Bone-targeting Ability Research Articles

Engineered extracellular vesicle-delivered TGF-β inhibitor for attenuating osteoarthritis by targeting subchondral bone

Osteoarthritis (OA) is a disease that affects the entire joint. To treat OA, it may be beneficial to inhibit the activity of TGF-β in the subchondral bone. However, delivering drugs to the subchondral bone using conventional methods is challenging. In this study, we developed an extracellular vesicle delivery system. The utilization of macrophage-derived extracellular vesicles as a drug-carrying platform enables drugs to evade immune clearance and cross biological barriers. By incorporating targeting peptides on the surface of extracellular vesicles, the drug platform becomes targeted. The combination of these two factors results in the successful delivery of the drug to the subchondral bone. The study evaluated the stability, cytotoxicity, and bone targeting capability of the engineered extracellular vesicle platform (BT-EV-G). It also assessed the effects of BT-EV-G on the differentiation, proliferation, and migration of bone mesenchymal stem cells (BMSCs). Additionally, the researchers administered BT-EV-G to anterior cruciate ligament transection (ACLT)-induced OA mice. The results showed that BT-EV-G had low toxicity and high bone targeting ability both in vitro and in vivo. BT-EV-G can restore coupled bone remodeling in subchondral bone by inhibiting pSmad2/3-dependent TGF-β signaling. This work provides new insights into the treatment of OA.

Alendronate carbon dots targeting bone immune microenvironment for the treatment of osteoporosis

Bisphosphonates (BPs) are some of the most widely used drugs in osteoporosis (OP) treatment, but they can cause severe side effects such as bisphosphonate-related osteonecrosis of the jaw (BRONJ), causing great pain in patients. It is necessary to develop a novel drug for treating OP with fewer side effects. In this study, novel carbon dots, ALEN-CDs, derived from polyethylene glycol (PEG) and alendronate (ALEN) are developed. ALEN-CDs have good biocompatibility, photoluminescence (PL) properties, and bone-targeting ability. They can inhibit the differentiation and maturation of osteoclasts, play an immunoregulatory role by inhibiting macrophage polarization to the pro-inflammatory M1 phenotype, and promote polarization to the anti-inflammatory M2 phenotype. It is worth noting that compared with ALEN, high-dose applications of ALEN-CDs do not lead to BRONJ, which may be related to the regulatory effect on M2 macrophage polarization. Moreover, in vivo studies show that ALEN-CDs significantly reduce bone loss and improve OP in ovariectomized mice (OVX). And a proteomic analysis suggestes that ALEN-CDs regulate the bone immune microenvironment by affecting mitochondrial metabolism, especially oxidative phosphorylation (OXPHOS). In conclusion, ALEN-CDs could directly inhibit osteoclast differentiation and regulate the bone immune microenvironment and may be a promising drug for OP treatment.

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.

Effects of chain lengths and backbone chirality on the bone-targeting ability of poly(glutamic acid)s.

Anionic synthetic polypeptides are promising candidates as standalone bone-targeting drug carriers. Nevertheless, the structure-property relationship of the bone-targeting ability of polypeptides remains largely unexplored. Herein we report the optimization of the in vitro and in vivo bone-targeting ability of poly(glutamic acid)s (PGAs) by altering their chain lengths and backbone chirality. PGA 100-mers exhibited higher hydroxyapatite affinity in vitro, but their rapid macrophage clearance limited their targeting ability. Shorter PGA was therefore favored in terms of in vivo bone targeting. Meanwhile, the backbone chirality showed less significant impact on the in vitro and in vivo targeting behavior. This study highlights the modulation of structural parameters on the bone-targeting performance of anionic polypeptides, shedding light on the future design of polypeptide-based carriers.

Bone-Targeting Peptide and RNF146 Modified Apoptotic Extracellular Vesicles Alleviate Osteoporosis.

Osteoporosis is a highly prevalent disease that causes fractures and loss of motor function. Current drugs targeted for osteoporosis often have inevitable side effects. Bone marrow mesenchymal stem cell (BMSCs)-derived apoptotic extracellular vesicles (ApoEVs) are nanoscale extracellular vesicles, which has been shown to promote bone regeneration with low immunogenicity and high biological compatibility. However, natural ApoEVs cannot inherently target bones, and are often eliminated by macrophages in the liver and spleen. Thus, our study aimed to reconstruct ApoEVs to enhance their bone-targeting capabilities and bone-promoting function and to provide a new method for osteoporosis treatment. We conjugated a bone-targeting peptide, (Asp-Ser-Ser)6 ((DSS)6), onto the surface of ApoEVs using standard carbodiimide chemistry with DSPE-PEG-COOH serving as the linker. The bone-targeting ability of (DSS)6-ApoEVs was determined using an in vivo imaging system and confocal laser scanning microscopy (CLSM). We then loaded ubiquitin ligase RING finger protein146 (RNF146) into BMSCs via adenovirus transduction to obtain functional ApoEVs. The bone-promoting abilities of (DSS)6-ApoEVs and (DSS)6-ApoEVsRNF146 were measured in vitro and in vivo. Our study successfully synthesized bone-targeting and gained functional (DSS)6-ApoEVsRNF146 and found that engineered ApoEVs could promote osteogenesis in vitro and exert significant bone-targeting and osteogenesis-promoting effects to alleviate osteoporosis in a mouse model. To promote the bone-targeting ability of natural ApoEVs, we successfully synthesized engineered ApoEVs, (DSS)6-ApoEVsRNF146 and found that they could significantly promote osteogenesis and alleviate osteoporosis compared with natural ApoEVs, which holds great promise for the treatment of osteoporosis.

A Janus-ROS Healing System Promoting Infectious Bone Regeneration via Sono-Epigenetic Modulation.

Elimination of bacterial infections and simultaneously promoting osteogenic differentiation are highly required for infectious bone diseases. Massive reactive oxygen species (ROS) can damage cells, while low ROS concentrations as a molecular signal can regulate cellular fate. In this study, a Janus-ROS healing system is developed for infectious bone regeneration. An alendronate (ALN)-mediated defective metal-organic framework (MOF) sonosensitizer is prepared, which can effectively clear Methicillin-resistant Staphylococcus aureus (MRSA) infections and promote osteogenic differentiation under differential ultrasonic irradiation. In the presence of zirconium-phosphate coordination, the ALN-mediated porphyrin-based MOF (HN25) with a proper defect has great sonodynamic antibacterial efficiency (98.97%, 15min) and bone-targeting ability. Notably, under low-power ultrasound irradiation, HN25 can increase the chromatin accessibility of ossification-related genes and FOXO1 to promote bone repair through low ROS concentrations. Animal models of paravertebral infection, fracture with infection, and osteomyelitis demonstrate that HN25 successfully realizes the targeted and potent repair of various infectious bone tissues through rapid MRSA elimination, inhibiting osteoclast activity and promoting bone regeneration. The results show that high catalytic efficiency and bioactive MOF can be constructed using pharmaceutical-mediated defect engineering. The Janus-ROS treatment is also a promising therapeutic mode for infectious tissue regeneration.

Targeted Nanoparticles Based on Alendronate Polyethylene Glycol Conjugated Chitosan for the Delivery of siRNA and Curcumin for Bone Metastasized Breast Cancer Applications.

Bone metastasized breast cancer reduces the quality of life and median survival. Targeted delivery of small interfering RNA (siRNA) and chemotherapeutic drugs using nanoparticles (NPs) is a promising strategy to overcome current limitations in treating these metastatic breast cancers. This research develops alendronate conjugated polyethylene glycol functionalized chitosan (ALD-PEG-CHI) NP for the delivery of cell death siRNA (CD-siRNA) and curcumin (CUR) and explores its targeting ability and in vitro cell cytotoxicity. Polyethylene glycol functionalized CHI (mPEG-CHI) NPs serve as control. The size of CD-siRNA loaded NPs is below 100nm while CUR loaded NPs is below 200nm, with near neutral zeta potential for all NPs. The CUR encapsulation efficiency (EE) is 70% and 88% for targeted and control NPs, respectively, while complete encapsulation of CD-siRNA is achieved in both NP systems. The bone targeting ability of CY5-dsDNA loaded ALD-PEG-CHI NPs using hydroxyapatite discs is fivefold compared to control indicating ALD presentation at the targeting NP surface. Delivery of CD-siRNA loaded NPs and CUR loaded NPs show synergistic and additive growth inhibition effects against MCF-7 cells by mPEG-CHI and ALD-PEG-CHI NPs, respectively. Overall, these in vitro results illustrate the potential of the targeted NPs as an effective therapeutic system toward bone metastasized breast cancer.

EGTA-Derived Carbon Dots with Bone-Targeting Ability: Target-Oriented Synthesis and Calcium Affinity.

The bone-targeting mechanism of clinic bisphosphonate-type drugs, such as alendronate, risedronate, and ibandronate, relies on chelated calcium ions on the surface of the bone mineralized matrix for the treatment of osteoporosis. EGTA with aminocarboxyl chelating ligands can specifically chelate calcium ions. Inspired by the bone-targeting mechanism of bisphosphonates, we hypothesize that EGTA-derived carbon dots (EGTA-CDs) hold bone-targeting ability. For the target-oriented synthesis of EGTA-CDs and to endow CDs with bone targeting, we designed calcium ion chelating agents as precursors, including aminocarboxyl chelating agents (EGTA and EDTA) and bisphosphonate agents (ALN and HEDP) for the target-oriented synthesis of aminocarboxyl-derived CDs (EGTA-CDs and EDTA-CDs) and bisphosphonate-derived CDs (ALN-CDs and HEDP-CDs) with high synthetic yield. The synthetic yield of EGTA-CDs reached 87.6%. Aminocarboxyl-derived CDs and bisphosphonate-derived CDs retain the chelation ability of calcium ions and can specifically bind calcium ions. The chemical environment bone-targeting value coordination constant K and chelation sites of EGTA-CDs were 6.48 × 104 M-1 and 4.12, respectively. A novel method was established to demonstrate the bone-targeting capability of chelate-functionalized carbon dots using fluorescence quenching in a simulated bone trauma microenvironment. EGTA-CDs exhibit superior bone-targeting ability compared with other aminocarboxyl-derived CDs and bisphosphonate-derived CDs. EGTA-CDs display exceptional specificity toward calcium ions and better bone affinity than ALN-CDs, suggesting their potential as novel bone-targeting drugs. EGTA-CDs with strong calcium ion chelating ability have calcium ion affinity in simulated body fluid and bone-targeting ability in a simulated bone trauma microenvironment. These findings offer new avenues for the development of advanced bone-targeting strategies.

Quasi-dendritic sulfonate-based organic small molecule for high-quality NIR-II bone-targeted imaging

The visualization of bone imaging in vivo is of great significance for the understanding of some bone-related diseases or physiological processes. Herein, a bone-targeted NIR-II small molecule (TTQF-SO3), which was modified with multiple sulfonate groups, was successfully fabricated for the second near-infrared (NIR-II) bone imaging. In vitro studies revealed that TTQF-SO3 showed high affinity for hydroxyapatite and excellent macrophage accumulation ability. In in vivo assays, TTQF-SO3 displayed high bone uptake ability and high NIR-II bone imaging quality, demonstrating the specific bone-targeting ability of the sulfonate-containing probe. In addition, the noninvasive NIR-II imaging detection in bone calcium loss was successfully verified in osteoporosis mice models. Moreover, the negative charge characteristic of TTQF-SO3 showed efficient lymphoid enrichment in living mice by intravenous injection. Overall, these warrant that our TTQF-SO3 is an optimal bone-targeted diagnostic agent for high-quality NIR-II imaging, highlighting its potential promise for clinical translation.Graphical

Phytic acid-modified manganese dioxide nanoparticles oligomer for magnetic resonance imaging and targeting therapy of osteosarcoma

Osteosarcoma is the most common malignant tumor in the skeletal system with high mortality. Phytic acid (PA) is a natural compound extracted from plant seeds, which shows certain antitumor activity and good bone targeting ability. To develop a novel theranostics for magnetic resonance imaging (MRI) and targeting therapy of osteosarcoma, we employed PA to modify manganese dioxide nanoparticles (MnO2@PA NPs) for osteosarcoma treatment. The MnO2 NPs oligomer was formed by PA modification with uniformed size distribution and negative zeta potential. Fourier-transform infrared spectroscopy, X-ray diffraction, energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis demonstrated that PA has been successfully modified on MnO2 NPs, and the structure of MnO2@PA NPs is amorphous. In vitro experiments demonstrated that MnO2@PA NPs oligomer can be efficiently internalized by tumor cell, and the internalized NPs can react with H2O2 under acid microenvironment to produce Mn2+ and O2. In vivo experiments demonstrated that MnO2@PA NPs oligomer can passively accumulate in tumor tissue, and the accumulated NPs can produce Mn2+ and O2 for MRI and targeting therapy of osteosarcoma. In conclusion, we prepared a novel bone-targeting nano theranostics for MRI and therapy of osteosarcoma.

Bone-targeted bioengineered bacterial extracellular vesicles delivering siRNA to ameliorate osteoporosis

Osteoporosis (OP), characterized by decreased bone mass and destruction of bone microarchitecture, is the most common bone degenerative disease. Conventional treatments for OP have several side effects, new treatment approaches are needed. Bacterial extracellular vesicles (BEVs) carrying curative molecules have emerged as a promising alternative due to their unique nanosized structures, stable loading capacity, good biocompatibility, ease of modification, and industrialization. In this study, we modified probiotics Escherichia coli Nissle 1917 (ECN) to overexpress hCXCR4 fused with the ClyA on the membrane surface of BEVs. The bone targeted BEVs took advantage of the intrinsic anti-OP function and loaded with SOST siRNA to generate BEVs-hCXCR4-SOST siRNA (BEVs-CSs). The customized BEVs-CSs have exhibited great bone targeting ability without long-term cytotoxicity. In addition, the bioengineered BEVs-CSs can be internalized by bone marrow mesenchymal stem cell and promote their osteogenic differentiation with significant cytocompatibility. Finally, the bifunctional BEVs-CSs successfully reversed the OP in an ovariectomized mouse model. Taken together, such a bioengineered BEVs-based strategy provides an innovative, safe, efficient and promising therapeutic solution for intractable OP treatment.

Alendronate modified mPEG-PLGA nano-micelle drug delivery system loaded with astragaloside has anti-osteoporotic effect in rats

Astragaloside (AS) has an anti-osteoporotic effect, but its poor water solubility and low bioavailability limit its application. In this study, a novel nano-carrier with bone targeting was prepared by modifying mPEG-PLGA with alendronate (AL) before incorporation into astragaloside nano-micelles (AS-AL-mPEG-PLGA) to enhance the oral bioavailability, bone targeting and anti-osteoporosis effect of AS. The release behavior of AS-AL-mPEG-PLGA in vitro was investigated via dialysis. The pharmacokinetics of AS-AL-mPEG-PLGA was studied in Sprague-Dawley (SD) rats. The cytotoxicity of AS-AL-mPEG-PLGA in vitro (via MTT method), coupled with bone targeting ability in vitro and in vivo were evaluated. The therapeutic effects of free AS and AS-AL-mPEG-PLGA (ELISA, micro-CT, H&E staining) were compared in osteoporotic rats. AS-AL-mPEG-PLGA with smaller particle size (45.3 ± 3.8 nm) and high absolute zeta potential (−23.02 ± 0.51 mV) were successfully prepared, wherein it demonstrated higher entrapment efficiency (96.16 ± 0.18%), a significant sustained-release effect for 96 h and acceptable safety within 10–200 μg/mL. AS-AL-mPEG-PLGA could enhance the hydroxyapatite affinity and bone tissue concentration of AS. The relative bioavailability of AS-AL-mPEG-PLGA was 233.90% compared with free AS. In addition, the effect of AS in reducing serum levels of bone metabolism-related indicators, restoring the bone microarchitecture and improving bone injury could be enhanced by AS-AL-mPEG-PLGA. AS-AL-mPEG-PLGA with small particle size, good stability, remarkable sustained-release effect, safety and bone targeting was successfully constructed in this experiment to potentially improve the oral bioavailability and anti-osteoporosis effect of AS. Thus, AS-AL-mPEG-PLGA may be a promising strategy to prevent and treat osteoporosis.

Bioinspired Nanovesicles Convert the Skeletal Endothelium-Associated Secretory Phenotype to Treat Osteoporosis.

Recently, bone marrow endothelial cells (BMECs) were found to play an important role in regulating bone homeostasis. However, few studies utilized BMECs to treat bone metabolic diseases including osteoporosis. Here, we reported bioinspired nanovesicles (BNVs) prepared from human induced pluripotent stem cells-derived endothelial cells under hypoxia culture through an extrusion approach. Abundant membrane C-X-C motif chemokine receptor 4 conferred these BNVs bone-targeting ability and the endothelial homology facilitated the BMEC tropism. Due to their unique endogenous miRNA cargos, these BNVs re-educated BMECs to secret cytokines favoring osteogenesis and anti-inflammation. Owing to the conversion of secretory phenotype, the osteogenic differentiation of bone mesenchymal stem cells was facilitated, and the M1-macrophage-dominant pro-inflammatory microenvironment was ameliorated in osteoporotic bones. Taken together, this study proposed BMEC-targeting nanovesicles treating osteoporosis via converting the skeletal endothelium-associated secretory phenotype.

Bone targeting antioxidative nano-iron oxide for treating postmenopausal osteoporosis

Osteoporosis is the most common degenerative orthopedic disease in the elderly. Recently, the therapeutic methods for osteoporosis have shifted towards the regulation of local immunity in bone tissues, which could provide a suitable environment for the positive regulation of bone metabolism, promoting osteogenic differentiation and inhibiting osteoclast differentiation. Our previous work demonstrated that iron oxide nanoparticles (IONPs) could positively regulate bone metabolism in vitro. In this study, we further demonstrated that daily administration of IONPs relieved estrogen deficiency-induced osteoporosis via scavenging reactive oxygen species in vivo. Meanwhile, IONPs promoted the osteogenic differentiation of bone marrow mesenchymal stem cells and inhibited the osteoclast differentiation of monocytes from IONPs treated mice. Besides, alendronate, a clinically used anti-osteoporosis bisphosphate, was employed to precisely deliver the IONPs to the bone tissues and played a synergically therapeutic role. Eventually, we verified the bone targeting ability, therapeutic efficiency, and biocompatibility of the novel bone target iron oxides in ovariectomy-induced osteoporotic mice. By applying BTNPs, the OVX-induced osteoporosis was significantly revised in mice models via the positive regulation of bone metabolism.

Fabrication of bone-targeting hyaluronic acid coupled alendronate-bioactive glass for osteosarcoma therapy

Osteosarcoma is a complicated clinical cancer for patients, which seriously reduces the quality of life. The current conventional treatment is focused on controlling cancer cell proliferation and osteoclast activity. The aim is to develop mesoporous bioactive glass (MBG) with bone-targeting hyaluronic acid-alendronate (HA-ALN) components for osteosarcoma treatment. The prepared MBG was enclosed by the HA-ALN to form mesoporous bioactive glass nanocomposites (MBGNCs) and characterized surface functionalization, size, shape, and morphology. MBG nanoparticles were spherical and smooth surfaces; after coating with HA-ALN they exhibited a stable structure with changes in the surface textures. Bisphosphonate coupled HA controls the swelling under physiological conditions by preventing rapid degradation of the nanocomposites. It also confirms the drug release, which shows a maximum of 65% DOX release at pH 4.5. Drug release studies confirm the pH variation was slightly altered in the DOX release ratio due to the HA-ALN. It also helps in higher binding ability on the hydroxyapatite components, indicating the bone targeting ability and nanocomposites. ALN components actively inhibit osteoclast-like cells. MBGNCs witnessed the higher toxicity to the osteosarcoma cancer cells of IC50 value of 4 μg/mL. MBGNCs inhibitory effects on the viability of the MG-63 osteosarcoma cancer cells were higher compared to free DOX. The bone targeting effect of HA-ALN coated MBGNCs shows higher cellular uptake, which helps inhibit tumor growth and helps in the long term of bone tissue regeneration. MBGNCs highly followed the bone targeting, pH-dependent drug release contributed to the treatment of bone metastasis and promoted osteoblast differentiation.

Azide-Dye Unexpected Bone Targeting for Near-Infrared Window II Osteoporosis Imaging.

Azide is an important chemical functional group and has been widely used in chemical biology. However, the impact of azide on the in vivo behaviors of compounds has been rarely studied. Herein, azide was introduced into a fluorescent dye for the near-infrared window two (NIR-II) bone imaging. Specifically, we designed and synthesized the small-molecule NIR-II dyes, N3-FEP-4T capped with azide and FEP-4T without azide capping. In vitro assays revealed that N3-FEP-4T showed 5- and 5.6- times higher hydroxyapatite accumulation and macrophage uptake than those of FEP-4T, respectively. Moreover, N3-FEP-4T displayed higher bone uptakes and much better bone NIR-II imaging quality, demonstrating the specific bone-targeting ability of the azide-containing probe. N3-FEP-4T was then further successfully used for osteoporosis NIR-II imaging. Overall, our study provides insights into the impact of azide on the in vivo behavior of azide-containing compounds and opens a new window for biological application of azide.

Targeting Burkitt's Lymphoma Using Novel, Discrete Carbon Nanotubes

Burkitt's lymphoma is an incredibly aggressive B-cell derived non-Hodgkin lymphoma that is quickly fatal if left untreated. Doxorubicin (Doxo) provides one method of treatment for this cancer, but has numerous common side effects including significant weight loss, nausea, hair loss, bone marrow suppression, vomiting, rash, heart damage, allergic reaction, tissue damage at injection site, and treatment-related leukemia. Therefore, better therapies which deliver Doxo specifically to tumor cells hold great promise for a more effective therapy with reduced side-effect severity. Carbon nanotubes (CNTs) have long been of interest as drug delivery transporters because of their unique structure, high drug-binding surface area, and variety of customization options. Unfortunately, most CNTs have proven toxic during in vivo studies because of the presence of high residual contaminants and near-unavoidable aggregative properties. A novel form of clean, discrete CNT (dCNT) marketed as Medical Grade MOLECULAR REBAR® (MGMR®) lack the aggregative problems and high toxin levels of CNT before them and show promise as a drug delivery technology.We observed no toxicity of dCNTs in vitro across multiple cell types or in vivo in mice establishing a high MTD of at least 70 mg/kg by an i.v. route. Biodistribution studies of Lu-177 radioisotope labeled dCNTs (single tail vein injection into BALB/C female mice) demonstrated tolerability and clearance from various organs. Mice were sacrificed at 7 timepoints under 34d and many organs were analyzed for accumulation. The liver, spleen, and blood identified one route of clearance and distribution, but it was interesting to note that the bone retained ~10% of injected dCNTs at all time points, demonstrating potential for bone targeted therapies. Further targeting to the bone was possible by grafting commonly available bone chelators to the surface of the dCNT to create BT-dCNT as shown by significantly great adhesion (p<0.05) to ex vivo bone.Protocols were then developed to saturate the surface of the dCNT with therapeutic Active Pharmaceutical Ingredients (API) and then characterize their elution/release over time. We then optimized methods for drug-loading and observed a slow drug release profile for most drugs. Enhanced pharmacokinetic information was tested in cell culture and then confirmed by animal experimentation. In addition, cell penetration and delivery study of MGMR® in vitro showed that endocytosis is nontoxic and well tolerated and that small peptides can be delivered to cancer cells and retain their functionality. Zeta Potential measurements (-40 to -50 mV) and Dynamic Light Scattering validated the stability of different dCNTs over time.Lastly, in a Raji-Burkitt's lymphoma mouse model, we saw significant increases in survival, and decreases in tumor burden in mice treated with Doxo (free, in dCNTs, and in BT-dCNTs vs no drug control). SCID mice were inoculated via the tail vein with 2x105 Raji B. luc+ tumor cells and treated once a week with one of the following: Doxo (5 mg/kg), dCNTs (14.29 mg/kg), dCNTs (14.29 mg/kg) + Doxo (5 mg/kg), BT-dCNTs (14.29 mg/kg) + Doxo (5 mg/kg), or no treatment. Using whole body bioluminescence imaging (BLI), we saw that the groups receiving both the Doxo-loaded dCNTs and the Doxo-loaded BT-dCNTs had greatly reduced tumor burden over time compared to untreated groups, and a tumor burden similar to those that received free Doxo alone (Figure 1A). Both groups receiving Doxo-loaded dCNTs also showed increased survival compared to the Doxo alone group (Figure 1B). Importantly, the typical signs of Doxo toxicity in mice, characterized by rapid weight loss or drug-related mortality, were not seen in the groups that received Doxo-loaded CNTs (Figure 1C).In summary, dCNTs is a highly promising biomedical tool for drug delivery for clinical applications. Our dCNTs represent a promising platform for use in biomedical research as they have proven to be nontoxic, tunable, stable, and capable of drug delivery and organ-specific targeting. This novel technology gives great promise for the bone-targeting ability of novel carbon nanotubes in vivo as a bone-specific drug delivery mechanism for diseases that grow in bone or bone marrow specifically. [Display omitted] DisclosuresFalank:BioPact Ventures, LLC: Research Funding. Tassett:BioPact Ventures, LLC: Employment. Harris:BioPact Ventures, LLC: Research Funding. Farrell:BioPact Ventures, LLC: Research Funding. Everill:BioPact Ventures, LLC: Employment. Reagan:BioPact Ventures, LLC: Research Funding.

Bone targeting nano-aggregates prepared from self-assembled polyaspartamide graft copolymers for pH sensitive DOX delivery.

Nanoparticles with bone targeting ability and pH-sensitivity were prepared with polyaspartamide (PASPAM) derivatives based on polysuccinimide (PSI) grafted with octadecylamine (C18), hydrazine (HYD) and polyethylene glycol (PEG, Mw: 5000). For the bone targeting, alendronate (ALN), which has bone affinity, was grafted to PEG and doxorubicin (DOX) was conjugated with linkers of acid sensitive hydrazone bonds, which can be cleaved most effectively in an intracellular acidic environment. At pH 5.0, ∼75% of the drug was released from ALN-PEG/C18/HYD-DOX-g-PASPAM due to the effective cleavage of HYD under the acidic condition. Also, ALN-PEG/C18/HYD-DOX-g-PASPAM particles were more effectively adsorbed on the surface of bone than PEG/C18/HYD-DOX-g-PASPAM. According to an in vivo antitumor activity test, the volume of tumor treated with ALN-PEG/C18/HYD-DOX-g-PASPAM decreased (1550 mm3) when compared with the PBS control sample (3850 mm3), proving that ALN-PEG/C18/HYD-DOX-g-PASPAM is an effective drug delivery system for the treatment of bone metastasis of breast cancer.

EDTA-Modified 17β-Estradiol-Laden Upconversion Nanocomposite for Bone-Targeted Hormone Replacement Therapy for Osteoporosis

Hormone therapy (HT) is one of the most effective treatments for osteoporosis. However, the nonselective accumulation of hormone in organs such as breast, heart and uterus other than bones causes serious side effects, which impedes the application of HT. Hence, it is critically important to develop a HT strategy with reduced non-specific enrichment of hormone drugs in non-target tissues and enhanced bone-targeting ability.Methods: Herein, a 17β-estradiol (E2)-laden mesoporous silica-coated upconversion nanoparticle with a surface modification of ethylenediaminetetraacetic acid (EDTA) (NaLuF4:Yb,Tm@NaLuF4@mSiO2-EDTA-E2, E2-csUCNP@MSN-EDTA) is developed for bone-targeted osteoporosis hormone therapy. EDTA was attached onto the surface of E2 upconversion nanocomposite to enhance its affinity and efficiency targeting bone tissue and cells to optimize hormone replacement therapy for osteoporosis. We characterized the size, cytotoxicity, loading and release efficiency, in situ and ex vivo imaging. Further, in vitro and in vivo osteogenic ability was tested using preosteoblast and ovariectomy mouse model of osteoporosis.Results: The upconversion core of E2-csUCNP@MSN-EDTA nanoparticle serves as an excellent imaging agent for tracking the loaded hormone drug in vivo. The mesoporous silica layer has a high loading efficiency for E2 and provides a relatively long-lasting drug release within 50 h. EDTA anchored on the silica layer endows the nanocomposite with a bone targeting property. The nanocomposite effectively reverses estrogen deficiency-induced osteoporosis and reduces the damage of hormone to the uterus. The bone mineral density in the nanocomposite treatment group is nearly twice that of the ovariectomized (OVX) group. Compared with the E2 group, the uterine weight and luminal epithelial height were significantly lower in the nanocomposite treatment group.Conclusion: This work demonstrated that E2-csUCNP@MSN-EDTA alleviates the side effect of hormone therapy while maintaining its therapeutic efficacy, which has great potential for developing the next generation of methods for osteoporosis treatment.

Near-Infrared Contrast Agents for Bone-Targeted Imaging.

For the bone-specific imaging, a structure-inherent targeting of bone tissue recently has been reported a new strategy based on incorporation of targeting moieties into the chemical structure of near-infrared (NIR) contrast agents, while conventional methods require covalent conjugation of bone-targeting ligands to NIR contrast agents. This will be a new approach for bone-targeted imaging by using the bifunctional NIR contrast agents. The goal of this review is to provide an overview of the recent advances in optical imaging of bone tissue, highlighting the structure-inherent targeting by developing NIR contrast agents without the need for a bone-targeting ligand such as bisphosphonates. A series of iminodiacetated and phosphonated NIR contrast agents for the structure-inherent targeting of bone tissue showed excellent bone-targeting ability in vivo without non-specific binding. Additionally, the phosphonated NIR contrast agents could be useful in the diagnosis of bone metastasis. By developing bone-targeted NIR contrast agents, optical imaging of bone tissue makes it very attractive for preclinical studies of bone growth or real-time fluorescence guided surgery resulting in high potential to shift the clinical paradigms.