title: Engineered nanomedicine for myeloma and bone microenvironment targeting.
abstract: 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.
authors: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Archana
authors: A
authors: Swami
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Michaela R
authors: MR
authors: Reagan
authors: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors: Pamela
authors: P
authors: Basto
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Yuji
authors: Y
authors: Mishima
authors: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Nazila
authors: N
authors: Kamaly
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Siobhan
authors: S
authors: Glavey
authors: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors: Sufeng
authors: S
authors: Zhang
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Michele
authors: M
authors: Moschetta
authors: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Dushanth
authors: D
authors: Seevaratnam
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Yong
authors: Y
authors: Zhang
authors: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Jinhe
authors: J
authors: Liu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Masoumeh
authors: M
authors: Memarzadeh
authors: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Jun
authors: J
authors: Wu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Salomon
authors: S
authors: Manier
authors: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Jinjun
authors: J
authors: Shi
authors: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors: Nicolas
authors: N
authors: Bertrand
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Zhi Ning
authors: ZN
authors: Lu
authors: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA 02115; and.
authors: Kenichi
authors: K
authors: Nagano
authors: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA 02115; and.
authors: Roland
authors: R
authors: Baron
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Antonio
authors: A
authors: Sacco
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
authors: Aldo M
authors: AM
authors: Roccaro
authors: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;King Abdulaziz University, Jeddah, Saudi Arabia ofarokhzad@zeus.bwh.harvard.edu irene_ghobrial@dfci.harvard.edu.
authors: Omid C
authors: OC
authors: Farokhzad
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; ofarokhzad@zeus.bwh.harvard.edu irene_ghobrial@dfci.harvard.edu.
authors: Irene M
authors: IM
authors: Ghobrial
mesh_terms: D019386:Alendronate / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D064593:Heterografts; D006801:Humans; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D000069286:Bortezomib; D019386:Alendronate
keywords: alendronate-PLGA-PEG; bisphosphonate; bone metastasis; targeting nanomedicine