Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy
The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2013
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| Online Access: | http://hdl.handle.net/1721.1/78881 https://orcid.org/0000-0003-0588-9286 https://orcid.org/0000-0002-2693-4982 https://orcid.org/0000-0002-2640-3006 https://orcid.org/0000-0003-4255-0492 |
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| author | Kolishetti, Nagesh Dhar, Shanta Valencia, Pedro Miguel Lin, Lucy Q. Karnik, Rohit Lippard, Stephen J. Langer, Robert Farokhzad, Omid C. |
| author2 | MIT-Harvard Center for Cancer Nanotechnology Excellence |
| author_facet | MIT-Harvard Center for Cancer Nanotechnology Excellence Kolishetti, Nagesh Dhar, Shanta Valencia, Pedro Miguel Lin, Lucy Q. Karnik, Rohit Lippard, Stephen J. Langer, Robert Farokhzad, Omid C. |
| author_sort | Kolishetti, Nagesh |
| collection | MIT |
| description | The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells. As proof of concept, we codelivered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. A polylactide (PLA) derivative with pendant hydroxyl groups was prepared and conjugated to a platinum(IV) [Pt(IV)] prodrug, c,t,c-[Pt(NH[subscript 3])[subscript 2](O[subscript 2]CCH[subscript 2]CH[subscript 2]COOH)(OH)Cl[subscript 2]] [PLA-Pt(IV)]. A blend of PLA-Pt(IV) functionalized polymer and carboxyl-terminated poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer in the presence or absence of Dtxl, was converted, in microfluidic channels, to NPs with a diameter of ∼100 nm. This process resulted in excellent encapsulation efficiency (EE) and high loading of both hydrophilic platinum prodrug and hydrophobic Dtxl with reproducible EEs and loadings. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48–72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment. |
| first_indexed | 2024-09-23T11:22:15Z |
| format | Article |
| id | mit-1721.1/78881 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:22:15Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/788812022-10-01T03:08:04Z Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy Kolishetti, Nagesh Dhar, Shanta Valencia, Pedro Miguel Lin, Lucy Q. Karnik, Rohit Lippard, Stephen J. Langer, Robert Farokhzad, Omid C. MIT-Harvard Center for Cancer Nanotechnology Excellence Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Mechanical Engineering Koch Institute for Integrative Cancer Research at MIT Kolishetti, Nagesh Dhar, Shanta Valencia, Pedro Miguel Lin, Lucy Q. Karnik, Rohit Lippard, Stephen J. Langer, Robert Farokhzad, Omid C. The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells. As proof of concept, we codelivered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. A polylactide (PLA) derivative with pendant hydroxyl groups was prepared and conjugated to a platinum(IV) [Pt(IV)] prodrug, c,t,c-[Pt(NH[subscript 3])[subscript 2](O[subscript 2]CCH[subscript 2]CH[subscript 2]COOH)(OH)Cl[subscript 2]] [PLA-Pt(IV)]. A blend of PLA-Pt(IV) functionalized polymer and carboxyl-terminated poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer in the presence or absence of Dtxl, was converted, in microfluidic channels, to NPs with a diameter of ∼100 nm. This process resulted in excellent encapsulation efficiency (EE) and high loading of both hydrophilic platinum prodrug and hydrophobic Dtxl with reproducible EEs and loadings. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48–72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment. National Cancer Institute (U.S.) (Grant CA119349) National Cancer Institute (U.S.) (Grant CA034992) National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant EB003647) David H. Koch (Prostate Cancer Foundation Award in Nanotherapeutics Award) National Science Foundation (U.S.) (Graduate Research Fellowship) 2013-05-14T15:49:01Z 2013-05-14T15:49:01Z 2010-10 2010-08 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/78881 Kolishetti, N., S. Dhar, P. M. Valencia, et al. Engineering of Self-assembled Nanoparticle Platform for Precisely Controlled Combination Drug Therapy. Proceedings of the National Academy of Sciences 107(42): 17939–17944, 2010. https://orcid.org/0000-0003-0588-9286 https://orcid.org/0000-0002-2693-4982 https://orcid.org/0000-0002-2640-3006 https://orcid.org/0000-0003-4255-0492 en_US http://dx.doi.org/10.1073/pnas.1011368107 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Kolishetti, Nagesh Dhar, Shanta Valencia, Pedro Miguel Lin, Lucy Q. Karnik, Rohit Lippard, Stephen J. Langer, Robert Farokhzad, Omid C. Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy |
| title | Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy |
| title_full | Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy |
| title_fullStr | Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy |
| title_full_unstemmed | Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy |
| title_short | Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy |
| title_sort | engineering of self assembled nanoparticle platform for precisely controlled combination drug therapy |
| url | http://hdl.handle.net/1721.1/78881 https://orcid.org/0000-0003-0588-9286 https://orcid.org/0000-0002-2693-4982 https://orcid.org/0000-0002-2640-3006 https://orcid.org/0000-0003-4255-0492 |
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