PMID- 24982170
OWN - NLM
STAT- MEDLINE
DCOM- 20140919
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 28
DP  - 2014 Jul 15
TI  - Engineered nanomedicine for myeloma and bone microenvironment targeting.
PG  - 10287-92
LID - 10.1073/pnas.1401337111 [doi]
AB  - 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.
FAU - Swami, Archana
AU  - Swami A
AD  - Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
FAU - Reagan, Michaela R
AU  - Reagan MR
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Basto, Pamela
AU  - Basto P
AD  - The David H. Koch Institute for Integrative Cancer Research, Massachusetts 
      Institute of Technology, Cambridge, MA 02139;
FAU - Mishima, Yuji
AU  - Mishima Y
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Kamaly, Nazila
AU  - Kamaly N
AD  - Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
FAU - Glavey, Siobhan
AU  - Glavey S
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Zhang, Sufeng
AU  - Zhang S
AD  - The David H. Koch Institute for Integrative Cancer Research, Massachusetts 
      Institute of Technology, Cambridge, MA 02139;
FAU - Moschetta, Michele
AU  - Moschetta M
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Seevaratnam, Dushanth
AU  - Seevaratnam D
AD  - Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
FAU - Zhang, Yong
AU  - Zhang Y
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Liu, Jinhe
AU  - Liu J
AD  - Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
FAU - Memarzadeh, Masoumeh
AU  - Memarzadeh M
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Wu, Jun
AU  - Wu J
AD  - Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
FAU - Manier, Salomon
AU  - Manier S
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Shi, Jinjun
AU  - Shi J
AD  - Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
FAU - Bertrand, Nicolas
AU  - Bertrand N
AD  - The David H. Koch Institute for Integrative Cancer Research, Massachusetts 
      Institute of Technology, Cambridge, MA 02139;
FAU - Lu, Zhi Ning
AU  - Lu ZN
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Nagano, Kenichi
AU  - Nagano K
AD  - Department of Oral Medicine, Infection and Immunity, Harvard School of Dental 
      Medicine, Harvard Medical School, Boston, MA 02115; and.
FAU - Baron, Roland
AU  - Baron R
AD  - Department of Oral Medicine, Infection and Immunity, Harvard School of Dental 
      Medicine, Harvard Medical School, Boston, MA 02115; and.
FAU - Sacco, Antonio
AU  - Sacco A
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Roccaro, Aldo M
AU  - Roccaro AM
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115;
FAU - Farokhzad, Omid C
AU  - Farokhzad OC
AD  - 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.
FAU - Ghobrial, Irene M
AU  - Ghobrial IM
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02115; ofarokhzad@zeus.bwh.harvard.edu 
      irene_ghobrial@dfci.harvard.edu.
LA  - eng
GR  - K1A1A2048701/PHS HHS/United States
GR  - U54 CA151884/CA/NCI NIH HHS/United States
GR  - R00CA160350/CA/NCI NIH HHS/United States
GR  - R01 CA154648/CA/NCI NIH HHS/United States
GR  - CAPMC/CIHR/Canada
GR  - R00 CA160350/CA/NCI NIH HHS/United States
GR  - CA151884/CA/NCI NIH HHS/United States
GR  - R01 FD003743/FD/FDA HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140630
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Boronic Acids)
RN  - 0 (Pyrazines)
RN  - 1SIA8062RS (Polylactic Acid-Polyglycolic Acid Copolymer)
RN  - 26009-03-0 (Polyglycolic Acid)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 69G8BD63PP (Bortezomib)
RN  - X1J18R4W8P (Alendronate)
SB  - IM
MH  - Alendronate/chemistry
MH  - Animals
MH  - *Antineoplastic Agents/chemistry/pharmacology
MH  - Bone Neoplasms/*drug therapy/metabolism/pathology
MH  - *Boronic Acids/chemistry/pharmacology
MH  - Bortezomib
MH  - Cell Line, Tumor
MH  - *Drug Delivery Systems
MH  - Heterografts
MH  - Humans
MH  - *Lactic Acid/chemical synthesis/chemistry/pharmacology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Multiple Myeloma/*drug therapy/metabolism/pathology
MH  - *Nanoparticles/chemistry/ultrastructure
MH  - Neoplasm Transplantation
MH  - Neoplasms, Experimental/drug therapy/metabolism/pathology
MH  - *Polyethylene Glycols/chemical synthesis/chemistry/pharmacokinetics
MH  - *Polyglycolic Acid/chemical synthesis/chemistry/pharmacology
MH  - Polylactic Acid-Polyglycolic Acid Copolymer
MH  - *Pyrazines/chemistry/pharmacology
MH  - Tumor Microenvironment/*drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC4104924
OTO - NOTNLM
OT  - alendronate-PLGA-PEG
OT  - bisphosphonate
OT  - bone metastasis
OT  - targeting nanomedicine
COIS- Conflict of interest statement: I.M.G. discloses her Advisory Board Membership 
      with Novartis, Onyx, and BMS. O.C.F. discloses his financial interest in BIND 
      Therapeutics, Selecta Biosciences, and Blend Therapeutics, three biotechnology 
      companies developing nanoparticle technologies for medical applications. BIND, 
      Selecta, and Blend did not support the aforementioned research, and currently 
      these companies have no rights to any technology or intellectual property 
      developed as part of this research.
EDAT- 2014/07/02 06:00
MHDA- 2014/09/23 06:00
PMCR- 2014/06/30
CRDT- 2014/07/02 06:00
PHST- 2014/07/02 06:00 [entrez]
PHST- 2014/07/02 06:00 [pubmed]
PHST- 2014/09/23 06:00 [medline]
PHST- 2014/06/30 00:00 [pmc-release]
AID - 1401337111 [pii]
AID - 201401337 [pii]
AID - 10.1073/pnas.1401337111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10287-92. doi: 
      10.1073/pnas.1401337111. Epub 2014 Jun 30.