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Formulating drugs into nanoparticles that target sites of disease can lead to strong therapeutic effects with lower doses of drugs and lower rates of off-target adverse effects. Few ways to target drugs to bone have been described, hampering the treatment of osteoporosis. Here we exploit the ability of alendronate to bind tightly to hydroxyapatite in bone as a tactic to target polymeric micelles loaded with the plant flavonoid icaritin to osteoporotic lesions. The traditional Chinese medicine icaritin, from Herba Epimedii, has previously been shown to inhibit adipogenesis and enhance osteogenesis by bone mesenchymal stem cells, but the compound on its own persists only briefly in the bloodstream. Our delivery system led to stronger inhibition of adipogenesis and activation of osteogenesis in a rat model of osteoporosis than when the icaritin-loaded micelles lacked alendronate. These results establish the feasibility of using alendronate to target osteogenic phytomolecules to sites of bone injury, which may guide the development of effective therapies against osteoporosis and, by extension, other bone disorders. [Display omitted] • Alendronate (ALN) targets icaritin to bone for treating osteoporosis. • ALN targets micelles to hydroxyapatite in bone through extensive ionic interactions. • Icaritin promotes BMSC differentiation into osteoblasts to regenerate injured bone. [ABSTRACT FROM AUTHOR]

Erik Briffault,1,2 Ricardo Reyes,2,3 Patricia Garcia-Garcia,1,2 Helena Rouco,1 Luis Diaz-Gomez,4 Maria Rosa Arnau,2,5 Carmen Evora,1,3 Patricia Diaz-Rodriguez,2,4 Araceli Delgado1,2 1Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, La Laguna, 38206, Spain; 2Institute of Biomedical Technologies (ITB), Universidad de La Laguna, La Laguna, 38320, Spain; 3Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, 38200, Spain; 4Department of Pharmacology, Pharmacy and Pharmaceutical Technology, I+D Farma Group (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, Santiago de Compostela, 15782, Spain; 5Servicio de Estabulario, Universidad de La Laguna, La Laguna, 38206, SpainCorrespondence: Patricia Diaz-Rodriguez; Araceli Delgado, Email patricia.diaz.rodriguez@usc.es; adelgado@ull.edu.esIntroduction: Osteoporosis is a metabolic disorder characterized by the loss of bone mass and density. Nucleic acid-based therapies are among the most innovative approaches for osteoporosis management, although their effective delivery to bone tissue remains a challenge. In this work, SFRP1-silencing GampeR loaded-nanoparticles were prepared and functionalized with specific moieties to improve bone targeting and, consequently, therapeutic efficacy. SFRP1-silencing would promote osteoblastic differentiation by enhancing the WNT/β-catenin pathway and thus diminishing the progression of osteoporosis.Methods: A nucleic acid-based delivery system consisting of lipid-polymer hybrid nanoparticles (LPNPs) loading a GapmeR for SFRP1 silencing was developed and further functionalized with two bone-targeting moieties: a specific aptamer (Apt) for murine mesenchymal stem cells and an antiresorptive drug, namely alendronate (ALD). These systems were tested in vivo in osteoporotic mice at different dosage regimens to analyze dose dependence in bone-forming activity and potential toxicity. The quality of trabecular and cortical bone was assessed by both micro computed tomography (micro-CT) and histological and histomorphometric analyses. Early and late osteogenesis were quantified by immunohistochemistry.Results: Results showed that functionalizing LPNPs loaded with an SFRP1-silencing GapmeR using both Apt and ALD improved bone quality and enhanced osteogenesis following a dose–effect relationship, as revealed by micro-CT, histological and immunohistochemical analyses. In contrast, non-functionalized LPNPs did not produce these effects.Conclusion: These findings highlight the relevance of proper targeting and dosage in nucleic acid-based therapeutics, proving to be crucial for exerting their therapeutic effect: a deficient targeting strategy and/or dosage may result in the therapeutic failure of an adequate gene therapy agent. Keywords: osteoporosis, bone targeting, nanoparticle dose-effect, gene therapy, aptamer, alendronate, micro-CT

Demeng Xia,1,2,* Qingqing Qian,1,* Sheng Wang,3,* Xiao Dong,4 Ying Liu5 1Department of Pharmacy, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, 200240, People’s Republic of China; 2Department of Pharmacy, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200120, People’s Republic of China; 3Department of Traumatic Orthopedics, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China; 4School of Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China; 5Institute of Translational Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying Liu; Xiao Dong, Email liuchanger1984@163.com; dong-xiao@shu.edu.cnIntroduction: Osteoporosis, characterized by dysregulation of osteoclastic bone resorption and osteoblastic bone formation, severely threatens human health during aging. However, there is still no good therapy for osteoporosis, so this direction requires our continuous attention, and there is an urgent need for new drugs to solve this problem.Methods: Traditional Chinese Medicine Salvia divinorum monomer pomolic acid (PA) could effectively inhibit osteoclastogenesis and ovariectomized osteoporosis. However, its poor solubility and lack of targeting severely limits its further application. A novel bone-targeting nanomedicine (PA@TLipo) has been developed to reconstruct the osteoporotic microenvironment by encapsulating pomolic acid in alendronate-functionalized liposomes. Through a series of operations such as synthesis, purification, encapsulation, and labeling, the PA@TLipo have been prepared. Moreover, the cytotoxicity, bone targeting and anti-osteoporosis effect was verified by cell and animal experiments.Results: In the aspect of targeting, the PA@TLipo can effectively aggregate on the bone tissue to reduce bone loss, and in terms of toxicity, PA@TLipo could increase the bone target ability in comparison to nontargeted liposome, thereby mitigating systemic cytotoxicity. Moreover, PA@TLipo inhibited osteoclast formation and bone resorption in vitro and reduced bone loss in ovariectomy-induced osteoporotic mice.Conclusion: In this study, a novel therapeutic agent was designed and constructed to treat osteoporosis, consisting of a liposome material as the drug pocket, PA as the anti-osteoporosis drug, and ALN as the bone-targeting molecule. And our study is the first to employ a bone-targeted delivery system to deliver PA for OVX-induced bone loss, providing an innovative solution for treating osteoporosis.Keywords: bone targeting, alendronate functionalized liposome, pomolic acid, osteoporosis therapy

Bone development is characterized by complex regulation mechanisms, including signal transduction and transcription factor-related pathways, glycobiological processes, cellular interactions, transportation mechanisms, and, importantly, chemical formation resulting from hydroxyapatite. Any abnormal regulation in the bone development processes causes skeletal system-related problems. To some extent, the avascularity of cartilage and bone makes drug delivery more challenging than that of soft tissues. Recent studies have implemented many novel bone-targeting approaches to overcome drawbacks. However, none of these strategies fully corrects skeletal dysfunction, particularly in growth plate-related ones. Although direct recombinant enzymes (e.g., Vimizim for Morquio, Cerezyme for Gaucher, Elaprase for Hunter, Mepsevii for Sly diseases) or hormone infusions (estrogen for osteoporosis and osteoarthritis), traditional gene delivery (e.g., direct infusion of viral or non-viral vectors with no modifications on capsid, envelope, or nanoparticles), and cell therapy strategies (healthy bone marrow or hematopoietic stem cell transplantation) partially improve bone lesions, novel delivery methods must be addressed regarding target specificity, less immunogenicity, and duration in circulation. In addition to improvements in bone delivery, potential regulation of bone development mechanisms involving receptor-regulated pathways has also been utilized. Targeted drug delivery using organic and inorganic compounds is a promising approach in mostly preclinical settings and future clinical translation. This review comprehensively summarizes the current bone-targeting strategies based on bone structure and remodeling concepts while emphasizing potential approaches for future bone-targeting systems. [ABSTRACT FROM AUTHOR]

Although various anti-osteoporosis drugs are available, the limitations of these therapies, including drug resistance and collateral responses, require the development of novel anti-osteoporosis agents. Rhizoma Drynariae displays a promising anti-osteoporosis effect, while the effective component and mechanism remain unclear. Here, we revealed the therapeutic potential of Rhizoma Drynariae-derived nanovesicles (RDNVs) for postmenopausal osteoporosis and demonstrated that RDNVs potentiated osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) by targeting estrogen receptor-alpha (ERα). RDNVs, a natural product isolated from fresh Rhizoma Drynariae root juice by differential ultracentrifugation, exhibited potent bone tissue-targeting activity and anti-osteoporosis efficacy in an ovariectomized mouse model. RDNVs, effectively internalized by hBMSCs, enhanced proliferation and ERα expression levels of hBMSC, and promoted osteogenic differentiation and bone formation. Mechanistically, via the ERα signaling pathway, RDNVs facilitated mRNA and protein expression of bone morphogenetic protein 2 and runt-related transcription factor 2 in hBMSCs, which are involved in regulating osteogenic differentiation. Further analysis revealed that naringin, existing in RDNVs, was the active component targeting ERα in the osteogenic effect. Taken together, our study identified that naringin in RDNVs displays exciting bone tissue-targeting activity to reverse osteoporosis by promoting hBMSCs proliferation and osteogenic differentiation through estrogen-like effects.

Abstract Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles.

Extracellular vesicles have received a great interest as safe biocarriers in biomedical engineering. There is a need to develop more efficient delivery strategies to improve localized therapeutic efficacy and minimize off-target adverse effects. Here, exosome mimetics (EMs) are reported for bone targeting involving the introduction of hydroxyapatite-binding moieties through bioorthogonal functionalization. Bone-binding ability of the engineered EMs is verified with hydroxyapatite-coated scaffolds and an ex vivo bone-binding assay. The EM-bound construct provided a biocompatible substrate for cell adhesion, proliferation, and osteogenic differentiation. Particularly, the incorporation of Smoothened agonist (SAG) into EMs greatly increased the osteogenic capacity through the activation of hedgehog signaling. Furthermore, the scaffold integrated with EM/SAG significantly improved in vivo reossification. Lastly, biodistribution studies confirmed the accumulation of systemically administered EMs in bone tissue. This facile engineering strategy could be a versatile tool to promote bone regeneration, offering a promising nanomedicine approach to the sophisticated treatment of bone diseases.

Although various anti-osteoporosis drugs are available, the limitations of these therapies, including drug resistance and collateral responses, require the development of novel anti-osteoporosis agents. Rhizoma Drynariae displays a promising anti-osteoporosis effect, while the effective component and mechanism remain unclear. Here, we revealed the therapeutic potential of Rhizoma Drynariae-derived nanovesicles (RDNVs) for postmenopausal osteoporosis and demonstrated that RDNVs potentiated osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) by targeting estrogen receptor-alpha (ER α). RDNVs, a natural product isolated from fresh Rhizoma Drynariae root juice by differential ultracentrifugation, exhibited potent bone tissue-targeting activity and anti-osteoporosis efficacy in an ovariectomized mouse model. RDNVs, effectively internalized by hBMSCs, enhanced proliferation and ER α expression levels of hBMSC, and promoted osteogenic differentiation and bone formation. Mechanistically, via the ER α signaling pathway, RDNVs facilitated mRNA and protein expression of bone morphogenetic protein 2 and runt-related transcription factor 2 in hBMSCs, which are involved in regulating osteogenic differentiation. Further analysis revealed that naringin, existing in RDNVs, was the active component targeting ER α in the osteogenic effect. Taken together, our study identified that naringin in RDNVs displays exciting bone tissue-targeting activity to reverse osteoporosis by promoting hBMSCs proliferation and osteogenic differentiation through estrogen-like effects. The natural product Rhizoma Drynariae-derived nanovesicles isolated and purified from fresh Rhizoma Drynariae, have a high efficacy agonist of estrogen receptor α and a potential nano-drug platform for the prevention and treatment of postmenopausal osteoporosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is a systematic bone disease characterized by low bone mass and fragile bone microarchitecture. Conventional treatment for OP has limited efficacy and long‐term toxicity. Synthetic biology makes bacterial extracellular vesicle (BEVs)‐based therapeutic strategies a promising alternative for the treatment of OP. Here, we constructed a recombinant probiotics Escherichia coli Nissle 1917‐pET28a‐ClyA‐BMP‐2‐CXCR4 (ECN‐pClyA‐BMP‐2‐CXCR4), in which BMP‐2 and CXCR4 were overexpressed in fusion with BEVs surface protein ClyA. Subsequently, we isolated engineered BEVs‐BMP‐2‐CXCR4 (BEVs‐BC) for OP therapy. The engineered BEVs‐BC exhibited great bone targeting in vivo. In addition, BEVs‐BC had good biocompatibility and remarkable ability to promote osteogenic differentiation of BMSCs. Finally, the synthetic biology‐based BEVs‐BC significantly prevented the OP in an ovariectomized (OVX) mouse model. In conclusion, we constructed BEVs‐BC with both bone‐targeting and bone‐forming in one‐step using synthetic biology, which provides an effective strategy for OP and has great potential for industrialization. [ABSTRACT FROM AUTHOR]

Caining Wen,1,* Xiao Xu,1,* Yuanmin Zhang,1 Jiang Xia,2 Yujie Liang,1,3 Limei Xu1 1Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, People’s Republic of China; 2Department of Chemistry, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, People’s Republic of China; 3Engineering Research Center of Intelligent Rehabilitation, College of Rehabilitation Medicine, Jining Medical University, Jining, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yujie Liang; Limei Xu, Email liangyjie@126.com; xulm2014@163.comAbstract: Osteoporosis (OP) affects millions of people worldwide, especially postmenopausal women and the elderly. Although current available anti-OP agents 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. Keywords: bone targeting, nanomedicine, osteoporosis therapy

Osteoporosis (OP) is a systemic bone disease characterized by decreased bone mass, damaged bone microstructure, increased bone fragility, and increased risk of fractures. It is more common in postmenopausal women and elderly people. The development of drugs with a high bone-targeting ability is urgently needed. We prepared a bioactive nanoparticle that modified the exosomes derived from human umbilical vein endothelial cells (HUVEC-ExomiR‑503‑high) to contain a large amount of miR-503-5p, with a diameter range of 30–150 nm. The HUVEC-ExomiR‑503‑high that we constructed had the same characteristics as ordinary exosomes and could bind to osteoblasts/osteoclasts in vitro. Moreover, they exhibited better bone-targeting ability than exosomes derived from other sources of bone marrow stromal cells in vivo. Bioinformatics analysis showed that miR-503-5p is strongly associated with bone-related pathways. In vitro experiments showed that HUVEC-ExomiR‑503‑high effectively inhibited osteoclast differentiation and promoted osteogenic differentiation. In vivo experiments showed that injecting HUVEC-ExomiR‑503‑high into OP mice significantly increased bone density and prevented OP. HUVEC-ExomiR‑503‑high can be used for bone-targeted therapy of OP, providing an approach to the clinical prevention and treatment of OP. [ABSTRACT FROM AUTHOR]

Abstract Osteoporosis (OP) is a systematic bone disease characterized by low bone mass and fragile bone microarchitecture. Conventional treatment for OP has limited efficacy and long‐term toxicity. Synthetic biology makes bacterial extracellular vesicle (BEVs)‐based therapeutic strategies a promising alternative for the treatment of OP. Here, we constructed a recombinant probiotics Escherichia coli Nissle 1917‐pET28a‐ClyA‐BMP‐2‐CXCR4 (ECN‐pClyA‐BMP‐2‐CXCR4), in which BMP‐2 and CXCR4 were overexpressed in fusion with BEVs surface protein ClyA. Subsequently, we isolated engineered BEVs‐BMP‐2‐CXCR4 (BEVs‐BC) for OP therapy. The engineered BEVs‐BC exhibited great bone targeting in vivo. In addition, BEVs‐BC had good biocompatibility and remarkable ability to promote osteogenic differentiation of BMSCs. Finally, the synthetic biology‐based BEVs‐BC significantly prevented the OP in an ovariectomized (OVX) mouse model. In conclusion, we constructed BEVs‐BC with both bone‐targeting and bone‐forming in one‐step using synthetic biology, which provides an effective strategy for OP and has great potential for industrialization.

Repair of osteoporotic bone defects (OBD) remains a clinical challenge due to dysregulated bone homeostasis, characterized by impaired osteogenesis and excessive osteoclast activity. While drug-loaded 3D-printed scaffolds hold great potential in the restoration of bone homeostasis for enhanced OBD repair, achieving the controlled release and targeted delivery of drugs in a 3D-printed scaffold is still unmet. Herein, we developed an electrostatic encapsulation strategy to motivate 3D-printed polyelectrolyte scaffolds (APS@P) with bone-targeting liposome formulation of salvianolic acid B (SAB-BTL). Benefiting from this strategy, SAB, an unstable and untargetable plant-derived osteogenic compound, was effectively encapsulated in APS@P, demonstrating stable and precise delivery with improved therapeutic efficacy. Owing to SAB-mediated bone homeostasis, APS@P significantly promoted angiogenesis and new bone formation while suppressing bone resorption, resulting in a significant 146 % increase in bone mass and improved microstructure compared to the OBD group. It was confirmed that the encapsulation of SAB into APS@P could promote the osteogenic differentiation of MSCs by stimulating Tph2/Wnt/β-catenin signaling axis, coupled with the stimulation of type H angiogenesis and the suppression of RANKL-mediate bone resorption, thereby enhance OBD repair. This study provides a universal platform for enhancing the bioactivity of tissue-engineered scaffolds, offering an effective solution for the efficient regeneration of osteoporotic bone.

The onset of osteoporosis leads to a gradual decrease in bone density due to an imbalance between bone formation and resorption. To achieve optimal drug efficacy with minimal side effects, targeted drug delivery to the bone is necessary. Previous studies have utilized peptides that bind to hydroxyapatite, a mineral component of bone, for bone‐targeted drug delivery. In this study, a hydroxyapatite binding (HAB) tag is fused to 30Kc19α‐Runt‐related transcription factor 2 (RUNX2) for bone‐targeting. This recombinant protein can penetrate the nucleus of human mesenchymal stem cells (hMSCs) and act as a master transcription factor for osteogenesis. The HAB tag increases the binding affinity of 30Kc19α‐RUNX2 to mineral deposition in mature osteoblasts and bone tissue, without affecting its osteogenic induction capability. In the osteoporosis mouse model, intravenous injection of HAB‐30Kc19α‐RUNX2 results in preferential accumulation in the femur and promotes bone formation while reducing toxicity in the spleen. These findings suggest that HAB‐30Kc19α‐RUNX2 may be a promising candidate for bone‐targeted therapy in osteoporosis. [ABSTRACT FROM AUTHOR]

Abstract Bone metastasis is the main cause of death in patients with prostate cancer (PCa), but there lacks effective treatment method. Immunotherapy shows new hopes for bone metastatic PCa patients, while the efficacy is still unsatisfactory and limited by the unique immunosuppressive microenvironment in metastatic bone site. Here, we developed a bone-targeted nano-delivery system as a nano-regulator to enhance the immunotherapy of bone metastatic PCa. The nanosystem was assembled via coordination between phytic acid (PA) and Fe3+ to form nano-sized metal–organic framework (MOF), through which mitoxantrone (MTO) was encapsulated. At cellular level, the nanosystem showed selective cytotoxicity towards RM-1 PCa cells over immune cells, and could induce tumor cells immunogenic cell death (ICD) to improve the immunogenicity of the tumor. Moreover, the nanosystem was able to induce ubiquitination of TGFβ receptor (TβR) on immune cells to promote its degradation, thus serving as a nano-regulator to block the functions of TGF-β, an abundant cytokine that has a systematically immunosuppressive effect in the tumor microenvironment. Upon intravenous injection, the nanoparticle showed pro-longed blood circulation and targeting accumulation into bone metastatic site, and imposed robust anti-tumor effect in combination with αCTLA-4. In addition, bone destruction was significantly alleviated after treatment to reduce the skeletal-related events. Overall, this work provides a biocompatible nanomedicine to restore immune sensitivity of bone metastatic tumor for enhanced immunotherapy by blocking TGF-β signaling pathway.

Abstract The onset of osteoporosis leads to a gradual decrease in bone density due to an imbalance between bone formation and resorption. To achieve optimal drug efficacy with minimal side effects, targeted drug delivery to the bone is necessary. Previous studies have utilized peptides that bind to hydroxyapatite, a mineral component of bone, for bone‐targeted drug delivery. In this study, a hydroxyapatite binding (HAB) tag is fused to 30Kc19α‐Runt‐related transcription factor 2 (RUNX2) for bone‐targeting. This recombinant protein can penetrate the nucleus of human mesenchymal stem cells (hMSCs) and act as a master transcription factor for osteogenesis. The HAB tag increases the binding affinity of 30Kc19α‐RUNX2 to mineral deposition in mature osteoblasts and bone tissue, without affecting its osteogenic induction capability. In the osteoporosis mouse model, intravenous injection of HAB‐30Kc19α‐RUNX2 results in preferential accumulation in the femur and promotes bone formation while reducing toxicity in the spleen. These findings suggest that HAB‐30Kc19α‐RUNX2 may be a promising candidate for bone‐targeted therapy in osteoporosis.

Abstracts: Background: Geniposidic acid (GPA), one of the active components of Eucommia ulmoides, promote bone formation and treat osteoporosis by activating farnesoid X receptor (FXR). However, GPA has low oral availability and lack of bone targeting in the treatment of bone related diseases. With the development of modern technology, small molecules, amino acids, or aptamers are used for biological modification of drugs and target cells in bone tissue, which has become the trend of bone targeted research. Methods: In this study, SDSSD (an osteoblast-targeting peptide) were modified in GPA using Fmoc solid-phase synthesis technique to form a new SDSSD-GPA conjugate (SGPA). The bone targeting of SGPA was evaluated using in vivo imaging and cell co-culture. In vitro, the effect of SGPA on cytotoxicity, osteoblastic activity, and mineralization ability were studied in mouse primary osteoblasts (OBs). In vivo, the therapeutic effect of SGPA on osteoporosis using an ovariectomized (OVX) mouse model. The bone mass, histomorphometry, serum biochemical parameters, and the molecular mechanism were evaluated. Results: SGPA was enriched in OBs and tends to accumulate in bone tissue. In vitro, SGPA significantly enhanced the osteogenic activity and mineralization of OBs compared with GPA. In vivo, SGPA enhanced serum BALP and P1NP levels, increased the trabecular bone mass of the mice, and SGPA administration have a higher bone mineralization deposition rate than the GPA-treated mice. Moreover, SGPA significantly activated FXR and Runt-related transcription factor 2 (RUNX2). Conclusions: Collectively, SGPA is enriched into OBs, and promotes bone formation by activating FXR-RUNX2 signalling, effectively treating osteoporosis at relatively low doses. The translational potential of this article: This study demonstrates a more efficient and safe application of GPA in treating osteoporosis, provide a new concept for the bone targeted application of natural compounds.

Abstract Background Due to the deep tissue penetration and reduced scattering, NIR-II fluorescence imaging is advantageous over conventional visible and NIR-I fluorescence imaging for the detection of bone growth, metabolism, metastasis, and other bone-related diseases. Methods Bone-targeted heptamethine cyanine fluorophores were synthesized by substituting the meso-carbon with a sulfur atom, resulting in a bathochromic shift and increased fluorescence intensity. The physicochemical, optical, and thermal stability of newly synthesized bone-targeted NIR fluorophores was performed in aqueous solvents. Calcium binding, bone-specific targeting, biodistribution, pharmacokinetics, and 2D and 3D NIR imaging were performed in animal models. Results The newly synthesized S-substituted heptamethine fluorophores demonstrated a high affinity for hydroxyapatite and calcium phosphate, which improved bone-specific targeting with signal-background ratios > 3.5. Particularly, P800SO3-PEG showed minimum nonspecific uptake, and most unbound molecules were excreted into the urinary bladder. Histological analyses demonstrated that P800SO3-PEG remained stable in the bone for over two weeks and was incorporated into bone matrices. Interestingly, the flexible thiol ethylene glycol linker on P800SO3-PEG induced a promising photothermal effect upon NIR laser irradiation, demonstrating potential theranostic imaging. Conclusions P800SO3-PEG shows a high affinity for bone tissues, deeper tissue imaging capabilities, minimum nonspecific uptake in the major organs, and photothermal effect upon laser irradiation, making it optimal for bone-targeted theranostic imaging.

Osteoporotic fracture, which is a clinical complication of osteoporosis featured with the imbalance of bone homeostasis. Non‐surgical intervention is frequently required post‐operatively to ameliorate the fracture healing. Nevertheless, current non‐surgical therapies are mostly performed in a non‐targeted manner without giving enough consideration to the pathological characteristics of osteoporosis. Therefore, it is highly desirable to develop an optimal strategy for promoting fracture healing under osteoporotic conditions. In this study, a multifunctional therapeutic nanoplatform is designed to work in conjunction with near‐infrared irradiation. Specifically, poly (lactic‐co‐glycolic acid) (PLGA) is functionalized with alendronate (ALE) and black phosphorus nanosheets (BPs) together with melatonin (MT) molecules are encapsulated by PLGA‐ALE to produce the multifunctional BPs/MT@PLGA‐ALE nanospheres. In this structure, BPs degrade gradually and deliver mild photothermal effects to facilitate bone regeneration, whereas MT has the dual‐capability of suppressing osteoclastogenesis and promoting osteogenesis. Moreover, ALE endows the nanoplatform with the reliable bone‐targeting capacity to improve the therapeutic effects. The combination of BPs/MT@PLGA‐ALE nanospheres and photothermal therapy significantly improve post‐surgical healing of osteoporotic fracture by modulating the tumor necrosis factor and cell death‐related signaling pathways. This study reveals a promising strategy to treat osteoporotic fracture and broadens the application of nanomaterials in the biomedical field. [ABSTRACT FROM AUTHOR]

Bone metastasis is the main cause of death in patients with prostate cancer (PCa), but there lacks effective treatment method. Immunotherapy shows new hopes for bone metastatic PCa patients, while the efficacy is still unsatisfactory and limited by the unique immunosuppressive microenvironment in metastatic bone site. Here, we developed a bone-targeted nano-delivery system as a nano-regulator to enhance the immunotherapy of bone metastatic PCa. The nanosystem was assembled via coordination between phytic acid (PA) and Fe3+ to form nano-sized metal–organic framework (MOF), through which mitoxantrone (MTO) was encapsulated. At cellular level, the nanosystem showed selective cytotoxicity towards RM-1 PCa cells over immune cells, and could induce tumor cells immunogenic cell death (ICD) to improve the immunogenicity of the tumor. Moreover, the nanosystem was able to induce ubiquitination of TGFβ receptor (TβR) on immune cells to promote its degradation, thus serving as a nano-regulator to block the functions of TGF-β, an abundant cytokine that has a systematically immunosuppressive effect in the tumor microenvironment. Upon intravenous injection, the nanoparticle showed pro-longed blood circulation and targeting accumulation into bone metastatic site, and imposed robust anti-tumor effect in combination with αCTLA-4. In addition, bone destruction was significantly alleviated after treatment to reduce the skeletal-related events. Overall, this work provides a biocompatible nanomedicine to restore immune sensitivity of bone metastatic tumor for enhanced immunotherapy by blocking TGF-β signaling pathway. [ABSTRACT FROM AUTHOR]

Objective Traditional Chinese medicine flavonoid monomers have the characteristics of poor water solubility and low bioavailability. The low efficiency of systemic administration limits its application in the treatment of bone diseases. In order to improve the limited status of flavonoid monomers in the treatment of osteoporosis. Methods In this study, the gel delivery system of alendronate modified hydrogel loaded with naringenin, the active flavonoid monomer of Chinese traditional medicine, was prepared. Its bone targeting performance was verified by in vivo fluorescence technology, and the effect of the gel delivery system on promoting osteogenic differentiation was further explored by PCR and WB techniques. Results The prepared gel drug delivery system was successfully prepared and had good stability. The drug release site was concentrated in rat bone tissue. After intervention with osteoblast MC3T3-E1 cells, the expression of osteogenic factors and related proteins was significantly enhanced. Conclusion Alendronic acid modified hydrogel loaded naringenin can achieve bone targeting in rat bone tissue, and can effectively promote osteogenic differentiation, which can potentially achieve the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Since the poor response to existing anti-tuberculosis drugs and low drug concentration in local bone tissues, the traditional drug therapy does not result in satisfactory treatment of osteoarticular tuberculosis. Thus, we report a rifapentine release system with imparted bone targeting potential using tetracycline (TC) -modified nanoparticles (NPs).Methods: TC was conjugated to PLGA-PEG copolymer via a DCC/NHS technique. Rifapentine-loaded NPs were prepared by premix membrane emulsification technique. The resulting NPs were characterized in terms of physicochemical characterization, hemolytic study, cytotoxicity, bone mineral binding ability, in vitro drug release, stability test and antitubercular activity. The pharmacokinetic and biodistribution studies were also performed in mice.Results: Rifapentine loaded TC-PLGA-PEG NPs were proved to be 48.8 nm in size with encapsulation efficiency and drug loading of 83.3% ± 5.5% and 8.1% ± 0.4%, respectively. The release of rifapentine from NPs could be maintained for more than 60 h. Most (68.0%) TC-PLGA-PEG NPs could bind to HAp powder in vitro. The cellular studies revealed that NPs were safe for intravenous administration. In vivo evaluations also revealed that the drug concentration of bone tissue in TC–PLGA–PEG group was significantly higher than that in other groups at all time (p < 0.05). Both NPs could improve pharmacokinetic parameters without evident organ toxicity. The minimal inhibitory concentration of NPs was 0.094 μg/mL, whereas this of free rifapentine was 0.25 μg/mL.Conclusion: Rifapentine loaded TC-PLGA-PEG NPs could increase the amount of rifapentine in bone tissue, prolong drug release in systemic circulation, enhance anti-tuberculosis activity, and thereby reducing dose and frequency of drug therapy for osteoarticular tuberculosis.

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.

Osteoporosis (OP) is a systemic metabolic orthopedic disorder prevalent in elderly people, that is characterized by a decrease in bone mass. Although many therapeutics have been adopted for OP treatment, many of them are still not well satisfied clinical requirements and therefore development of novel therapeutics is of great significance. In this work, a novel bone-targeting drug self-frame delivery system (DSFDS) with high drug loading efficiency and pH responsive drug release was fabricated by condensation of curcumin (Cur), amino group terminated polyethylene glycol (NH2-PEG), and alendronate (ALN) using hexachlorocyclotriphosphonitrile (HCCP) as the linker. The final product named as HCCP-Cur-PEG-ALN (HCPA NPs) displayed excellent water dispersity with small size (181.9 ​± ​25.9 ​nm). Furthermore, the drug loading capacity of Cur can reach 25.8%, and Cur can be released from HCPA NPs under acidic environment. Owing to the introduction of ALN, HCPA NPs exhibited strong binding to HAp in vitro and excellent bone-targeting effect in vivo. Results from cellular and biochemical analyses revealed that HCPA NPs could effectively inhibit the formation and differentiation function of osteoclasts. More importantly, we also demonstrated that HCPA NPs could effectively reduce bone loss in OVX mice with low toxicity to major organs. The above results clearly demonstrated that HCPA NPs are promising for OP treatment. Given the simplicity and well designability of fabrication strategy, explicit therapy efficacy and low toxicity of HCPA NPs, we believe that this work should be of great interest for fabrication of various DSFDS to deal with many diseases.

Osteomyelitis is a limb- and life-threatening orthopedic infection predominantly caused by Staphylococcus aureus biofilms. Bone infections are extremely challenging to treat clinically. Therefore, we have been designing, synthesizing, and testing novel antibiotic conjugates to target bone infections. This class of conjugates comprises bone-binding bisphosphonates as biochemical vectors for the delivery of antibiotic agents to bone minerals (hydroxyapatite). In the present study, we utilized a real-time impedance-based assay to study the growth of Staphylococcus aureus biofilms over time and to test the antimicrobial efficacy of our novel conjugates on the inhibition of biofilm growth in the presence and absence of hydroxyapatite. We tested early and newer generation quinolone antibiotics (ciprofloxacin, moxifloxacin, sitafloxacin, and nemonoxacin) and several bisphosphonate-conjugated versions of these antibiotics (bisphosphonate-carbamate-sitafloxacin (BCS), bisphosphonate-carbamate-nemonoxacin (BCN), etidronate-carbamate-ciprofloxacin (ECC), and etidronate-carbamate-moxifloxacin (ECX)) and found that they were able to inhibit Staphylococcus aureus biofilms in a dose-dependent manner. Among the conjugates, the greatest antimicrobial efficacy was observed for BCN with an MIC of 1.48 µg/mL. The conjugates demonstrated varying antimicrobial activity depending on the specific antibiotic used for conjugation, the type of bisphosphonate moiety, the chemical conjugation scheme, and the presence or absence of hydroxyapatite. The conjugates designed and tested in this study retained the bone-binding properties of the parent bisphosphonate moiety as confirmed using high-performance liquid chromatography. They also retained the antimicrobial activity of the parent antibiotic in the presence or absence of hydroxyapatite, albeit at lower levels due to the nature of their chemical modification. These findings will aid in the optimization and testing of this novel class of drugs for future applications to pharmacotherapy in osteomyelitis. [ABSTRACT FROM AUTHOR]

Although mild photothermal therapy (mild-PTT) avoids treatment bottleneck of the traditional PTT, the application of mild-PTT in deep and internal tumors is severely restricted due to thermal resistance, limited irradiation area and penetration depth. In addition, bone resorption caused by tumor colonization in distal bone tissue exacerbates tumor progression. Here, a strategy was developed for the treatment of bone metastasis and alleviation of bone resorption, which was based on liquid metal (LM) nanoparticle to resist thermal resistance induced by mild-PTT via autophagy activation. Briefly, LM and autophagy activator (Curcumin, Cur) were loaded into zeolitic imidazolate framework-8 (ZIF-8), which was then functionalized with hyaluronic acid/alendronate (CLALN). CLALN exhibited good photothermal performance, drug release ability under acidic environment, specifical recognition and aggregation at bone metastasis sites. CLALN combined with mild-PPT dramatically inhibited tumor progress by inducing the impaired autophagy and reduced the expression of programmed cell death ligand 1 (PD-L1) protein triggered by mild-PTT, resisting thermal resistance and alleviating the immunosuppression. Besides, CLALN combined with mild-PPT effectively alleviated osteolysis compared with only CLALN or mild-PPT. Our experiments demonstrated that this multi-functional LM-based nanoparticle combined with autophagy activation provided a promising therapeutic strategy for bone metastasis treatment. Due to the limited light penetration, photothermal therapy (PTT) has limited inhibitory effect on tumor cells colonized in the bone. In addition, nonspecific heat diffusion of PTT may accidentally burn normal tissues and damage peripheral blood vessels, which can block the accumulation of drugs in deep tumors. Here, a multifunctional liquid metal based mild-PTT delivery system is designed to inhibit tumor growth and bone resorption by modulating the bone microenvironment and activating autophagy "on demand". It can overcome the treatment bottleneck of traditional PTT and improve the treatment effect of mild-PTT by resisting photothermal resistance and immune suppression. In addition, it also exhibits favorable heat/acid-responsive drug release performance and can specifically target tumor cells at the site of bone metastases. [Display omitted] [ABSTRACT FROM AUTHOR]

The treatment of malignant bone tumors by chemotherapeutics often receives poor therapeutic response due to the specific physiological bone environment, and thus calls for the development of new therapeutic options. Here, we reported a bone-targeted protein nanomedicine for this purpose. Saporin, a toxin protein, was co-assembled with a boronated polymer for intracellular protein delivery, and the formed nanoparticles were further coated with an anionic polymer poly (aspartic acid) to shield the positive charges on nanoparticles and provide the bone targeting function. The prepared ternary complex nanoparticles showed high bone accumulation both in vitro and in vivo, and could reverse the surface charge property from negative to positive after locating at tumor site triggered by tumor extracellular acidity. The boronated polymer in the de-shielded nanoparticles further promote intracellular delivery of saporin into tumor cells, exerting the anticancer activity of saporin by inactivation of ribosomes. As a result, the bone-targeted and saporin-loaded nanomedicine could kill cancer cells at a low saporin dose, and efficiently prevented the progression of osteosarcoma xenograft tumors and bone metastatic breast cancer in vivo. This study provides a facile and promising strategy to develop protein-based nanomedicines for the treatment of malignant bone tumors.

Abstract Background Osteoporosis is a chronic condition affecting patients’ morbidity and mortality and represents a big socioeconomic burden. Because stem cells can proliferate and differentiate into bone-forming cells, stem cell therapy for osteoporosis has been widely studied. However, cells as a live drug face multiple challenges because of their instability during preservation and transportation. In addition, cell therapy has potential adverse effects such as embolism, tumorigenicity, and immunogenicity. Results Herein, we sought to use cell-mimicking and targeted therapeutic nanoparticles to replace stem cells. We fabricated nanoparticles (NPs) using polylactic-co-glycolic acid (PLGA) loaded with the secretome (Sec) from mesenchymal stem cells (MSCs) to form MSC-Sec NPs. Furthermore, we cloaked the nanoparticles with the membranes from C–X–C chemokine receptor type 4 (CXCR4)-expressing human microvascular endothelial cells (HMECs) to generate MSC-Sec/CXCR4 NP. CXCR4 can target the nanoparticles to the bone microenvironment under osteoporosis based on the CXCR4/SDF-1 axis. Conclusions In a rat model of osteoporosis, MSC-Sec/CXCR4 NP were found to accumulate in bone, and such treatment inhibited osteoclast differentiation while promoting osteogenic proliferation. In addition, our results showed that MSC-Sec/CXCR4 NPs reduce OVX-induced bone mass attenuation in OVX rats. Graphical Abstract

Therapeutic efficacy of skeletal diseases is usually limited by unfavorable drug delivery due to incapable bone targeting and low bone affinity of conventional drug carriers, as well as relatively reduced vascularization and dense structure of bone tissues. Due to CXC chemokine receptor 4 (CXCR4)/CXC chemokine ligand 12 (CXCL12) signal axis-guided recruitment, osteoprogenitor cells (OPCs) can actively migrate to bone disease nidus. Here, drugs-loaded nanoliposomes are prepared and decorated onto OPCs by biotin-streptavidin linkage for precise bone disease targeting and effective drug delivery. In mouse models of tibia defect and orthotopic osteosarcoma, superior targeting property of OPCs-based drug delivery systems toward diseased bone niduses is verified. By encapsulating antitumor and antiosteoporosis drugs into nanoliposomes, OPCs-based drug delivery systems effectively inhibit disease development and restore bone destruction in mouse models of orthotopic osteosarcoma and ovariectomized osteoporosis. This study reveals a cell-based drug delivery system for precise bone disease targeting and highly effective drug delivery, which will find great potential as a universal drug delivery platform for targeting treatment of various bone diseases.

Phosphorus is a ubiquitous and one of the most common elements found in living organisms. Almost all molecules containing phosphorus in our body exist as analogs of phosphate salts or phosphoesters. Their functions are versatile and important, being responsible for forming the genetic code, cell membrane, and mineral components of hard tissue. Several materials inspired from these phosphorus-containing biomolecules have been recently developed. These materials have shown unique properties at the biointerface, such as nonfouling ability, blood compatibility, lubricity, mineralization induction capability, and bone affinity. Several unfavorable events occur at the interface of materials and living organisms because most of these materials have not been designed while taking host responses into account. These unfavorable events are directly linked to reducing functions and shorten the usable periods of medical devices. Biomimetic phosphorus-containing polymers can improve the reliability of materials in biological systems. In addition, phosphorus-containing biomimetic polymers are useful not only for improving the biocompatibility of material surfaces but also for adding new functions due to the flexibility in molecular design. In this review, we describe the recent advances in the control of biointerfacial phenomena with phosphorus-containing polymers. We especially focus on zwitterioninc phosphorylcholine polymers and polyphosphoesters.

Abstract Background Jaw bones are the most common organs to be invaded by oral malignancies, such as oral squamous cell carcinoma (OSCC), because of their special anatomical relationship. Various serious complications, such as pathological fractures and bone pain can significantly decrease the quality of life or even survival outcomes for a patient. Although chemotherapy is a promising strategy for bone invasion treatment, its clinical applications are limited by the lack of tumor-specific targeting and poor permeability in bone tissue. Therefore, it is necessary to develop a smart bone and cancer dual targeting drug delivery platform. Results We designed a dual targeting nano-biomimetic drug delivery vehicle Asp8[H40-TPZ/IR780@(RBC-H)] that has excellent bone and cancer targeting as well as immune escape abilities to treat malignancies in jaw bones. These nanoparticles were camouflaged with a head and neck squamous cell carcinoma WSU-HN6 cell (H) and red blood cell (RBC) hybrid membrane, which were modified by an oligopeptide of eight aspartate acid (Asp8). The spherical morphology and typical core-shell structure of biomimetic nanoparticles were observed by transmission electron microscopy. These nanoparticles exhibited the same surface proteins as those of WSU-HN6 and RBC. Flow cytometry and confocal microscopy showed a greater uptake of the biomimetic nanoparticles when compared to bare H40-PEG nanoparticles. Biodistribution of the nanoparticles in vivo revealed that they were mainly localized in the area of bone invasion by WSU-HN6 cells. Moreover, the Asp8[H40-TPZ/IR780@(RBC-H)] nanoparticles exhibited effective cancer growth inhibition properties when compared to other TPZ or IR780 formulations. Conclusions Asp8[H40-TPZ/IR780@(RBC-H)] has bone targeting, tumor-homing and immune escape abilities, therefore, it is an efficient multi-targeting drug delivery platform for achieving precise anti-cancer therapy during bone invasion. Graphical Abstract

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. [ABSTRACT FROM AUTHOR]

Aim: We aimed to create a nano drug delivery system with tetracycline (TC)-grafted methoxy poly-(ethylene-glycol)poly-(D, L-lactic-co-glycolic acid) (mPEGPLGA) micelles (TCmPEGPLGA) with TC and mPEGPLGA for potential bone targeting. Prospectively, TCmPEGPLGA aims to deliver bioactive compounds, such as astragaloside IV (AS), for osteoporotic therapy. Methods: Preparation and evaluation of TCmPEGPLGA were accomplished via nano-properties, cytotoxicity, uptake by MC3T3-E1 cells, ability of hydroxyapatite targeting and potential bone targeting in vivo, as well as pharmacodynamics in a rat model. Results: The measured particle size of AS-loaded TCmPEGPLGA micelles was an average of 52.16 ± 2.44 nm, which exhibited a sustained release effect compared to that by free AS. The TCmPEGPLGA demonstrated low cytotoxicity and was easily taken by MC3T3-E1 cells. Through assaying of bone targeting in vitro and in vivo, we observed that TCmPEGPLGA could effectively increase AS accumulation in bone. A pharmacodynamics study in mice suggested potentially increased bone mineral density by AS-loaded TC mPEGPLGA in ovariectomized rats compared to that by free AS. Conclusion: The nano drug delivery system (TCmPEGPLGA) could target bone in vitro and in vivo, wherein it may be used as a novel delivery method for the enhancement of therapeutic effects of drugs with osteoporotic activity. [ABSTRACT FROM AUTHOR]

The differentiation shift from osteogenesis to adipogenesis of bone marrow mesenchymal stem cells (BMSCs) characterizes many pathological bone loss conditions. Stromal cell-derived factor-1 (SDF1) is highly enriched in the bone marrow for C-X-C motif chemokine receptor 4 (CXCR4)-positive hematopoietic stem cell (HSC) homing and tumor bone metastasis. In this study, we displayed CXCR4 on the surface of exosomes derived from genetically engineered NIH-3T3 cells. CXCR4+ exosomes selectively accumulated in the bone marrow. Then, we fused CXCR4+ exosomes with liposomes carrying antagomir-188 to produce hybrid nanoparticles (NPs). The hybrid NPs specifically gathered in the bone marrow and released antagomir-188, which promoted osteogenesis and inhibited adipogenesis of BMSCs and thereby reversed age-related trabecular bone loss and decreased cortical bone porosity in mice. Taken together, this study presents a novel way to obtain bone-targeted exosomes via surface display of CXCR4 and a promising anabolic therapeutic approach for age-related bone loss.

Insufficient drug delivery efficiency in vivo and robust drug resistance are two major factors to induce suboptimal efficacy in chemotherapy of osteosarcoma (OS). To address these challenges, we developed polysaccharide hyaluronic acid (HA)-functionalized ruthenium nanoaggregates (Ru NAs) to enhance the chemotherapy of doxorubicin (DOX) for OS. These NAs, comprising Ru nanoparticles (NPs) and alendronate-modified HA (HA-ALN), effectively load DOX, resulting in DOX@Ru-HA-ALN NAs. The combination of HA and ALN in NAs ensures outstanding cascade targeting towards tumor-invaded bone tissues and CD44-overexpressing tumor cells, maximizing therapeutic efficacy while minimizing off-target effects. Concurrently, the Ru NPs in NAs function as "smart" photoenzymatic agent to not only in situ relieve hypoxia of OS via the catalysis of overexpressed H 2 O 2 to produce O 2 , but also generate mild photothermal effect under 808-nm laser irradiation. They can bidirectionally overcome drug resistance of DOX via downregulation of resistance-related factors including multi-drug resistant associate protein, P-glycoprotein, heat shock factor 1, etc. The integration of cascade targeting with bidirectional modulation of drug resistance positions Ru-HA-ALN NAs to substantially enhance DOX chemotherapy for OS. Therefore, the present work highlights the potential of polysaccharide-functionalized nanomaterials in advancing tumor chemotherapy by addressing challenges of both delivery efficiency and drug resistance. [Display omitted] [ABSTRACT FROM AUTHOR]

• A composite material was developed using hydroxypropyl methylcellulose, sodium alginate, and hydroxyapatite functionalized with zinc. • The developed composite material was formulated into a nanocomposite and was evaluated for bone tissue regeneration on glucocorticoid-induced bone tissue degenerative rat model. • Pharmacological studies in validation with molecular docking evaluation indicated that the nanocomposite had potential effectiveness in targeting and enhancing bone density by blocking farnesyl diphosphate synthetase (FDPS) in the mevalonate pathway. Bone is a dynamic connective tissue that provides structural support and locomotion to human physiology. Severe bone degeneration can occur in cases of trauma, infections, genetic disorders, tumors, and hormonal imbalances. This leads to a demand for scaffolds and composites to enhance bone tissue regeneration. The present study aimed to develop a composite material using hydroxypropyl methylcellulose and sodium alginate in combination with hydroxyapatite. The composite was doped with zinc and developed into a nanocomposite using ionic gelation and solvent precipitation methods. The prepared nanocomposite was characterized by scanning electron microscopy, atomic force microscopy, dynamic light scattering, FTIR, and XRD studies. In vivo pharmacological studies were conducted to establish the bone targeting and bone tissue regeneration efficacy of the developed nanocomposite. The nanocomposite was checked for cell toxicity by performing an MTT assay using MG63 cell line and the molecular mechanism of targeting efficiency was assessed by an in silico evaluation method. The results of the study confirmed the polymeric interlinking in the nanocomposite and the successful preparation of a composite material using biodegradable excipients. SEM and AFM studies indicated that the nanocomposite was within the 80–200 nm size range. MTT assay indicated that the developed nanocomposite was not cytotoxic and well tolerated by the MG63 cell line. In vivo , studies in validation with molecular docking evaluation suggested that the nanocomposite was effectively targeted to the bone and enhanced the bone density by blocking Farnesyl Diphosphate Synthetase (FDPS) in the mevalonate pathway which is essential for inhibiting the osteoclastic activity and promoting osteogenesis. [Display omitted] [ABSTRACT FROM AUTHOR]

Bone metastasis has been considered the fatal phase of cancers, which remains incurable and to be a challenge due to the non-availability of the ideal treatment strategy. Unlike bone cancer, bone metastasis involves the spreading of the tumor cells to the bones from different origins. Bone metastasis generally originates from breast and prostate cancers. The possibility of bone metastasis is highly attributable to its physiological milieu susceptible to tumor growth. The treatment of bone-related diseases has multiple complications, including bone breakage, reduced quality of life, spinal cord or nerve compression, and pain. However, anticancer active agents have failed to maintain desired therapeutic concentrations at the target site; hence, uptake of the drug takes place at a non-target site responsible for the toxicity at the cellular level. Interestingly, lipid-based drug delivery systems have become the center of interest for researchers, thanks to their biocompatible and bio-mimetic nature. These systems possess a great potential to improve precise bone targeting without affecting healthy tissues. The lipid nano-sized systems are not only limited to delivering active agents but also genes/peptide sequences/siRNA, bisphosphonates, etc. Additionally, lipid coating of inorganic nanomaterials such as calcium phosphate is an effective approach against uncontrollable rapid precipitation resulting in reduced colloidal stability and dispersity. This review summarizes the numerous aspects, including development, design, possible applications, challenges, and future perspective of lipid nano-transporters, namely liposomes, exosomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid nanoparticulate gels to treat bone metastasis and induce bone regeneration. Additionally, the economic suitability of these systems has been discussed and different alternatives have been discussed. All in all, through this review we will try to understand how far nanomedicine is from clinical and industrial applications in bone metastasis. [ABSTRACT FROM AUTHOR]

Limited treatment options exist for cancer within the bone, as demonstrated by the inevitable, pernicious course of metastatic and blood cancers. The difficulty of eliminating bone‐residing cancer, especially drug‐resistant cancer, necessitates novel, alternative treatments to manipulate tumor cells and their microenvironment, with minimal off‐target effects. To this end, bone‐targeted conjugate (BP‐Btz) was generated by linking bortezomib (Btz, an anticancer, bone‐stimulatory drug) to a bisphosphonate (BP, a targeting ligand) through a cleavable linker that enables spatiotemporally controlled delivery of Btz to bone under acidic conditions for treating multiple myeloma (MM). Three conjugates with different linkers were developed and screened for best efficacy in mouse model of MM. Results demonstrated that the lead candidate BP‐Btz with optimal linker could overcome Btz resistance, reduced tumor burden, bone destruction, or tumor metastasis more effectively than BP or free Btz without thrombocytopenia and neurotoxicity in mice bearing myeloma. Furthermore, pharmacokinetic and pharmacodynamic studies showed that BP‐Btz bound to bone matrix, released Btz in acidic conditions, and had a higher local concentration and longer half‐life than Btz in bone. Our findings suggest the potential of bone‐targeted Btz conjugate as an efficacious Btz‐resistant MM treatment mechanism. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Breast cancer bone metastasis poses significant challenge for therapeutic strategies. Inside the metastatic environment, osteoclasts and tumor cells interact synergistically to promote cancer progression. In this study, the proprotein convertase furin is targeted due to its critical roles in both tumor cell invasion and osteoclast function. Importantly, the furin inhibitor is specifically delivered by bone targeting superparamagnetic iron oxide (SPIO) nanoparticles. Our in vitro and in vivo data demonstrate that this system can effectively inhibit both osteoclastic bone resorption and breast cancer invastion, leading to alleviated osteolysis. Therefore, the bone targeting & furin inhibition nanoparticle system is a promising therapeutic and diagnostic strategy for breast cancer bone metastasis.

Background: Osteoporosis is a chronic condition affecting patients' morbidity and mortality and represents a big socioeconomic burden. Because stem cells can proliferate and differentiate into bone-forming cells, stem cell therapy for osteoporosis has been widely studied. However, cells as a live drug face multiple challenges because of their instability during preservation and transportation. In addition, cell therapy has potential adverse effects such as embolism, tumorigenicity, and immunogenicity. Results: Herein, we sought to use cell-mimicking and targeted therapeutic nanoparticles to replace stem cells. We fabricated nanoparticles (NPs) using polylactic-co-glycolic acid (PLGA) loaded with the secretome (Sec) from mesenchymal stem cells (MSCs) to form MSC-Sec NPs. Furthermore, we cloaked the nanoparticles with the membranes from C–X–C chemokine receptor type 4 (CXCR4)-expressing human microvascular endothelial cells (HMECs) to generate MSC-Sec/CXCR4 NP. CXCR4 can target the nanoparticles to the bone microenvironment under osteoporosis based on the CXCR4/SDF-1 axis. Conclusions: In a rat model of osteoporosis, MSC-Sec/CXCR4 NP were found to accumulate in bone, and such treatment inhibited osteoclast differentiation while promoting osteogenic proliferation. In addition, our results showed that MSC-Sec/CXCR4 NPs reduce OVX-induced bone mass attenuation in OVX rats. [ABSTRACT FROM AUTHOR]

Despite efforts to achieve tissue selectivity, the majority of systemically administered drug delivery systems (DDSs) are cleared by the mononuclear phagocyte system (MPS) before reaching target tissues regardless of disease or injury pathology. Previously, we showed that while tartrate‐resistant acid phosphatase (TRAP) binding peptide (TBP)‐targeted polymeric nanoparticles (TBP‐NP) delivering a bone regenerative Wnt agonist improved NP fracture accumulation and expedited healing compared with controls, there was also significant MPS accumulation. Here we show that TBP‐NPs are taken up by liver, spleen, lung, and bone marrow macrophages (Mϕ), with 76 ± 4%, 49 ± 11%, 27 ± 9%, and 92 ± 5% of tissue‐specific Mϕ positive for NP, respectively. Clodronate liposomes (CLO) significantly depleted liver and spleen Mϕ, resulting in 1.8‐fold and 3‐fold lower liver and spleen and 1.3‐fold and 1.6‐fold greater fracture and naïve femur accumulation of TBP‐NP. Interestingly, depletion and saturation of MPS using 10‐fold greater TBP‐NP doses also resulted in significantly higher TBP‐NP accumulation at lungs and kidneys, potentially through compensatory clearance mechanisms. The higher NP dose resulted in greater TBP‐NP accumulation at naïve bone tissue; however, other MPS tissues (i.e., heart and lungs) exhibited greater TBP‐NP accumulation, suggesting uptake by other cell types. Most importantly, neither Mϕ depletion nor saturation strategies improved fracture site selectivity of TBP‐NPs, possibly due to a reduction of Mϕ‐derived osteoclasts, which deposit the TRAP epitope. Altogether, these data support that MPS‐mediated clearance is a key obstacle in robust and selective fracture accumulation for systemically administered bone‐targeted DDS and motivates the development of more sophisticated approaches to further improve fracture selectivity of DDS. [ABSTRACT FROM AUTHOR]

The “vicious cycle” established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis, leading to life-threatening skeletal-related events that severely reduce survival and quality of life. To effectively interrupt the “vicious cycle”, innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed. Herein, a bone-seeking moiety, alendronate (ALN), functionalized coordination polymer nanoparticles (DZ@ALN) co-delivering cisplatin prodrug (DSP) and antiresorptive agent zoledronate (ZOL) via Zn2+ crosslinking for combination therapy was reported. The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries, and possesses an excellent bone-seeking ability both in vitro and in vivo. Additionally, DZ@ALN could synergistically inhibit the proliferation of cancer cells, suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro. Importantly, it could preferentially accumulate in bone affected site, remarkably inhibit the proliferation of tumor cells, relieving bone pain, and significantly inhibit the activation of osteoclasts, protecting the bone from destruction in vivo, eventually leading to the breakdown of “vicious cycle” without inducing obvious systemic toxicity. This innovative nanoagent combines chemotherapy and osteolysis inhibition, exhibiting an inspiring strategy for effective treatment of bone metastasis.

Phosphorus is a ubiquitous and one of the most common elements found in living organisms. Almost all molecules containing phosphorus in our body exist as analogs of phosphate salts or phosphoesters. Their functions are versatile and important, being responsible for forming the genetic code, cell membrane, and mineral components of hard tissue. Several materials inspired from these phosphorus-containing biomolecules have been recently developed. These materials have shown unique properties at the biointerface, such as nonfouling ability, blood compatibility, lubricity, mineralization induction capability, and bone affinity. Several unfavorable events occur at the interface of materials and living organisms because most of these materials have not been designed while taking host responses into account. These unfavorable events are directly linked to reducing functions and shorten the usable periods of medical devices. Biomimetic phosphorus-containing polymers can improve the reliability of materials in biological systems. In addition, phosphorus-containing biomimetic polymers are useful not only for improving the biocompatibility of material surfaces but also for adding new functions due to the flexibility in molecular design. In this review, we describe the recent advances in the control of biointerfacial phenomena with phosphorus-containing polymers. We especially focus on zwitterioninc phosphorylcholine polymers and polyphosphoesters. [ABSTRACT FROM AUTHOR]

Background: Jaw bones are the most common organs to be invaded by oral malignancies, such as oral squamous cell carcinoma (OSCC), because of their special anatomical relationship. Various serious complications, such as pathological fractures and bone pain can significantly decrease the quality of life or even survival outcomes for a patient. Although chemotherapy is a promising strategy for bone invasion treatment, its clinical applications are limited by the lack of tumor-specific targeting and poor permeability in bone tissue. Therefore, it is necessary to develop a smart bone and cancer dual targeting drug delivery platform. Results: We designed a dual targeting nano-biomimetic drug delivery vehicle Asp8[H40-TPZ/IR780@(RBC-H)] that has excellent bone and cancer targeting as well as immune escape abilities to treat malignancies in jaw bones. These nanoparticles were camouflaged with a head and neck squamous cell carcinoma WSU-HN6 cell (H) and red blood cell (RBC) hybrid membrane, which were modified by an oligopeptide of eight aspartate acid (Asp8). The spherical morphology and typical core-shell structure of biomimetic nanoparticles were observed by transmission electron microscopy. These nanoparticles exhibited the same surface proteins as those of WSU-HN6 and RBC. Flow cytometry and confocal microscopy showed a greater uptake of the biomimetic nanoparticles when compared to bare H40-PEG nanoparticles. Biodistribution of the nanoparticles in vivo revealed that they were mainly localized in the area of bone invasion by WSU-HN6 cells. Moreover, the Asp8[H40-TPZ/IR780@(RBC-H)] nanoparticles exhibited effective cancer growth inhibition properties when compared to other TPZ or IR780 formulations. Conclusions: Asp8[H40-TPZ/IR780@(RBC-H)] has bone targeting, tumor-homing and immune escape abilities, therefore, it is an efficient multi-targeting drug delivery platform for achieving precise anti-cancer therapy during bone invasion. [ABSTRACT FROM AUTHOR]

Abstract Bone diseases constitute a major issue for modern societies as a consequence of progressive aging. Advantages such as open mesoporous channel, high specific surface area, ease of surface modification, and multifunctional integration are the driving forces for the application of mesoporous nanoparticles (MNs) in bone disease diagnosis and treatment. To achieve better therapeutic effects, it is necessary to understand the properties of MNs and cargo delivery mechanisms, which are the foundation and key in the design of MNs. The main types and characteristics of MNs for bone regeneration, such as mesoporous silica (mSiO2), mesoporous hydroxyapatite (mHAP), mesoporous calcium phosphates (mCaPs) are introduced. Additionally, the relationship between the cargo release mechanisms and bone regeneration of MNs‐based nanocarriers is elucidated in detail. Particularly, MNs‐based smart cargo transport strategies such as sustained cargo release, stimuli‐responsive (e.g., pH, photo, ultrasound, and multi‐stimuli) controllable delivery, and specific bone‐targeted therapy for bone disease diagnosis and treatment are analyzed and discussed in depth. Lastly, the conclusions and outlook about the design and development of MNs‐based cargo delivery systems in diagnosis and treatment for bone tissue engineering are provided to inspire new ideas and attract researchers’ attention from multidisciplinary areas spanning chemistry, materials science, and biomedicine.

Bone diseases constitute a major issue for modern societies as a consequence of progressive aging. Advantages such as open mesoporous channel, high specific surface area, ease of surface modification, and multifunctional integration are the driving forces for the application of mesoporous nanoparticles (MNs) in bone disease diagnosis and treatment. To achieve better therapeutic effects, it is necessary to understand the properties of MNs and cargo delivery mechanisms, which are the foundation and key in the design of MNs. The main types and characteristics of MNs for bone regeneration, such as mesoporous silica (mSiO2), mesoporous hydroxyapatite (mHAP), mesoporous calcium phosphates (mCaPs) are introduced. Additionally, the relationship between the cargo release mechanisms and bone regeneration of MNs‐based nanocarriers is elucidated in detail. Particularly, MNs‐based smart cargo transport strategies such as sustained cargo release, stimuli‐responsive (e.g., pH, photo, ultrasound, and multi‐stimuli) controllable delivery, and specific bone‐targeted therapy for bone disease diagnosis and treatment are analyzed and discussed in depth. Lastly, the conclusions and outlook about the design and development of MNs‐based cargo delivery systems in diagnosis and treatment for bone tissue engineering are provided to inspire new ideas and attract researchers' attention from multidisciplinary areas spanning chemistry, materials science, and biomedicine. [ABSTRACT FROM AUTHOR]

Advances in the design of potential bone-selective drugs for the treatment of various bone-related diseases are creating exciting new directions for multiple unmet medical needs. For bone-related cancers, off-target/non-bone toxicities with current drugs represent a significant barrier to the quality of life of affected patients. For bone infections and osteomyelitis, bacterial biofilms on infected bones limit the efficacy of antibiotics because it is hard to access the bacteria with current approaches. Promising new experimental approaches to therapy, based on bone-targeting of drugs, have been used in animal models of these conditions and demonstrate improved efficacy and safety. The success of these drug-design strategies bodes well for the development of therapies with improved efficacy for the treatment of diseases affecting the skeleton. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc. [ABSTRACT FROM AUTHOR]

In this study, we explored and optimized the preparation process of bone-targeting liposomes from the effective components of Huangqi Sanyan decoction (Astragaloside IV, Icariin, and Notoginsenoside R1) and set up a method that can simultaneous determine Astragaloside IV, Icariin, and Notoginsenoside R1. The physicochemical properties, stability, and bone targeting in vitro of the liposome are evaluated. According to the proportion of clinical combined use, we encapsulated three effective components of Astragalus Sanxian Decoction in liposome by thin-film dispersion method and prepared the bone targeting liposome. And an HPLC method for the simultaneous determination of Astragaloside IV, Icariin, and Notoginsenoside R1 was established. The optimal formulation and preparation process of the liposome is determined as follows: lecithin 100 mg, cholesterol 10 mg, sodium cholate 10 mg, Astragaloside IV 6 mg, Icariin 3 mg, Notoginsenoside R1 3 mg, E-DTMPA 2 mg, organic solvent 10 mL, hydration 30 min, ultrasound 6 min. And the in vitro adsorption test of hydroxyapatite showed that the bone targeting of the EDTA ultrasonic liposome which contains the effective component of Astragalus Sanxian Decoction had significantly enhanced. [ABSTRACT FROM AUTHOR]