Engineered nanomedicine for myeloma and bone microenvironment targeting
Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing p...
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| 格式: | 文件 |
| 语言: | en_US |
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National Academy of Sciences (U.S.)
2015
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| 在线阅读: | http://hdl.handle.net/1721.1/93754 https://orcid.org/0000-0002-9481-2258 |
| _version_ | 1826203991549149184 |
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| author | Swami, Archana Reagan, Michaela R. Basto, Pamela Antonia Mishima, Yuji Kamaly, Nazila Glavey, Siobhan Zhang, Sufeng Moschetta, Michele Seevaratnam, Dushanth Zhang, Yong Liu, Jinhe Memarzadeh, Masoumeh Manier, Salomon Shi, Jinjun Bertrand, Nicolas Lu, Zhi Ning Nagano, Kenichi Baron, Roland Sacco, Antonio Roccaro, Aldo M. Farokhzad, Omid C. Ghobrial, Irene M. Wu, Jun, 1968- |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Swami, Archana Reagan, Michaela R. Basto, Pamela Antonia Mishima, Yuji Kamaly, Nazila Glavey, Siobhan Zhang, Sufeng Moschetta, Michele Seevaratnam, Dushanth Zhang, Yong Liu, Jinhe Memarzadeh, Masoumeh Manier, Salomon Shi, Jinjun Bertrand, Nicolas Lu, Zhi Ning Nagano, Kenichi Baron, Roland Sacco, Antonio Roccaro, Aldo M. Farokhzad, Omid C. Ghobrial, Irene M. Wu, Jun, 1968- |
| author_sort | Swami, Archana |
| collection | MIT |
| description | Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d,l-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM. |
| first_indexed | 2024-09-23T12:47:07Z |
| format | Article |
| id | mit-1721.1/93754 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:47:07Z |
| publishDate | 2015 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/937542022-10-01T11:05:36Z Engineered nanomedicine for myeloma and bone microenvironment targeting Swami, Archana Reagan, Michaela R. Basto, Pamela Antonia Mishima, Yuji Kamaly, Nazila Glavey, Siobhan Zhang, Sufeng Moschetta, Michele Seevaratnam, Dushanth Zhang, Yong Liu, Jinhe Memarzadeh, Masoumeh Manier, Salomon Shi, Jinjun Bertrand, Nicolas Lu, Zhi Ning Nagano, Kenichi Baron, Roland Sacco, Antonio Roccaro, Aldo M. Farokhzad, Omid C. Ghobrial, Irene M. Wu, Jun, 1968- Koch Institute for Integrative Cancer Research at MIT Basto, Pamela Antonia Zhang, Sufeng Bertrand, Nicolas Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d,l-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM. United States. Dept. of Defense (Grant W81XWH-05-1-0390) Movember Foundation (Movember Prostate Cancer Foundation Challenge Award) National Research Foundation of Korea (K1A1A2048701) David H. Koch Institute for Integrative Cancer Research at MIT (David Koch-Prostate Cancer Foundation Award in Nanotherapeutics) Canadian Institutes of Health Research National Institutes of Health (U.S.) (grant R00 CA160350) National Institutes of Health (U.S.) (grant R01 FD003743) National Institutes of Health (U.S.) (grant R01 CA154648) National Institutes of Health (U.S.) (grant CA151884) 2015-02-04T17:56:10Z 2015-02-04T17:56:10Z 2014-06 2014-01 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/93754 Swami, A., M. R. Reagan, P. Basto, Y. Mishima, N. Kamaly, S. Glavey, S. Zhang, et al. “Engineered Nanomedicine for Myeloma and Bone Microenvironment Targeting.” Proceedings of the National Academy of Sciences 111, no. 28 (June 30, 2014): 10287–10292. https://orcid.org/0000-0002-9481-2258 en_US http://dx.doi.org/10.1073/pnas.1401337111 Proceedings of the National Academy of Sciences 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.) National Academy of Sciences (U.S.) |
| spellingShingle | Swami, Archana Reagan, Michaela R. Basto, Pamela Antonia Mishima, Yuji Kamaly, Nazila Glavey, Siobhan Zhang, Sufeng Moschetta, Michele Seevaratnam, Dushanth Zhang, Yong Liu, Jinhe Memarzadeh, Masoumeh Manier, Salomon Shi, Jinjun Bertrand, Nicolas Lu, Zhi Ning Nagano, Kenichi Baron, Roland Sacco, Antonio Roccaro, Aldo M. Farokhzad, Omid C. Ghobrial, Irene M. Wu, Jun, 1968- Engineered nanomedicine for myeloma and bone microenvironment targeting |
| title | Engineered nanomedicine for myeloma and bone microenvironment targeting |
| title_full | Engineered nanomedicine for myeloma and bone microenvironment targeting |
| title_fullStr | Engineered nanomedicine for myeloma and bone microenvironment targeting |
| title_full_unstemmed | Engineered nanomedicine for myeloma and bone microenvironment targeting |
| title_short | Engineered nanomedicine for myeloma and bone microenvironment targeting |
| title_sort | engineered nanomedicine for myeloma and bone microenvironment targeting |
| url | http://hdl.handle.net/1721.1/93754 https://orcid.org/0000-0002-9481-2258 |
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