Engineered nanomedicine for myeloma and bone microenvironment targeting

被引：241

作者：

Swami, Archana ^{[1
]}

Reagan, Michaela R. ^{[2
]}

Basto, Pamela ^{[3
]}

Mishima, Yuji ^{[2
]}

Kamaly, Nazila ^{[1
]}

Glavey, Siobhan ^{[2
]}

Zhang, Sufeng ^{[3
]}

Moschetta, Michele ^{[2
]}

Seevaratnam, Dushanth ^{[1
]}

Zhang, Yong ^{[2
]}

Liu, Jinhe ^{[1
]}

Memarzadeh, Masoumeh ^{[2
]}

Wu, Jun ^{[1
]}

Manier, Salomon ^{[2
]}

Shi, Jinjun ^{[1
]}

Bertrand, Nicolas ^{[3
]}

Lu, Zhi Ning ^{[2
]}

Nagano, Kenichi ^{[4
]}

Baron, Roland ^{[4
]}

Sacco, Antonio ^{[2
]}

Roccaro, Aldo M. ^{[2
]}

Farokhzad, Omid C. ^{[1
,5
]}

Ghobrial, Irene M. ^{[2
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Nanomed & Biomat,Dept Anesthesiol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[4] Harvard Univ, Sch Med, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA

[5] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 28期

基金：

美国国家卫生研究院; 新加坡国家研究基金会;

关键词：

targeting nanomedicine; alendronate-PLGA-PEG; bone metastasis; bisphosphonate; MULTIPLE-MYELOMA; IN-VITRO; ANTITUMOR-ACTIVITY; BORTEZOMIB; CELLS; VIVO; DEXAMETHASONE; ACTIVATION; THERAPY; PATHWAY;

D O I：

10.1073/pnas.1401337111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 bio-distribution 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.

引用

页码：10287 / 10292

页数：6

共 25 条

[1] CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy [J].

Azab, Abdel Kareem ;

Runnels, Judith M. ;

Pitsillides, Costas ;

Moreau, Anne-Sophie ;

Azab, Feda ;

Leleu, Xavier ;

Jia, Xiaoying ;

Wright, Renee ;

Ospina, Beatriz ;

Carlson, Alicia L. ;

Alt, Clemens ;

Burwick, Nicholas ;

Roccaro, Aldo M. ;

Ngo, Hai T. ;

Farag, Mena ;

Melhem, Molly R. ;

Sacco, Antonio ;

Munshi, Nikhil C. ;

Hideshima, Teru ;

Rollins, Barrett J. ;

Anderson, Kenneth C. ;

Kung, Andrew L. ;

Lin, Charles P. ;

Ghobrial, Irene M. .

BLOOD, 2009, 113 (18) :4341-4351

[2] Dual Inhibition of Akt/Mammalian Target of Rapamycin Pathway by Nanoparticle Albumin-Bound-Rapamycin and Perifosine Induces Antitumor Activity in Multiple Myeloma [J].

Cirstea, Diana ;

Hideshima, Teru ;

Rodig, Scott ;

Santo, Loredana ;

Pozzi, Samantha ;

Vallet, Sonia ;

Ikeda, Hiroshi ;

Perrone, Giulia ;

Gorgun, Gullu ;

Patel, Kishan ;

Desai, Neil ;

Sportelli, Peter ;

Kapoor, Shweta ;

Vali, Shireen ;

Mukherjee, Siddhartha ;

Munshi, Nikhil C. ;

Anderson, Kenneth C. ;

Raje, Noopur .

MOLECULAR CANCER THERAPEUTICS, 2010, 9 (04) :963-975

[3] Metastatic bone disease: clinical features, pathophysiology and treatment strategies [J].

Coleman, RE .

CANCER TREATMENT REVIEWS, 2001, 27 (03) :165-176

[4] Standardized Nomenclature, Symbols, and Units for Bone Histomorphometry: A 2012 Update of the Report of the ASBMR Histomorphometry Nomenclature Committee [J].

Dempster, David W. ;

Compston, Juliet E. ;

Drezner, Marc K. ;

Glorieux, Francis H. ;

Kanis, John A. ;

Malluche, Hartmut ;

Meunier, Pierre J. ;

Ott, Susan M. ;

Recker, Robert R. ;

Parfitt, A. Michael .

JOURNAL OF BONE AND MINERAL RESEARCH, 2013, 28 (01) :1-16

[5] Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro [J].

Garrett, IR ;

Chen, D ;

Gutierrez, G ;

Zhao, M ;

Escobedo, A ;

Rossini, G ;

Harris, SE ;

Gallwitz, W ;

Kim, KB ;

Hu, S ;

Crews, CM ;

Mundy, GR .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (11) :1771-1782

[6] The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients [J].

Giuliani, Nicola ;

Morandi, Francesca ;

Tagliaferri, Sara ;

Lazzareffi, Mirca ;

Bonomini, Sabrina ;

Crugnola, Monica ;

Mancini, Cristina ;

Martella, Eugenia ;

Ferrari, Luca ;

Tabilio, Antonio ;

Rizzoli, Vittorio .

BLOOD, 2007, 110 (01) :334-338

[7] Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment [J].

Heider, Ulrike ;

Kaiser, Martin ;

Mueller, Christian ;

Jakob, Christian ;

Zavrski, Ivana ;

Schulz, Carsten-Oliver ;

Fleissner, Claudia ;

Hecht, Monica ;

Sezer, Orhan .

EUROPEAN JOURNAL OF HAEMATOLOGY, 2006, 77 (03) :233-238

[8] Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile [J].

Hrkach, Jeffrey ;

Von Hoff, Daniel ;

Ali, Mir Mukkaram ;

Andrianova, Elizaveta ;

Auer, Jason ;

Campbell, Tarikh ;

De Witt, David ;

Figa, Michael ;

Figueiredo, Maria ;

Horhota, Allen ;

Low, Susan ;

McDonnell, Kevin ;

Peeke, Erick ;

Retnarajan, Beadle ;

Sabnis, Abhimanyu ;

Schnipper, Edward ;

Song, Jeffrey J. ;

Song, Young Ho ;

Summa, Jason ;

Tompsett, Douglas ;

Troiano, Greg ;

Hoven, Tina Van Geen ;

Wright, Jim ;

LoRusso, Patricia ;

Kantoff, Philip W. ;

Bander, Neil H. ;

Sweeney, Christopher ;

Farokhzad, Omid C. ;

Langer, Robert ;

Zale, Stephen .

SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (128)

[9] Targeted polymeric therapeutic nanoparticles: design, development and clinical translation [J].

Kamaly, Nazila ;

Xiao, Zeyu ;

Valencia, Pedro M. ;

Radovic-Moreno, Aleksandar F. ;

Farokhzad, Omid C. .

CHEMICAL SOCIETY REVIEWS, 2012, 41 (07) :2971-3010

[10] The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia [J].

Leleu, Xavier ;

Jia, Xiaoying ;

Runnels, Judith ;

Ngo, Hai T. ;

Moreau, Anne-Sophie ;

Farag, Mena ;

Spencer, Joel A. ;

Pitsillides, Costas M. ;

Hatjiharissi, Evdoxia ;

Roccaro, Aldo ;

O'Sullivan, Garrett ;

McMillin, Douglas W. ;

Moreno, Daisy ;

Kiziltepe, Tanyel ;

Carrasco, Ruben ;

Treon, Steven P. ;

Hideshima, Teru ;

Anderson, Kenneth C. ;

Lin, Charles P. ;

Ghobrial, Irene M. .

BLOOD, 2007, 110 (13) :4417-4426

← 1 2 3 →