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(12) Patent Application Publication (10) Pub. No.: US 2008/0081074 A1 Gu Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2008/0081074 A1 Gu Et Al US 20080081074A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0081074 A1 Gu et al. (43) Pub. Date: Apr. 3, 2008 (54) POLYMERS FOR FUNCTIONAL PARTICLES (52) U.S. Cl. .......................... 424/489: 424/94.1; 506/23; 5147772.4 (75) Inventors: Frank X. Gu, Cambridge, MA (US); Benjamin A. Teply, Omaha, NE (US); Robert S. Langer, Newton, MA (US); (57) ABSTRACT Omid C. Farokhzad, Chestnut Hill, MA (US) The present invention generally relates to polymers and macromolecules, in particular, to block polymers useful in Correspondence Address: particles Such as nanoparticles. One aspect of the invention WOLF GREENFIELD & SACKS, P.C. is directed to a method of developing nanoparticles with 6OO ATLANTIC AVENUE desired properties. In one set of embodiments, the method BOSTON, MA 02210-2206 (US) includes producing libraries of nanoparticles having highly controlled properties, which can be formed by mixing (73) Assignees: Massachusetts Institute of Technology, together two or more macromolecules in different ratios. Cambridge, MA: The Brigham & Wom One or more of the macromolecules may be a polymeric en's Hospital, Inc., Boston, MA conjugate of a moiety to a biocompatible polymer. In some cases, the nanoparticle may contain a drug. The moiety, in (21) Appl. No.: 11/803,843 Some embodiments, may have a molecular weight greater than about 1000 Da; for example, the moiety may include a (22) Filed: May 15, 2007 polypeptide or a polynucleotide. Such as an aptamer. The moiety may also be a targeting moiety, an imaging moiety, Related U.S. Application Data a chelating moiety, a charged moiety, or a therapeutic (60) Provisional application No. 60/747,240, filed on May moiety. Another aspect of the invention is directed to sys 15, 2006. tems and methods of producing Such polymeric conjugates. In some embodiments, a solution containing a polymer is Publication Classification contacted with a liquid, such as an immiscible liquid, to form nanoparticles containing the polymeric conjugate. Other (51) Int. Cl. aspects of the invention are directed to methods using such A6 IK 9/14 (2006.01) libraries, methods of using or administering Such polymeric A6 IK 38/43 (2006.01) conjugates, methods of promoting the use of Such polymeric C4OB 50/00 (2006.01) conjugates, kits involving Such polymeric conjugates, or the A6 IK 47/32 (2006.01) like. PGA PEG APT Drug Aptamer Patent Application Publication Apr. 3, 2008 Sheet 1 of 19 US 2008/0081074 A1 Patent Application Publication Apr. 3, 2008 Sheet 2 of 19 US 2008/0081074 A1 VZ-61-I Patent Application Publication Apr. 3, 2008 Sheet 3 of 19 US 2008/0081074 A1 —) + Patent Application Publication Apr. 3, 2008 Sheet 4 of 19 US 2008/0081074 A1 Patent Application Publication Apr. 3, 2008 Sheet 5 of 19 US 2008/0081074 A1 })^^~~~ Patent Application Publication Apr. 3, 2008 Sheet 6 of 19 US 2008/0081074 A1 ?—~~~~ Patent Application Publication Apr. 3, 2008 Sheet 7 of 19 US 2008/0081074 A1 /^^_^~~~ })^^~~~ DE‘6H Patent Application Publication Apr. 3, 2008 Sheet 8 of 19 US 2008/0081074 A1 }~~~~ ^^~~~~ Patent Application Publication Apr. 3, 2008 Sheet 9 of 19 US 2008/0081074 A1 /^^_^)!~~/^^~~~~ })^^~~~~ ?—~~~~ Patent Application Publication Apr. 3, 2008 Sheet 10 of 19 US 2008/0081074 A1 })^^~~~ ~~~~+e^~~~~3)^^) Patent Application Publication Apr. 3, 2008 Sheet 11 of 19 US 2008/0081074 A1 ^~~~~+))^^~~~ }~~~~ Patent Application Publication Apr. 3, 2008 Sheet 12 of 19 US 2008/0081074 A1 r &E8 83 17 1S 17 1O Patent Application Publication Apr. 3, 2008 Sheet 13 of 19 US 2008/0081074 A1 Patent Application Publication Apr. 3, 2008 Sheet 14 of 19 US 2008/0081074 A1 70 60 LNCap (+PSMA) 50 PC3 (PSMA) 40 30 20 0% 0.05% 0.1% 0.5% 2%. 5% 10% Aptamer surface density Fig. 7A -Y PSMA aptamer 1C Paclitaxel Patent Application Publication Apr. 3, 2008 Sheet 15 of 19 US 2008/0081074 A1 12O Intratumoral injectionv 1 OO 5% Apt-PEG-PLGA 8O 60 40 Blood Tumor Spleen Liver Kidney Lung Heart Fig.8A Patent Application Publication Apr. 3, 2008 Sheet 16 of 19 US 2008/0081074 A1 3H PLGA 10oligotrib Odiblock0 21 Apt. S5Aptamer E10Aptamer p??23[u]go36e?uÐDuÐd ?nss11go6uÐdasoq Tumor Blood Heart Kidney Lung Splee Fig.8B ?-|||||||||TOE|||||||||||||| LL „C) CO Patent Application Publication Apr. 3, 2008 Sheet 17 of 19 US 2008/0081074 A1 70 60 50 40 30 2O 10 O.OO 0.02 0.04 O.O6 0.08 0.10 % Triblock in NP formulation Fig.9A 132 OOO OOO O O.OO 0.02 004 O.O6 O.08 0.10 % Triblock in NP formulation Fig.9B Patent Application Publication Apr. 3, 2008 Sheet 18 of 19 US 2008/0081074 A1 -- - - - - - - - - - al w W : t p A O i-----------------------------------4--; a -s d-e----: a-s----- a--------------------r - y -------------------------------------f * w es t -------- --- F. W. O) A a --------- w L - - - - - - - - - - - was a r ... ------- - - - ----------. U) s C) CC 2 (uu) eZS epuedoueN Patent Application Publication Apr. 3, 2008 Sheet 19 of 19 US 2008/0081074 A1 H ia ::::22 5 %3 s s £25 is of N 3, , , , , NB S. g . i O 9 C. C. C. -9 S. CC. C. C. S Ca aS S S S as s to C re r view S S 2 2 8 3 S. s O ?y N ur O onSSI go 6 ued eSod enSSI) Jo 6 ued eSOO papeful Jo e6enuebled pede?u go offeuedued assaga s - H - - - - g , g 5 CC 3 u 5 is 52 5 Ni 955, E On- N r 3, it LL aS S S S 3S as v- d r- i? r- S & O R Cd O Cd C ?y N tage C vid e on enss of Jed eSoC enSS Jo 6 Jed eSoC peapeful go effeueled pepe?uyo effeueoued US 2008/008 1074 A1 Apr. 3, 2008 POLYMERS FOR FUNCTIONAL PARTICLES useful in particles such as nanoparticles. The Subject matter of the present invention involves, in some cases, interrelated RELATED APPLICATIONS products, alternative Solutions to a particular problem, and/ 0001) This application claims the benefit of U.S. Provi or a plurality of different uses of one or more systems and/or sional Patent Application Ser. No. 60/747,240, filed May 15, articles. 2006, entitled “Multi-Block Co-Polymers for Development 0008. In one aspect, the present invention is directed to a of Functional Particles.” by Farokhzad, et al., incorporated method. In one set of embodiments, the method is a method herein by reference. of developing nanoparticles with desired properties. Accord ing to a first embodiment, the method includes acts of GOVERNMENT FUNDING providing a first macromolecule comprising a first biocom patible polymer and a moiety selected from the group 0002 Research leading to various aspects of the present consisting of a targeting moiety, an imaging moiety, a invention was sponsored, at least in part, by the National chelating moiety, a moiety having multiple charge groups, Cancer Institute, Grant No. CA 119349, and the National and a therapeutic moiety; providing a second macromol Institute of Biomedical Imaging and Bioengineering, Grant ecule comprising a second biocompatible polymer; produc No. EB 003.647. The U.S. Government may have certain ing a library of nanoparticles having different ratios of the rights in the invention. first and second macromolecules by forming nanoparticles from mixtures comprising the first and second macromol FIELD OF INVENTION ecules at different ratios; and identifying a nanoparticle from 0003. The present invention generally relates to polymers the library of nanoparticles having one or more desired and macromolecules and, in particular, to block polymers properties. useful in particles Such as nanoparticles. 0009. The method, in another embodiment, includes acts of providing a first macromolecule comprising a first block BACKGROUND having a repeat unit and a second block comprising a moiety 0004 The delivery of a drug to a patient with controlled selected from the group consisting of a targeting moiety, an release of the active ingredient has been an active area of imaging moiety, a chelating moiety, a moiety having mul research for decades and has been fueled by the many recent tiple charge groups, and a therapeutic moiety; providing a developments in polymer Science and the need to deliver second polymer comprising the first repeat unit but not more labile pharmaceutical agents such as nucleic acids, comprising the targeting moiety; and producing a library of proteins, and peptides. In addition, controlled release poly nanoparticles having different ratios of the first macromol mer systems can be designed to provide a drug level in the ecule and second polymer by forming nanoparticles from optimum range over a longer period of time than other drug mixtures comprising the first macromolecule and the second delivery methods, thus increasing the efficacy of the drug polymer at different ratios. and minimizing problems with patient compliance. 0010. In yet another embodiment, the method includes acts of providing a first biocompatible hydrophobic poly 0005 Biodegradable particles have been developed as mer, providing a second biocompatible hydrophilic poly Sustained release vehicles used in the administration of Small mer, providing a moiety selected from the group consisting molecule drugs as well as protein and peptide drugs and of a targeting moiety, an imaging moiety, a chelating moiety, nucleic acids. The drugs are typically encapsulated in a a moiety having multiple charge groups, and a therapeutic polymer matrix which is biodegradable and biocompatible. moiety; reacting the first biocompatible hydrophobic poly As the polymer is degraded and/or as the drug diffuses out mer, the second biocompatible hydrophilic polymer, and the of the polymer, the drug is released into the body. Typically, moiety to produce a macromolecule; producing a library of polymers used in preparing these particles are polyesters nanoparticles comprising the macromolecule and at least Such as poly(lactide-co-glycolide) (PLGA), polyglycolic one other polymer by forming nanoparticles from mixtures acid, poly-beta-hydroxybutyrate, polyacrylic acid ester, etc.
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