(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/089768 Al 5 July 2012 (05.07.2012) P O P C T (51) International Patent Classification: (74) Agent: CARPINTERO LOPEZ, Francisco; Herrero & A61K 47/48 (2006.01) A61P 35/00 (2006.01) Asociados, S.L., Alcala, 35, E-280014 Madrid (ES). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/EP20 11/074150 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 28 December 201 1 (28. 12.201 1) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, P201031 971 28 December 2010 (28. 12.2010) ES SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): ENDOR NANOTECHNOLOGIES, S.L. [ES/ES]; Edificio Helix - (84) Designated States (unless otherwise indicated, for every c/ Baldiri Reixac, 15, E-08028 Barcelona (ES). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (72) Inventors; and UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, (75) Inventors/Applicants (for US only): VIVERO SANC¬ TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, HEZ, Laura [ES/ES]; Edificio Helix, c/ Baldiri Reixac, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 15, E-08028 Barcelona (ES). SENDRA CUADAL, Judith LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, [ES/ES]; Edificio Helix, c/ Baldiri Reixac, 15, E-08028 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Barcelona (ES). PARKKOLA, Hanna [FI/ES]; Edificio GW, ML, MR, NE, SN, TD, TG). Helix, c/ Baldiri Reixac, 15, E-08028 Barcelona (ES). QUEROL SASTRE, Joaquin [ES/ES]; Edificio Helix, c/ Published: Baldiri Reixac, 15, E-08028 Barcelona (ES). RAMIS — with international search report (Art. 21(3)) CASTELLTORT, Marc [ES/ES]; Edificio Helix, c/ Baldiri Reixac, 15, E-08028 Barcelona (ES). (54) Title: SYSTEM FOR THE RELEASE OF A THERAPEUTIC AGENT, PHARMACEUTICAL COMPOSITIONS CONTAIN ING IT, THE PREPARATION AND MEDICAL USE THEREOF - .. ύ ~ 00 HO 00 © FIG. 1 o (57) Abstract: The present invention describes a new system for the selective and controlled release of a therapeutic agent compris - ing: (i) a carrier comprising: a) a metal nanoparticle and b) a hydrophilic HA coating bound to the metal nanoparticle through at least a first ligand, and (ii) at least one therapeutic agent bound to the nanoparticle, to the HA or encapsulated in the HA coating. The in o vention also describes pharmaceutical compositions containing the system for release, their use in the treatment of diseases such as cancer and a method for obtaining them. SYSTEM FOR THE RELEASE OF A THERAPEUTIC AGENT. PHARMACEUTICAL COMPOSITIONS CONTAINING IT, THE PREPARATION AND MEDICAL USE THEREOF Field of the Invention The present invention relates to a new system for the selective and controlled release of a therapeutic agent, comprising a metal nanoparticle, hyaluronic acid and a therapeutic agent. The invention also relates to compositions containing it and to the use of said system and said compositions in therapeutic treatments. Background of the Invention Therapeutic agents administered to the human or animal body are distributed throughout the organism according to their physicochemical properties. The therapeutic agents used today in general do not have specific properties for acting selectively on the selected cells targeted for treatment. These agents therefore randomly affect the cells of the organism, including both the selected cells targeted for application as well as different types of cells not targeted for medical application, causing unwanted side effects. Today, the development of new systems for the controlled and selective release of therapeutic agents is a technological and scientific field in which there is a great deal of activity. The objective of a system for release is to make the desired amount of the therapeutic agent reach the selected cells to obtain a desired therapeutic effect, thereby minimizing the unwanted exposure of the rest of the organism to the agent. In order for the necessary amount to be the minimum amount possible and at the same time therapeutically effective, it is desirable for the system for release to improve the effectiveness of the therapeutic agent. In particular, many therapeutic agents used today, for example in oncological treatments, are specific at the molecular level but not at the cellular level. Therefore, in some cases only a small fraction of the agent reaches the tumor, whereas the rest acts in other tissues of the organism or, in other cases, it is rapidly eliminated from the organism before it can produce any effect in the target tissues, or in contrast, it has a high circulation time and can act in other tissues of the organism causing unwanted effects. A property that systems for the release of therapeutic agents must have is remaining the necessary time in the circulatory system to passively and with the highest probability possible access the target cells. However, if the system for release is not suitably protected, the phagocytic cells of the mononuclear phagocyte system (MPS) can rapidly eliminate it. One of the most widely used techniques for protecting the system for release against the MPS is to coat it with a type of hydrophilic agent that provides it with an aqueous coating that protects it. The components making up the system for release, including the therapeutic agent, are protected and less susceptible to being internalized by the cells of the MPS, which results in a longer blood circulation time. An example of a widely used hydrophilic agent is the polyethylene glycol (PEG). Furthermore, a system for the release of a therapeutic agent must exert a selective action on the target cells. In this sense, in order to direct the system for release to a target cell of the organism it is necessary to have molecules with an affinity for said target cell. Specifically, some monoclonal antibodies recognizing tumor markers are used in the case of tumors due to their capacity to be selectively bound to tumor cells (for example Herceptin (trastuzumab) is a widely used antibody in breast cancer). Binding the antibody that performs vector functions to the system for release can provide it with selectivity but it is still necessary to protect the system for release to prevent it from being internalized by cells of the MPS. Therefore, in order for a system for release to be effective it is desirable for it to have this dual protection and selectivity functionality. Specifically, the system for release must be made up of a hydrophilic agent (for example, PEG) to remain in the blood for the necessary time and a vector molecule conferring selectivity (for example, a monoclonal antibody) and selectively releasing the agent on the target cells. In many cases, the hydrophilic agent and the vector molecule interfere in their functions such that both the hydrophilic capacity and the selectivity of the system for release are lost. This effect limits the application of these systems and in many cases it is necessary to choose between a high blood circulation time or optimal selectivity on the target cells. One way to solve this problem is to have a system for release made up of a single molecule that performs the protection and selectivity functions. Said molecule must keep the system with the agent protected while it is circulating throughout the organism and until it is released in the target cells; it must reach the target cells in the shortest circulation time possible such that the system for release does not circulate more time than that necessary, causing unwanted side effects and its accumulation in other organs. Furthermore, said molecule must have optimal affinity and selectivity in order to be internalized into target cells such that it can perform vector functions. Finally, the release of the therapeutic agent by the system for release is a decisive factor for determining the effectiveness of the system. The objective in this case is for the system to stably conserve the agent until reaching the target cell and once there, to release it without the molecular structure of the agent being altered. Diverse strategies have been designed in the last decade for controlling the kinetics and release of agents. One of the most widespread strategies is the use of liposomes synthesized from biodegradable materials which store the therapeutic agent therein and, as they degrade, gradually release the agent. In order for a system for release made up of liposomes to be effective it must also include a hydrophilic agent protecting against the MPS on the surface of the liposome and a vector molecule which preferably directs the agent to the cells targeted for treatment. Such systems for release have several drawbacks such as the progressive uncontrolled degradation of the liposome in biological medium, making the agent be gradually released as the liposome degrades, compromising the arrival and the release of the agent in the target cell.