after a single intratumoral administration of NPAu@G (0.3 mg gold / mL, 20% of tumor volume), in female C57BL6 mice inoculated with 5 x 105 B16F10 melanoma cells.

[0036] (J: day after IT injection).

[0037] [Fig.4] [Fig.4]: Efficacy of TSK01 treatment after one or two nanoparticle injections followed by NIR laser a) with a TV of 20% of the injected NPAu@G nanoparticles or b) with a TV of 40% of the injected nanoparticles.

[0038] [Fig.5][Fig.5]: Survival curve of mice as a function of the treatment received

[0039] [Fig.6] [Fig.6]: Regression of tumor volume during the first injection of nanoparticles at 20% of the TV injection

[0040] [Fig.7] [Fig.7]: Tension index measured using Silflo® resin for Analyze the skin's microrelief and study the impact of treatments on the skin. EXAMPLES

[0041] EXAMPLE 1: SYNTHESIS OF GOLD NANOPARTICLES ACCORDING TO THE INVENTION (AuNPs) Preparation of a crude total plant extract

[0042] Hubertia ambavilla which is a shrub endemic to the island of Réunion.

[0043] Freshly harvested plants are washed with deionized water. Three grams are mixed with 50 mL of deionized water, and the mixture is then heated to 60°C for 5 minutes, which releases the biological material through lysis of the plant cells. The supernatant is then cooled to room temperature and then over hanging ice for 10 minutes. The cooled supernatant is then filtered through a grade 2 pore size filter. No organic solvents are used in this preparation.

[0044] Isolation of the total number of plant flavonoids

[0045] The extraction method used is a cold maceration method. The plants are crushed on a 10 mm diameter sieve and then macerated under agitation at 150 rpm for 20 hours at room temperature. A mixture of equal parts water and ethanol is added to the mixture in a solid / solvent ratio of 1:20 to obtain the best possible yield of phenolic compounds. After extraction, the macerates are filtered, dried at low pressure (maximum bath temperature: 45°C, pressure between 50 and 150 bar), and then freeze-dried for 48 hours.

[0046] Preparation of spherical gold nanoparticles by mixing with a total of flavonoids extracted from Hubertia ambavilla plants

[0047] Tetrachloroauric acid (HAuCLO, Ie G-glucose were purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

[0048] 4 mL of an aqueous solution of total flavonoids are refluxed under stirring The solution is stirred vigorously in a two-necked round-bottom flask fitted with a reflux condenser, protected from light. When fine droplets appear on the walls, 4 mL of an aqueous HAuC14 solution is added very rapidly. The solution then quickly turns reddish-brown within 1 minute. The flask is then removed from the oil bath, and the solution is stirred vigorously for an additional 15 minutes. Finally, the solution is kept at 4°C, protected from light.

[0049] The nanoparticles obtained have a diameter measured by TEM of approximately 15 nm.

[0050] A specific molar ratio between the reactants allows for the production of spherical gold nanoparticles. This ratio is as follows: n(flavonoids) / n(HAuC14) = 21

[0051] An aliquot of AuNP solution is mixed with the same volume of D-Glucose under vigorous stirring for 1h at room temperature. The resulting solution is centrifuged and resuspended in a 0.9% NaCl solution.

[0052] The nanoparticles thus obtained are named AuNP@G in the experimental part and the figures. Furthermore, the description mentions "NPAu" which corresponds to the therapeutic NPAu coated with glucose.

[0053] EXAMPLE 2: EVALUATION OF THE ANTITUMORAL EFFECT OF GOLD NANOPARTICLES ACCORDING TO THE INVENTION COMBINED WITH PLASMON PHOTOTHERMAL TREATMENT (PPTT) A - MATERIALS AND METHODS Cell culture

[0054] The TE 354.T cell line was used. The human basal cell line was purchased from ATCC (ATCC® CRL-7762™) and cultured in DMEM supplemented with 10% heat-inactivated fetal bovine serum, 50 U / ml penicillin, and 50 pg / ml streptomycin. The cell line was maintained at 37°C in 5% CO2 and 95% air in an air chamber under a humidified atmosphere. Animals and tumor model

[0055] Seven-week-old nude BALB / c female mice were used. The animals were reared in plastic cages within a controlled environment on a ventilated shelf with free access to food and water. All experiments were conducted in accordance with national animal care guidelines (EC Directive 86 / 609 / EEC, French Decree No. 87-848). Tumor xenografts were obtained by subcutaneous injection of a tumor cell suspension (1 x 10⁶ cells in 100 µl of 0.9% NaCl) into the right flank. To assess tumor growth, the tumor volume (V in mm³) was measured using calipers and calculated as follows: V = (length x width x thickness) / 1. Photothermal therapy (PTT)

[0056] Mice were anesthetized with 2.5% isoflurane and a subcutaneous injection of buprenorphine (0.1 mg / kg) was administered prior to the injection of the nanoparticles. Tumors were then measured, and the AuNP@G were injected into the center of the tumor using a 31G insulin syringe. One hour later, the mice were placed under the medical laser (Hyper Diode 808, Hyper Photonics, Italy) for treatment. The treatment administration protocol is summarized in [Fig. 1].

[0057] When the tumors reached a volume of 500 mm3 ± 21% (Day 0), the mice were randomly divided into 9 groups (4 mice per group). In the "control" group (Ctrl), the mice were not treated; in the "Laser" group, 0.9% NaCl (injected volume = 20% of the tumor volume) was injected into the tumor, and then the anesthetized mice received photothermal plasmonic therapy (PPTT). The group that received AuNP@G was split into two different cohorts that received: either one dose on Day 0 (injected volume = 20% of the tumor or 40%), or two doses of AuNP@G (injected volume = 20% on Day 0 and Day 14); OD = 6 and OD = 12 corresponding to 0.3 and 0.6 mg / ml respectively); The injections were performed into the tumor, and then the anesthetized mice received PPTT. Tumor irradiation was performed 1 hour after the injection of 0.9% NaCl or AuNP@G.

[0058] For the evaluation of the antitumor effect, the mice were weighed and the tumors were measured every 3 days until the death of the mice or until the tumor volume reached 1500 mm3 or the weight loss was greater than 20% of the initial weight.

[0059] The plasmonic photothermal treatment consisted of laser irradiation of the tumor, with the following parameters:

[0060] - Wavelength: 808nm

[0061] - Power: 1 W / cm2 (5W with the 25mm probe)

[0062] - Visit duration: 10 min

[0063] - Irradiated surface area: 4.9 cm² (probe diameter: 2.5 cm)

[0064] Experimental protocols for the in vivo evaluation of plasmonic photothermal activity after injection of AuNP@G

[0065] [Tables 1] Effect of the laser power (WfemT) (Group Oose OsNP Vote) (Affect anSÉURWaï of differentiable tastemsrsis with 1 - - 2 Laser rie >• In ta 1 3 CspnMg. MP 12 - 4 PTT 0.3 mg / mJ 40 6 S PTT 0.6 rhg / ml 40 12 1 6 PTT 0.3 nsg / rnl 20 a 7 PTT 0.6 mg / ml 20 12 8 PTT 0.3 mg / mJ 20 2 6 Comparison with te of teférsHœ 9 fîhTsM'S.

[0066] Table 1: Description of mouse groups for in vivo evaluation of plasmonic photothermal activity

[0067] [Tables2] Peender Group Treatment Second treatment Day NP volume (% of tumor volume) Laser power Laser probe (mm) Day NP volume (% of tumor volume) Laser power (W / cm*) Laser probe (mm) 1 0 - 1 25 14 1 25 4 S 40 1 25 5 0 40 1 25 6 0 20 1 25 7 S 20 1 25 8 0 20 1 25 14 20 1 25

[0068] Table 2: Description of treatments applied to the different groups Surgery: tumor resection

[0069] On day 0, some mice underwent tumor resection with a margin of 3 mm then the skin was sutured. Assessment of toxic side effects

[0070] Maximum weight loss or gain, expressed as a percentage of the initial body weight of the experimental animals, was used to assess the toxicity of AuNP@G. According to the NCI (National Cancer Institute), a dose is considered toxic if the induced body weight loss exceeds 20% of the mouse's initial body weight. It should be noted that these weights also include tumor weight, which increases over time.

[0071] Evaluation of antitumor activity / Tumor growth

[0072] The efficacy of the treatment was evaluated in terms of the effects of the compound on tumor volume for PTT-treated mice compared to control mice.

[0073] Two evaluation criteria were used in parallel: (i) growth inhibition, calculated as the ratio of the median tumor volume of the AuNP@G treated groups to the control groups: T / C, % = (median tumor volume of the AuNP@G treated groups on day X / median tumor volume of the control group on day X) x 100, the optimal value being the minimum T / C ratio that reflects the maximum tumor growth inhibition achieved; (ii) relative area under the tumor growth curve, rAUC (%), representative of the tumor growth curve as a whole, reflects the overall effect of a tested compound over time. rAUC = [(area under the growth curve of the tumor volume of the treated group / area median under the tumor volume growth curve of the control group) x 100]. The more active the compound, the lower the rAUC value.

[0074] Tumor volume was monitored by measuring tumors using a digital caliper and according to the following formula: (L x 1 xe) / 2.

[0075] Histological analysis was performed at different times after treatment (21 days, 3 months and 6 months) on mice with complete regression and on operated mice to confirm the absence of tumor.

[0076] Comparison with surgery (reference treatment) - Measurement of the tension index

[0077] Skin impressions were taken with Silflo® resin to analyze the microrelief of the skin and to study the impact of treatments (PPTT and surgery) on the skin. Statistical analysis

[0078] The data are presented as mean ± STD. Statistical analysis was performed using GraphPad 8.0. B - RESULTS

[0079] Mice bearing basal cell carcinoma (BCC) under treatment did not show significant weight loss (the toxicity limit set by the NCI is -20%) ([Fig. 2]), and no clinical signs of toxicity were observed except in groups 4 and 5, which correspond to the injection of NP at 40% of the tumor volume (Table 2). Indeed, in these two groups, significant weight loss was observed, and necropsies showed intestinal burns. While some disagreements remain regarding the greater efficacy of one method or the other in vitro, all studies seem to agree that PTT will induce more apoptosis if continuous irradiation is used, and conversely, PTT treatment will induce more necrosis in the case of pulsed irradiation.

[0080] However, necrosis leads to significant destructive local inflammation, thus creating a microenvironment conducive to the development of potentially surviving cancer cells. In this study, laser irradiation is applied continuously to promote apoptosis of tumor cells.

[0081] Biodistribution studies of nanoparticles have shown that the majority of injected nanoparticles are present in the tumor for up to 7 days. Very few are observed in adjacent tissues and other organs from 1 to 16 days, as shown in [Fig. 3].

[0082] [Tables3] Maximum median weight variation group: XW Presumed deaths related to h iiiiiiiiiiii 4 -20.2 20 5 -21.4 20 2 6 -2.6 o- 0 7 ■1.2 0 0 8 -L3 0 0

[0083] Table 3: Monitoring of weight loss in mice treated with AuNP@G + PPTT injection

[0084] Figure 4 shows the tumor size monitoring curves when varying either the concentration or the injection volume. Partial tumor regression is observed from 1 to 14 days after injection, followed by an increase in tumor volume at 14 days. A single injection of 20% nanoparticles is not sufficient to induce complete tumor regression but demonstrates the absence of toxicity, whereas a 40% injection appears toxic, as shown in Figure 4b. Injection of two doses of nanoparticles at 20% of tumor volume leads to complete regression, without recurrence.

[0085] The [Fig.5] is the survival curve showing the highest survival rate for the surgery group, followed by the group that received two doses of nanoparticles and 20% of TV by injection.

[0086] The effects of plasmonic photothermal treatment on tumor volume in a mouse bearing a subcutaneous xenograft of human BCC were observed before treatment and 3, 14, and 21 days after treatment. Before treatment, the tumor was clearly visible. Three days after treatment, the tumor mass had completely disappeared, leaving smooth skin. The tumor was again visible at 14 days and larger at 21 days (photos not shown).

[0087] Comparing the evolution of the visible scar after treatment with plasmonic photothermal therapy and after surgery, it was observed that the mice treated with surgery showed disappearance of the tumor accompanied by ascites. In comparison, the skin of the mice treated with plasmonic photothermal therapy was smoother (photos not shown).

[0088] Figure 6 shows the regression of the tumor volume during the first injection at 20% of the TV. It can be observed that the exponential curves are quite similar for The injection of 20% gold nanoparticles was used for the two concentrations tested: 0.3 or 0.6 mg / mL. The curves at 40% TV are not compared due to the significant toxicity associated with this dose.

[0089] Figure 7 shows the tension index measured using Silflo resin to analyze the skin microrelief. It can be seen that the treated mice have less skin tension along the X, Y, and Z axes than the surgically treated group.

Claims

Demands

1. Nanoparticle obtained from a mixture of gold and Hubertia Ambavilla extract coated with glucose for use in the treatment of a skin tumor with a volume greater than or equal to 500 mm3.

2. Nanoparticle according to claim 1 for its use according to claim 1 wherein the concentration of said nanoparticle in solution is between 0.2 and 0.6 mg / ml.

3. Gold nanoparticle according to claim 1 or 2 for its use according to claim 1 or 2 wherein said treatment comprises thermal ablation, said thermal ablation being achieved by exposing said tumor to plasmonic phototherapy.

4. Gold nanoparticle according to claim 3 for its use according to claim 3 wherein said phototherapy consists of continuous laser irradiation at a wavelength between 755-1064 nm at a power between 0.5 and 2 W / cm2 for a duration of 5 to 20 min.

5. Nanoparticle according to any one of the preceding claims for its use according to any one of the preceding claims in a form suitable for intradermal administration.

6. Gold nanoparticle according to claim 5 for its use according to claim 5 in a form suitable for intratumoral administration.

7. Nanoparticle according to any one of the preceding claims for its use according to any one of the preceding claims wherein said skin tumor is selected from melanoma, basal cell carcinoma or squamous cell carcinoma.

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