Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer

Abstract

Advanced-stage prostate cancer usually metastasizes to bone and is untreatable due to poor biodistribution of intravenously administered anticancer drugs to bone. In this study, we modulated the surface charge/composition of biodegradable nanoparticles (NPs) to sustain their blood circulation time and made them small enough to extravasate through the openings of the bone’s sinusoidal capillaries and thus localize into marrow. NPs with a neutral surface charge, achieved by modulating the NP surface-associated emulsifier composition, were more effective at localizing to bone marrow than NPs with a cationic or anionic surface charge. These small neutral NPs (~150 nm vs. the more usual ~320 nm) were also ~7-fold more effective in localizing in bone marrow than large NPs. We hypothesized that NPs that effectively localize to marrow could improve NP-mediated anticancer drug delivery to sites of bone metastasis, thereby inhibiting cancer progression and preventing bone loss. In a PC-3M-luc cell-induced osteolytic intraosseous model of prostate cancer, these small neutral NPs demonstrated greater accumulation in bone within metastatic sites than in normal contralateral bone as well as co-localization with the tumor mass in marrow. Significantly, a single-dose intravenous administration of these small neutral NPs loaded with paclitaxel (PTX-NPs), but not anionic PTX-NPs, slowed the progression of bone metastasis. In addition, neutral PTX-NPs prevented bone loss, whereas animals treated with the rapid-release drug formulation Cremophor EL (PTX-CrEL) or saline (control) showed >50% bone loss. Neutral PTX-NPs did not cause acute toxicity, whereas animals treated with PTX-CrEL experienced weight loss. These results indicate that NPs with appropriate physical and sustained drug-release characteristics could be explored to treat bone metastasis, a significant clinical issue in prostate and other cancers.

Nonspherical Nanoparticle Shape Stability Is Affected by Complex Manufacturing Aspects: Its Implications for Drug Delivery and Targeting

“…It was already known that WoA 3 only demonstrates the short‐term affinity, while IFT 1.2 describes the tension left in the formed bond (i.e., the bond's potential to break), characterizing long‐term affinity . From the deduction of our results and others, the nonwashability of PVA, sulfate esters, CTAB, and Triton X‐100 from various nanoparticles may strongly correlate to their primary and secondary interfacial activity parameters (Figure e and Figure S4, Supporting Information). Interfacial‐activity‐based algorithms to determine the stabilizer nonwashability and suitability for particle formation are suggested (Figure S4c, Supporting Information).…”

“…This may be the proper explanation for the poor protection of TPGS for nonspherical PLA‐COOH nanoparticles fabricated by emulsion solvent extraction. In contrary, the particular amount and type of PVA (possessing high interfacial activity) could adhere irreversibly on particles surface prepared by emulsion solvent extraction via molecular interpenetration and multilayer adsorption mechanism, thus affects particle's physical properties (including drug release from nanoparticles) and cellular uptake . Interestingly, with regard to the residual stabilizers, the affinity and extent of residual PVA, Poloxamer, and TPGS on aliphatic polyester nanoparticles prepared by emulsion solvent extraction can also be differentiated from the freeze‐drying results in HPW and without additional cryoprotectant (our unpublished data; in preparation).…”

Porous Electrospun Fibers with Self‐Sealing Functionality: An Enabling Strategy for Trapping Biomacromolecules

“…This apparent rise in fiber diameter upon decreasing PEO content might be ascribed to the decreased solution conductivity, which causes a weaker electrical drag force that can be used for elongating the fiber along its length . As is well‐known, the size of the pores and the distribution of the fibers are vital factors determining the matrix degradation, biomacromolecule encapsulation/release, and host responses …”

<p>PSMA-Targeting Reduction-Cleavable Hyperbranched Polyamide-Amine Gene Delivery System to Treat the Bone Metastases of Prostate Cancer</p>

“…Nanomaterials with neutral potentials have more effective bone marrow localization than those with anionic or cationic potentials because nanomaterials with neutral potentials have reduced interaction with serum proteins, unlike anionic or cationic nanomaterials that are opsonized to the same extent. [28][29][30] The Specificity of Aptamers Using immunocytochemistry, the chemically synthesized A 10-3.2 aptamer demonstrated its capacity for binding to prostate cancer cells with positive PSMA expression. In LNCaP cells, the Cy5-labeled HPAA-PEG-APT complex colocalized on the cell membrane of LNCaP cells ( Figure 2AH).…”