Bone-targeted Nanoparticles Research Articles

Synthesis and evaluation of bone targeting PLGA nanoparticles loaded with components of traditional Chinese medicine formulas.

Targeted nanoparticles' preparation can enhance local drug concentration and reduce the side effects of drugs in non-targeted organs. At present, many patents have been applied for in the field of bone-targeted nanoparticles' preparations. They play an important role in the treatment and diagnosis of diseases. In this experiment, nanoparticles with bone targeting function were prepared by poly(lactic-co-glycolic acid) (PLGA) copolymer and tetracycline. These nanoparticles contain active ingredients in the Huangqi Sanxian decoction, a kind of Traditional Chinese Medicine (TCM) compound formula. These nanoparticles are predicted to be useful in the treatment of osteoporosis. Synthesis of tetracycline targeting groups was performed by acylation reaction, and PLGA nanoparticles were prepared by the Emulsification-solvent Evaporation Method. The appearance and particle size of the product were evaluated, and the effects of nanoparticles on the physiological activities of osteoblasts were observed. Finally, the bone-targeting ability of targeted nanoparticles in vivo and in vitro was investigated. The average particle size of the nanoparticles was about 200 nm, and the average drug entrapment was 60%. In vitro evaluation of osteoblasts assay showed that the nanoparticles can be well taken by cells. Their good biocompatibility and sustained-release properties reduce the toxic side effects of drugs when they promote osteoblasts' physiological activities. The results of the in vitro and in vivo bone targeting ability assays showed that tetracycline modified nanoparticles could effectively accumulate in the bone, indicating the great bone-targeting ability of the nanoparticles. The use of PLGA to load active components in the TCM compound formulas and remodel targeting groups is expected to improve drug efficacy, reduce drug dosage, and effects on non- action sites. This may provide new ideas for the development of TCM compound dosage forms. In summary, we prepared PLGA nanoparticles of multiple TCM ingredients with bone targeting ability, and they had good morphological appearance, and a promoting effect on various physiological activities of osteoblasts.

Bone Targeting Nanoparticles for the Treatment of Osteoporosis.

Osteoporosis (OP) affects millions of people worldwide, especially postmenopausal women and the elderly. Although currentavailableanti-OPagents can show promise in slowing down bone resorption, most are not specifically delivered to the hard tissue, causing significant toxicity. A bone-targeted nanodrug delivery system can reduce side effects and precisely deliver drug candidates to the bone. This review focuses on the progress of bone-targeted nanoparticles in OP therapy. We enumerate the existing OP medications, types of bone-targeted nanoparticles and categorize pairs of the most common bone-targeting functional groups. Finally, we summarize the potential use of bone-targeted nanoparticles in OP treatment. Ongoing research into the development of targeted ligands and nanocarriers will continue to expand the possibilities of OP-targeted therapies into clinical application.

Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing.

Despite decades of progress, developing minimally invasive bone-specific drug delivery systems (DDS) to improve fracture healing remains a significant clinical challenge. To address this critical therapeutic need, nanoparticle (NP) DDS comprised of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) functionalized with a peptide that targets tartrate-resistant acid phosphatase (TRAP) and achieves preferential fracture accumulation has been developed. The delivery of AR28, a glycogen synthase kinase-3 beta (GSK3β) inhibitor, via the TRAP binding peptide-NP (TBP-NP) expedites fracture healing. Interestingly, however, NPs are predominantly taken up by fracture-associated macrophages rather than cells typically associated with fracture healing. Therefore, the underlying mechanism of healing via TBP-NP is comprehensively investigated herein. TBP-NPAR28 promotes M2 macrophage polarization and enhances osteogenesis in preosteoblast-macrophage co-cultures in vitro. Longitudinal analysis of TBP-NPAR28 -mediated fracture healing reveals distinct spatial distributions of M2 macrophages, an increased M2/M1 ratio, and upregulation of anti-inflammatory and downregulated pro-inflammatory genes compared to controls. This work demonstrates the underlying therapeutic mechanism of bone-targeted NP DDS, which leverages macrophages as druggable targets and modulates M2 macrophage polarization to enhance fracture healing, highlighting the therapeutic benefit of this approach for fractures and bone-associated diseases.

Molecular Complex of HSIM-loaded Polymeric Nanoparticles: Potential Carriers in Osteoporosis.

Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity via the BMP-Smad signaling pathway. Statins present the liver first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis. Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed via the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and in vitro drug release studies. in vitro binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model. The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively (P < 0.05). Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach.

Dual-responsive nanoparticles targeting bone microenvironment for synergistic chemoimmunotherapy of osteosarcoma by remodeling immune microenvironment

Low delivery efficiency of chemotherapy drugs, poor immunogenicity and suppressive immune microenvironment of tumors seriously affect the prognosis of osteosarcoma (OS) patients. Although promising strategies concerning delivery approaches and immunotherapy have been proposed, few patients with OS could actually benefit from them. The reasons may be attributed to the low efficiency for passive accumulation, the deficiency in tumor immunogenicity, and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Here, we report dual-responsive (pH-responsive and glutathione [GSH]- responsive) nanoparticles (NP2), which possess a high affinity for bone minerals and tumors, to simultaneously enhance the antitumor efficacy and stimulate the immune response. Specifically, upon reaching the acidic tumor microenvironment (TME), NP2 released positively charged nanoparticles (NP1) and negatively charged zoledronic acid (ZA). NP1 exhibited powerful antitumor effects with the assistance of ZA and triggered strong immunogenic cell death (ICD) effect, thereby promoting the maturation of dendritic cells (DCs) and infiltration of CTLs. Meanwhile, NP2 remodeled suppressive TME with the adjuvanticity of ZA, reducing myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and repolarizing tumor associated macrophages (TAMs). At the same time, NP2 could increase programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, revealing excellent inhibitory effects for tumor growth with immune-checkpoint blockade (ICB) immunotherapy. To sum up, this study exemplified a rational design of bone-targeting nanoparticles to promote antitumor efficacy and immune response, thereby shedding light on the strategy of the combination of chemotherapy and immunotherapy as a potential clinical therapy for OS.

Antibiotic delivery from bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus

Osteomyelitis is a hard-to-treat infection of the bone and bone marrow that is mainly caused by Staphylococcus aureus, with an increasing incidence of methicillin-resistant S. aureus (MRSA). Owing to the aggressiveness of these bacteria in colonizing and destroying the bone, systemic antibiotic treatments fail to eradicate the infection. Instead, it normally entails surgery to remove the dead or infected bone. In this work, we report bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis. The nanoparticles have been engineered with a functional gelatine/colistin coating able to hamper premature release from the mesopores while effectively disaggregating the bacterial biofilm. Because antibiotic resistance is a global emergency, we have designed two sets of identical nanoparticles, carrying each of them a clinically relevant antibiotic, that have demonstrated to have synergistic effect. The bone-targeted nanoparticles have been thoroughly evaluated in vitro and in vivo, obtaining a notable reduction of the amount of bacteria in the bone in just 24 h after only one dose, and paving the way for localized, nanoparticle-mediated treatment of MRSA-caused osteomyelitis. Statement of significanceIn this work, we propose the use of bone-targeted mesoporous silica nanoparticles to address S. aureus-caused osteomyelitis that render synergistic therapeutic effect via multidrug delivery. Because the bacterial biofilm is responsible for an aggressive surgical approach and prolonged antibiotic treatment, the nanoparticles have been functionalized with a functional coating able to both disaggregate the biofilm, hamper premature antibiotic release and protect the intact bone. These engineered nanoparticles are able to effectively target bone tissue both in vitro and in vivo, showing high biocompatibility and elevated antibacterial effect.

Bone-Targeting Nanoparticles of a Dendritic (Aspartic acid)3-Functionalized PEG-PLGA Biopolymer Encapsulating Simvastatin for the Treatment of Osteoporosis in Rat Models.

Simvastatin (SIM) is a lipid-lowering drug that also promotes bone formation, but its high liver specificity may cause muscle damage, and the low solubility of lipophilic drugs limits the systemic administration of SIM, especially in osteoporosis (OP) studies. In this study, we utilized the bone-targeting moiety of dendritic oligopeptides consisting of three aspartic acid moieties (dAsp3) and amphiphilic polymers (poly(ethylene glycol)-block-poly(lactic-co-glycolic acid); PEG-PLGA) to create dAsp3-PEG-PLGA (APP) nanoparticles (NPs), which can carry SIM to treat OP. An in vivo imaging system showed that gold nanocluster (GNC)-PLGA/APP NPs had a significantly higher accumulation rate in representative bone tissues. In vivo experiments comparing low-dose SIM treatment (0.25 mg/kg per time, 2 times per week) showed that bone-targeting SIM/APP NPs could increase the bone formation effect compared with non-bone-targeting SIM/PP NPs in a local bone loss of hindlimb suspension (disuse) model, but did not demonstrate good bone formation in a postmenopausal (ovariectomized) model of systemic bone loss. The APP NPs could effectively target high mineral levels in bone tissue and were expected to reduce side effects in other organs affected by SIM. However, in vivo OP model testing showed that the same lower dose could not be used to treat different types of OP.

Aptamer-immobilized bone-targeting nanoparticles in situ reduce sclerostin for osteoporosis treatment

Bone-targeted drug delivery to reduce systemic complications and maintain sufficient doses in bone tissues is the main challenge for osteoporosis treatment. Here, we develop a novel, and simply synthesized bone-targeting nanomedicine (DNA-MSN, DNAM) containing a PEGylated dendritic mesoporous silica nanoparticle (MSN) core (~ 65 nm) and an anti-sclerostin aptamer (Aptscl56) layer, to treat osteoporosis. The nanoparticle core protects the immobilized Aptscl56 from rapid nuclease degradation and renal filtration, prolonging in vivo half-lives. The DNAM-immobilized Aptscl56 layer exhibits dual functions to direct bone-attachment of ovariectomized mice, due to the interaction between phosphate groups in DNA aptamer Aptscl56 and bone calcium in hydroxyapatites, and to in situ capture sclerostin with picomolar affinities. Moreover, we show DNAM significantly reverses the serum level of sclerostin and osteoporotic bone loss to a normal level, improving bone histomorphology parameters and mechanical properties in the femur, and recovering serum levels of bone turnover markers, without systemic toxicity. Notably, the therapeutic effect of DNAM is superior to the "gold standard" drug alendronate, and the systemic dose of DNAM-immobilized Aptscl56 is only 25% of free Aptscl56. The present study provides insights into the regulation of unwanted circulating biohazards and represents a promising approach to deliver nanomedicines to treat osteoporosis.

Bone-Targeted Nanoparticle Drug Delivery System: An Emerging Strategy for Bone-Related Disease.

Targeted delivery by either systemic or local targeting of therapeutics to the bone is an attractive treatment for various bone metabolism diseases such as osteoporosis, osteoarthritis, osteosarcoma, osteomyelitis, etc. To overcome the limitations of direct drug delivery, the combination of bone-targeted agents with nanotechnology has the opportunity to provide a more effective therapeutic approach, where engineered nanoparticles cause the drug to accumulate in the bone, thereby improving efficacy and minimizing side effects. Here, we summarize the current advances in systemic or local bone-targeting approaches and nanosystem applications in bone diseases, which may provide new insights into nanocarrier-delivered drugs for the targeted treatment of bone diseases. We envision that novel drug delivery carriers developed based on nanotechnology will be a potential vehicle for the treatment of currently incurable bone diseases and are expected to be translated into clinical applications.

Nanoparticle‐Mediated Delivery of Micheliolide Analogs to Eliminate Leukemic Stem Cells in the Bone Marrow (Adv. Therap. 1/2022)

In article 2100100, Marian A. Ackun-Farmmer, Hanan Alwaseem, and co-workers use late-stage chemoenzymatic C—H functionalization to synthesize a library of leukemia stem cell (LSC) cytotoxic drug analogs from micheliolide. After rigorous selection, the lead candidate is delivered using bone targeting nanoparticles, which effectively decreases bone marrow LSCs and improves survival without affecting normal hematopoiesis.

Construction and evaluation of detachable bone-targeting MOF carriers for the delivery of proteasome inhibitors.

Tumor bone metastasis is an important cause of tumor recurrence and death. Although bone-targeting nanoparticles decorated with targeting ligands have shown good affinity for bone tissues with the properties of adhesion to the bone matrix, it is not easy to detach from the surface of the bone matrix in the tumor-bone microenvironment, attributed to the robust coordination force between the targeting ligands, such as bisphosphates with bone-deposited calcium. This may hinder the transport of nanoparticles from bone tissue to bone metastatic tumors. In this research, we designed a bone-targeting nanocarrier with detachable bone-targeting character for the therapy of bone metastases. The nanoparticles were constructed by using ZIF-8 and bone-targeting and MMP enzyme sensitive polypeptide-modified hyaluronic acid as a carrier and proteasome inhibitor Bortezomib (BTZ) as cargo. The results show that the constructed D8-M3-HA-ZIF8@BTZ nanoparticles possessed several favorable properties such as good colloidal stability, acid-sensitive drug release, D8 peptide mediated bone targeting and MMP enzyme-responsive desorption. Besides, nanoparticle endocytosis and cytotoxicity were enhanced through HA-mediated targeting to CD44 over-expressing tumor cells. Altogether, this study provides a potential cascade targeting strategy for improving the delivery effects of bone targeted nanoparticles for the delivery of proteasome inhibitors.

Reduction of leukemic burden via bone-targeted nanoparticle delivery of an inhibitor of C-chemokine (C-C motif) ligand 3 (CCL3) signaling.

Leukemias are challenging diseases to treat due, in part, to interactions between leukemia cells and the bone marrow microenvironment (BMME) that contribute significantly to disease progression. Studies have shown that leukemic cells secrete C-chemokine (C-C motif) ligand 3 (CCL3), to disrupt the BMME resulting in loss of hematopoiesis and support of leukemic cell survival and proliferation. In this study, a murine model of blast crisis chronic myelogenous leukemia (bcCML) that expresses the translocation products BCR/ABL and Nup98/HoxA9 was used to determine the role of CCL3 in BMME regulation. Leukemic cells derived from CCL3-/- mice were shown to minimally engraft in a normal BMME, thereby demonstrating that CCL3 signaling was necessary to recapitulate bcCML disease. Further analysis showed disruption in hematopoiesis within the BMME in the bcCML model. To rescue the altered BMME, therapeutic inhibition of CCL3 signaling was investigated using bone-targeted nanoparticles (NP) to deliver Maraviroc, an inhibitor of C-C chemokine receptor type 5 (CCR5), a CCL3 receptor. NP-mediated Maraviroc delivery partially restored the BMME, significantly reduced leukemic burden, and improved survival. Overall, our results demonstrate that inhibiting CCL3 via CCR5 antagonism is a potential therapeutic approach to restore normal hematopoiesis as well as reduce leukemic burden within the BMME.

Fabrication of nanoparticles for bone regeneration: new insight into applications of nanoemulsion technology.

Introducing synthetic bone substitutes into the clinic was a major breakthrough in the regenerative medicine of bone. Despite many advantages of currently available bone implant materials such as biocompatiblity and osteoconductivity, they still suffer from relatively poor bioactivity, osteoinductivity and osteointegration. These properties can be effectively enhanced by functionalization of implant materials with nanoparticles such as osteoinductive hydroxyapatite nanocrystals, resembling inorganic part of the bone, or bioactive polymer nanoparticles providing sustained delivery of pro-osteogenic agents directly at implantation site. One of the most widespread techniques for fabrication of nanoparticles for bone regeneration applications is nanoemulsification. It allows manufacturing of nanoscale particles (<100 nm) that are injectable, 3D-printable, offer high surface-area-to-volume-ratio and minimal mass transport limitations. Nanoparticles obtained by this technique are of particular interest for biomedical engineering due to fabrication procedures requiring low surfactant concentrations, which translates into reduced risk of surfactant-related in vivo adverse effects and improved biocompatibility of the product. This review discusses nanoemulsion technology and its current uses in manufacturing of nanoparticles for bone regeneration applications. In the first section, we introduce basic concepts of nanoemulsification including nanoemulsion formation, properties and preparation methods. In the next sections, we focus on applications of nanoemulsions in fabrication of nanoparticles used for delivery of drugs/biomolecules facilitating osteogenesis and functionalization of bone implants with special emphasis on biomimetic hydroxyapatite nanoparticles, synthetic polymer nanoparticles loaded with bioactive compounds and bone-targeting nanoparticles. We also highlight key challenges in formulation of nanoparticles via nanoemulsification and outline potential further improvements in this field.

Recent advances in bone-targeting nanoparticles for biomedical applications

This review summarizes the progress in bone-targeting ligands, bone-targeting nanoparticles and their potential biomedical applications.

Abstract 6237: Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis

Abstract Background: Protein drugs are one of the most promising new areas in drug research and development, however, great challenges are still faced in the drug delivery in vivo. Previously, we constructed bone targeted micelles for bone metastases. In order to address the issues of protein delivery in vivo and enhanced cancer bone metastasis treatment, we engineered and evaluated a bone-targeting nanoparticles by using metal organic framework nanoparticles (MOFs), bone-targeting agents (Alendronate) and hyaluronic acid (HA) as materials and a protein toxin as therapeutic. Methods: Alendronate (ALN) were conjugated to HA through PEG as linker and ALN-PEG-HA were obtained. Cytochrome C, as modle proteins, were caged in the MOFs (ZIF-8) by selfassembly of Zn2+ and organic ligands (2-methylimidazole) to form protein-encapsulated nanoparticles (ZIF8-CC). And ALN-PEG-HA were further decorated on the surface of ZIF8-CC nanoparticles via the coordination effect between its carboxyls and metal ions in ZIF-8 to result in active-targeting ALN-HA@ZIF8-CC nanopartilces. The materials and nanoparticles were synthesized and characterized by NMR, FT-IR, TEM, DLS, XRD, TGA and N2 adsorption−desorption isotherms analysis. The in vitro release profiles, stability and cytocompatibility were also studied. Results: The synthesis of ALN-PEG-HA was confirmed by 1H-NMR and FT-IR. TEM, XRD and DLS showed that ALN-HA@ZIF8-CC nanopartilces had been prepared, and the experiment of washing nanoparticles with SDS confirmed that protein was encapsulated in ZIF-8 instead of adsorbed on its surface. TGA and N2 absorption-degradation isotherms analysis also confirmed the formation of the crystal structure and porous structure, respectively. HA coated nanoparticles have good stability while ZIF8-CC were easy to aggregate. The results of in vitro release showed that the nanoparticles have acid sensitive release properties and excellent cell compatibility. In addition, In vitro bone fragment targeting experiment confirmed that nanoparticles have strong bone affinity. Conclusions: Our data demonstrated that bone-targeted protein drug-encapsulated MOFs were constructed. Citation Format: Yimin Niu, Cuicui Gao, Hongbin Yang, Qiang Huo, Andrew Wang, Ming Xu, Yang Liu. Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6237.

One stone with two birds: Phytic acid-capped platinum nanoparticles for targeted combination therapy of bone tumors

Targeted drug delivery to malignant bone lesions remains a challenging task in the treatment of bone tumors. In this article, we reported a naturally occurring phytic acid (PA) with both bone-targeting capability and anticancer activity. The PA-capped platinum nanoparticles showed high affinity to hydroxyapatite in vitro and in vivo, and maintained both the inherent anticancer ability of PA and photothermal effect of platinum nanoparticles. PA-capped nanoparticles displayed a 4-fold higher accumulation in the osteolytic lesions than sodium citrate-templated ones, and efficiently inhibited bone tumor growth and the tumor associated-osteolysis upon exposure to a near-infrared light. This study provides a novel and efficient strategy to prepare bone-targeted nanoparticles with inherent anticancer activity for combination therapy of malignant bone tumors.

Abstract B51: Targeted nanoparticle approach to treating metastatic prostate cancer

Abstract Introduction: Treatment outcomes of bone metastatic prostate cancer remain poor despite an increasing number of therapeutic options approved in recent years. Limitations exist in the drugs that are approved, such as no overall survival benefits or serious dose-limiting toxicities. We have engineered a targeted nanoparticle (NP) system to deliver cabazitaxel to bone lesions. The amino-bisphosphonate, alendronate, was used as the bone-targeting moiety on the surface of the NP. The objective of this approach is to increase therapeutic payload at the site of bone metastasis to achieve an improved therapeutic index. Methods: Poly(lactic-co-glycolic acid) NPs were synthesized using a modified water-in-oil-in-water double-emulsion solvent evaporation technique followed by binding of alendronate to the surface of the NP. We characterized NPs for size and zeta potential using dynamic light scattering. Cabazitaxel encapsulation efficiency, drug loading, and release kinetics were optimized by quantification with HPLC analysis. In vitro cell viability studies were performed on C4-2B and PC3 prostate cancer cell lines. 3D prostate cancer spheroids were utilized as well to test cell viability and NP penetration. Ex vivo bone binding studies were used to test nanoparticle affinity for hydroxyapatite structure. In vivo tumor efficacy studies were carried out with male athymic nude mice implanted with intraosseous tumors consisting of PC3-luciferase cells. After bone tumors were established for 1 week, mice were treated via tail vein injection with either saline, free cabazitaxel, non-targeted NPs, or targeted NPs for one month (starting n=6 per group). Response was measured with in vivo bioluminescence imaging, tumor limb weight at conclusion of experiment, and mouse x-ray monitoring. In addition, animal behavior experiments were performed on all treatment groups to assess functional status through gait analysis and pain through von Frey filament assay. Results: NPs were successfully synthesized to mean size of 236 nm with a PDI of .120. Highest encapsulation of cabazitaxel into nanoparticle was 55.8% with a drug loading of 3.7%. Release kinetics showed a strong burst phase release over the first 8 hours and subsequent sustained release up to 72 hours. In vitro cell viability and 3D spheroid experiments showed targeted and nontargeted NP to be equivalent to free drug. Ex vivo bone binding experiment showed targeted NP had a 4-fold increase in binding to bone at 6 hours and an 8-fold increase in bone binding at 72 hours compared to nontargeted NP. Tumor efficacy experiment showed targeted NP and nontargeted NP had a statistically significant overall reduction in tumor measured by bioluminescence (P value &amp;lt; 0.005). Interestingly, mice treated with targeted NP had no bone lesions on x-ray, whereas 100% of mice in saline group, 100% of mice in cabazitaxel group, and 33% of mice in nontargeted NP group had bone lesions. Gait analysis did not show a statistically significant difference between groups. However, von Frey assay showed a significant reduction in relative response in the targeted NP group (P value &amp;lt; 0.005). Conclusion: We have successfully synthesized a bone-targeted NP system. In this project, we have shown that targeted NPs help maintain bone structure in tumor-burdened limbs as well as decrease tumor size. We have also shown that these targeted NPs reduce the relative response to von Frey filament pain stimulation in the tumor limb. This bone-targeted NP system is a promising potential therapeutic in developing improved treatments for bone-metastatic prostate cancer patients. Note: This abstract was not presented at the conference. Citation Format: Andrew Gdowski, Amalendu Ranjan, Marjana Sarker, Jamboor Vishwanatha. Targeted nanoparticle approach to treating metastatic prostate cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B51.

Bone-targeting nanoparticle to co-deliver decitabine and arsenic trioxide for effective therapy of myelodysplastic syndrome with low systemic toxicity

Myelodysplastic syndromes (MDS) are a diverse group of bone marrow disorders and clonal hematopoietic stem cell disorders characterized by abnormal blood cells, or reduced peripheral blood cell count. Recent clinical studies on combination therapy of decitabine (DAC) and arsenic trioxide (ATO) have demonstrated synergy on MDS treatment, but the treatment can cause significant side effects to patients. In addition, both drugs have to be administered on a daily basis due to their short half-lives. In addressing key issues of reducing toxic side effects and improving pharmacokinetic profiles of the therapeutic agents, we have developed a new formulation by co-packaging DAC and ATO into alendronate-conjugated bone-targeting nanoparticles (BTNPs). Our pharmacokinetic studies revealed that intravenously administered BTNPs increased circulation time up to 3days. Biodistribution analysis showed that the BTNP facilitated DAC and ATO accumulation in the bone, which is 6.7 and 7.9 times more than untargeted NP. Finally, MDS mouse model treated with BTNPs showed better restoration of complete blood count to normal level, and significantly longer median survival as compared to free drugs or untargeted NPs treatment. Our results support bone-targeted co-delivery of DAC and ATO for effective treatment of MDS.

Fracture-Targeted Delivery of β-Catenin Agonists via Peptide-Functionalized Nanoparticles Augments Fracture Healing.

Despite several decades of progress, bone-specific drug delivery is still a major challenge. Current bone-acting drugs require high-dose systemic administration which decreases therapeutic efficacy and increases off-target tissue effects. Here, a bone-targeted nanoparticle (NP) delivery system for a β-catenin agonist, 3-amino-6-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-N-(pyridin-3-yl)pyrazine-2-carboxamide, a glycogen synthase kinase 3 beta (GSK-3β) inhibitor, was developed to enhance fracture healing. The GSK-3β inhibitor loading capacity was found to be 15 wt % within highly stable poly(styrene-alt-maleic anhydride)-b-poly(styrene) NPs, resulting in ∼50 nm particles with ∼ -30 mV surface charge. A peptide with high affinity for tartrate-resistant acid phosphatase (TRAP), a protein deposited by osteoclasts on bone resorptive surfaces, was introduced to the NP corona to achieve preferential delivery to fractured bone. Targeted NPs showed improved pharmacokinetic profiles with greater accumulation at fractured bone, accompanied by significant uptake in regenerative cell types (mesenchymal stem cells (MSCs) and osteoblasts). MSCs treated with drug-loaded NPs in vitro exhibited 2-fold greater β-catenin signaling than free drug that was sustained for 5 days. To verify similar activity in vivo, TOPGAL reporter mice bearing fractures were treated with targeted GSK-3β inhibitor-loaded NPs. Robust β-galactosidase activity was observed in fracture callus and periosteum treated with targeted carriers versus controls, indicating potent β-catenin activation during the healing process. Enhanced bone formation and microarchitecture were observed in mice treated with GSK-3β inhibitor delivered via TRAP-binding peptide-targeted NPs. Specifically, increased bone bridging, ∼4-fold greater torsional rigidity, and greater volumes of newly deposited bone were observed 28 days after treatment, indicating expedited fracture healing.

Redox and pH dual sensitive bone targeting nanoparticles to treat breast cancer bone metastases and inhibit bone resorption.

Bone is an especially prone metastatic site for breast cancer, and to block the vicious cycle between bone resorption and tumor growth is an important strategy for the treatment of breast cancer bone metastasis. In this paper, pH- and redox-sensitive as well as breast cancer bone metastasis-targeting nanoparticles (DOX@ALN-(HA-PASP)CL) were prepared, and also their anti-tumor activity and anti-bone resorption effect were investigated in detail. The in vitro experimental results indicated that DOX released from DOX@ALN-(HA-PASP)CL exhibited a GSH-, DTT- and pH-dependent manner. Moreover, in an in vitro 3D breast cancer bone metastasis model, DOX@ALN-(HA-PASP)CL decreased bone resorption through inhibiting the proliferation of human breast cancer cells (MDA-MB-231 cells) and reducing the activity of osteoclasts. The in vivo experimental results indicated that a large amount of DOX was delivered to a breast cancer bone metastasis site after tumor-bearing mice were treated with DOX@ALN-(HA-PASP)CL; meanwhile, DOX@ALN-(HA-PASP)CL significantly decreased the tumor volume and bone resorption in tumor-bearing mice without causing obvious systemic toxicity. In conclusion, the in vitro and in vivo experimental results indicate that DOX@ALN-(HA-PASP)CL has great potential in the treatment of breast cancer bone metastasis.