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Engineered nanomedicine for myeloma and bone microenvironment targeting.

Proceedings of the National Academy of Sciences of the United States of America (2014-07-02)
Archana Swami, Michaela R Reagan, Pamela Basto, Yuji Mishima, Nazila Kamaly, Siobhan Glavey, Sufeng Zhang, Michele Moschetta, Dushanth Seevaratnam, Yong Zhang, Jinhe Liu, Masoumeh Memarzadeh, Jun Wu, Salomon Manier, Jinjun Shi, Nicolas Bertrand, Zhi Ning Lu, Kenichi Nagano, Roland Baron, Antonio Sacco, Aldo M Roccaro, Omid C Farokhzad, Irene M Ghobrial
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Lactic acid solution, ACS reagent, ≥85%
Sigma-Aldrich
Lactic acid, 85%, FCC
Sigma-Aldrich
DL-Lactic acid, ~90% (T)
Sigma-Aldrich
Lactic acid, meets USP testing specifications
Sigma-Aldrich
Lactic acid, natural, ≥85%
Supelco
Lactic acid, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
DL-Lactic acid, 85 % (w/w), syrup
Sigma-Aldrich
Alendronate sodium trihydrate, ≥97% (NMR), powder
Sigma-Aldrich
Polyglycolic acid
USP
Lactic acid, United States Pharmacopeia (USP) Reference Standard
USP
Alendronate sodium, United States Pharmacopeia (USP) Reference Standard