Affinity For Hydroxyapatite Research Articles

In vitro Preparation and Evaluation of Alendronate-modified Hyaluronic acid-based Nanomicelles as a Bone-Targeted Drug delivery system

Nanomicelles based on Hyaluronic acid (HA), a linear polysaccharide with high affinity to the CD44 receptor on cancerous cells, offer considerable potential to transport drugs to the target tissue while reducing exposure to normal tissues. The high affinity of alendronate (ALN) to hydroxyapatite crystals, the crucial component of bone, makes it an ideal candidate for bone-targeted delivering therapeutic nanoparticles. Here, we developed targeted and self-assembled nanocarriers by modifying HA nanomicelles with ALN to attach to hydroxyapatite. Curcumin (CUR), as a hydrophobic model drug, was used to evaluate the efficiency of developed nanomicelles. The size of blank and CUR-loaded nanomicelles was below 200 nm and their critical micelle concentrations were in the range of 38 μg/ml, which is suitable for delivery to bone tissue. The CUR-loaded ALN-HA-AC (CUR@ALN-HA-AC) nanomicelles showed a two-step release pattern, a first accelerated release period (12 % in 1 h) followed by a sustained release (65 % up to 50 h). The hydroxyapatite affinity experiment indicated that CUR@ALN-HA-AC nanomicelles exhibited significantly high affinity to the bone. Cytotoxicity studies on MG-63 cell lines demonstrated that CUR-loaded micelles exhibited much higher cytotoxic activity compared to free CUR, indicating that encapsulation in HA-ALN-AC micelles significantly enhanced the tumor cell-killing ability of CUR.

Design, Synthesis, and Characterization of HBP-Vectorized Methotrexate Prodrug Molecule 1102-39: Evaluation of In Vitro Cytotoxicity Activity in Cell Culture Models, Preliminary In Vivo Safety and Efficacy Results in Rodents.

A novel bone-targeted prodrug, 1102-39, is discussed with the aim of enhancing the therapeutic effects of methotrexate (MTX) within bone tissues while minimizing systemic toxicity. Within the 1102-39 molecule, the central linker part forms a cleavable ester group, with MTX being also linked by a stable imine bond to the specially designed hydroxybisphosphonic (HBP) vector. Synthesized through a convergent approach starting from MTX, this prodrug advantageously modulates MTX's activity by selective esterification of its α-carboxyl group. In vitro tests revealed a 10-fold reduction in cytotoxicity compared to standard MTX, in alignment with prodrug behavior and correlated with gradual MTX release. In vivo in rodents, 1102-39 displayed preliminary encouraging antitumor effects on orthotopic osteosarcoma. Furthermore, various aspects of designing molecules for selective therapy in bone tissue based on bisphosphonate molecules as vectors for delivering active compounds to the bone are discussed. The 1102-39 molecule exhibits strong affinity for hydroxyapatite and a progressive release of MTX in aqueous environments, enhancing the safety and efficacy of bone-specific treatments and enabling sustained activity within bone and bone joints in the therapy of tumor and inflammation.

Alendronate/lactoferrin-dual decorated lipid nanocarriers for bone-homing and active targeting of ivermectin and methyl dihydrojasmonate for leukemia

Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC50), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.

Acquired pellicle and biofilm engineering with CaneCPI-5: Insights from proteomic and microbiomics analysis

ObjectiveIn this in vivo proof-of-concept study, acquired pellicle engineering was implemented to promote alterations in the protein composition of the acquired enamel pellicle (AEP) and the bacterial composition of the dental biofilm after treatment with Sugarcane cystatin (CaneCPI-5). DesignAfter prophylaxis, 10 volunteers rinsed (10 mL, 1 min) with the following solutions: 1) deionized water (H2O- negative control or 2) 0.1 mg/mL CaneCPI-5. The AEP and biofilm were formed along 2 or 3 h, respectively. The AEP was collected with electrode filter papers soaked in 3 % citric acid. After protein extraction, samples were analyzed by quantitative shotgun label-free proteomics. The biofilm microbiome was collected with a dental curette. The DNA was extracted, amplified, and analyzed by 16S-rRNA Next Generation Sequencing (NGS). ResultsTreatment with CaneCPI-5 increased several proteins with antimicrobial, acid-resistance, affinity for hydroxyapatite, structural and calcium binding properties, such as Cysteine-rich-3 (6-fold-p = 0.03), Cystatin-B (5.5-fold-p < 0.01), Neutrophil-defensin 1 (4.7-fold-p < 0.01), Mucin (3.9-fold-p < 0.01), Immunoglobulin-heavy-constant (3.8-fold-p < 0.01) and Lactotransferrin (2.8-fold-p < 0.01). Microbiome revealed that several commensal bacteria had their abundance increased after rinsing with CaneCPI-5, such as Corynebacterium and Neisseria, while Streptococcus and Prevotella nigrescens were decreased. The results indicate the efficiency of CaneCPI-5 in promoting beneficial changes in the AEP and biofilm, making this phytocystatin a potential target for incorporation into dental products. ConclusionCane demonstrated the capability to alter the protein composition of the acquired enamel pellicle (AEP) and the initial colonizers of the biofilm, enhancing the presence of proteins and bacteria crucial for dental protection.

Isolation and differential structure characteristics of calcium-binding peptides derived from Pacific cod bones by hydroxyapatite affinity

Calcium-chelating peptides were found in Pacific cod bone, but their binding structure and properties have not been elucidated. Novel calcium-binding peptides were isolated by hydroxyapatite affinity chromatography (HAC), and their binding structure and properties were investigated by isothermal titration calorimetry (ITC), multispectral techniques, and mass spectrometry. Based on multiple purifications, the calcium binding capacity (CBC) of Pacific cod bone peptides (PBPs) was increased from 1.71 ± 0.15 μg/mg to 7.94 ± 1.56 μg/mg. Peptides with a molecular weight of 1–2 kDa are closely correlated with CBC. After binding to calcium, the secondary structure of peptides transitioned from random coil to β-sheet, resulting in a loose and porous microstructure. Hydrogen bonds, electrostatic interaction, and hydrophobic interaction contribute to the formation of peptide‑calcium complexes. The F21 contained 42 peptides, with repeated “GE” motif. Differential structure analysis provides a theoretical basis for the targeted preparation of high CBC peptides.

Abstract 2157 Strengthening Oral Defenses through Modification of Cystatin-SA: A Molecular exploration of Protease Interactions and Hydroxyapatite Affinity

Abstract 2157 Strengthening Oral Defenses through Modification of Cystatin-SA: A Molecular exploration of Protease Interactions and Hydroxyapatite Affinity

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.

Upconversion Nanoparticles as Imaging Agents for Dental Caries.

Dental caries (cavities) is the most prevalent disease worldwide; however, current detection methods suffer from issues associated with sensitivity, subjective interpretations, and false positive identification of carious lesions. Therefore, there is a great need for the development of more sensitive, noninvasive imaging methods. The 30 nm core@shell NaYF4; Yb20%, Er2%@NaYF4 upconversion nanoparticles (UCNPs), exhibiting strong upconversion emission from erbium upon excitation at 975 nm, were used in the imaging of locations of demineralized enamel and oral biofilm formation for the detection of dental caries. UCNPs were modified with poly(acrylic acid) (PAA) or poly-d-lysine (PDL), and targeting peptides were conjugated to their surface with affinity for either hydroxyapatite (HA), the material dentin is composed of, or the caries causing bacteria Streptococcus mutans. A statistical difference in the binding of targeted vs nontargeted UCNPs to HA was observed after 15 min, using both upconversion fluorescence of UCNP (p < 0.001) and elemental analysis (p = 0.0091). Additionally, using the HA targeted UCNPs, holes drilled in the enamel of bovine teeth with diameters of 1.0 and 0.5 mm were visible by the green emission after a 20 min incubation with no observable nonspecific binding. A statistical difference was also observed in the binding of targeted versus nontargeted UCNPs to S. mutans biofilms. This difference was observed after 15 min, using the fluorescence measurements (p = 0.0125), and only 10 min (p < 0.001) using elemental analysis via ICP-OES measurements of Y3+ concentration present in the biofilms. These results highlight the potential of these UCNPs for use in noninvasive imaging diagnosis of oral disease.

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

Bone tumor-homing nanotherapeutics for prolonged retention in tumor microenvironment and facilitated apoptotic process via mevalonate pathway inhibition.

Bone malignancy features a mineralized extracellular matrix primarily composed of hydroxyapatite, which interferes with the distribution and activity of antineoplastic agents. Herein, we report bone tumor-homing polymeric nanotherapeutics consisting of alendronate-decorated chondroitin sulfate A-graft-poly(lactide-co-glycolide) and doxorubicin (DOX), named PLCSA-AD, which displayed a prolonged retention profile in the tumor microenvironment and augmented therapeutic efficacy via inhibition of the mevalonate pathway. PLCSA-AD exhibited a 1.72-fold lower IC50 value than free DOX and a higher affinity for hydroxyapatite than PLCSA in HOS/MNNG cell-based 2D bone tumor-mimicking models. The inhibition of the mevalonate pathway by PLCSA-AD in tumor cells was verified by investigating the cytosolic fraction of unprenylated proteins, where blank PLCSA-AD significantly increased the expression of cytosolic Ras and RhoA without changing their total cellular amounts. In a bone tumor-mimicking xenografted mouse model, AD-decorated nanotherapeutics significantly increased tumor accumulation (1.73-fold) compared with PLCSA, and higher adsorption to hydroxyapatites was observed in the histological analysis of the tumor. As a result, inhibition of the mevalonate pathway and improvement in tumor accumulation led to markedly enhanced therapeutic efficacy in vivo, suggesting that PLCSA-AD could be promising nanotherapeutics for bone tumor treatment.

Pyrophosphorylated-Cholesterol-Modified Bone-Targeting Liposome Formulation Procedure.

Bone-targeting drug delivery systems have been rapidly developed to increase drug efficacy and safety for musculoskeletal diseases in the past decades. Bone-targeting drug delivery is mainly based on ligands that have hydroxyapatite affinity. We previously reported a pyrophosphorylated cholesterol ligand-based bone-targeting liposome formulation for the treatment of bone fracture delayed union. Different from traditional bone-targeting ligands: bisphosphonates tetracyclines and polyanion peptides. Pyrophosphorylated cholesterol has no intrinsic pharmacological effects and can be naturally degraded into metabolites (both pyrophosphate and cholesterol are substances that naturally exist in the body), leading to minimal safety concerns. Pyrophosphorylated cholesterol is not only biodegradable, but it also provides strong bone affinity, which could target different bone substructures/surfaces, further improving drug delivery efficiency in vivo. Here, we describe the synthesis protocol of pyrophosphorylated cholesterol and a reverse-evaporation-based formulation protocol of pyrophosphorylated-cholesterol-modified bone-targeting liposomes for hydrophilic drug encapsulation. We also provide instructions for the bone-targeting property evaluation of the pyrophosphorylated-cholesterol-modified liposome in vitro and in vivo. Our system has wide applications and has already been used to study drug treatment for fracture delayed union and nonunion. As a promising bone-targeting drug delivery system, our system may be extrapolated to clinical applications of other bone anabolic agents for different bone diseases.

P800SO3-PEG: a renal clearable bone-targeted fluorophore for theranostic imaging

BackgroundDue 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.MethodsBone-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.ResultsThe 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.ConclusionsP800SO3-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.

Drug-Inclusive Inorganic-Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate.

Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). In this work, the third generation BP drug zoledronate (ZOL) was combined with alkaline earth metal ions (e.g., Sr2+ and Ba2+) in an effort to synthesize new materials. These metal–ZOL compounds can operate as CRSs when exposed to appropriate experimental conditions, such as the low pH of the human stomach, thus releasing the active drug ZOL. CRS networks containing Sr2+ or Ba2 and ZOL were physicochemically and structurally characterized and were evaluated for their ability to release the free ZOL drug during an acid-driven hydrolysis process. Various release and kinetic parameters were determined, such as initial rates and release plateau values. Based on the drug release results of this study, there was an attempt to correlate the ZOL release efficiency with the structural features of these CRSs.

Fluorescent risedronate analogue 800CW-pRIS improves tooth extraction-associated abnormal wound healing in zoledronate-treated mice

BackgroundBisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but serious side effect of nitrogen-containing bisphosphonate drugs (N-BPs) frequently prescribed to reduce skeletal-related events in bone malignancies and osteoporosis. BRONJ is associated with abnormal oral wound healing after dentoalveolar surgery and tooth extraction. We previously found that N-BP chemisorbed to bone mineral hydroxyapatite was dissociated by secondary applied N-BP. This study investigated the effect of the surface equilibrium-based removal of N-BP from jawbone on tooth extraction wound healing of zoledronate (ZOL)-treated mice.MethodsA pharmacologically inactive N-BP derivative (the 4-pyridyl isomer of risedronate equipped with a near-infrared 800CW fluorescent imaging dye, 800CW-pRIS) was designed and synthesized. 800CW-pRIS was intra-orally injected or topically applied in a deformable nano-scale vesicle formulation (DNV) to the palatal tissue of mice pretreated with ZOL, a potent N-BP. The female C56BL6/J mice were subjected to maxillary molar extraction and oral wound healing was compared for 800CW-pRIS/ZOL, ZOL and untreated control groups.Results800CW-pRIS is confirmed to be inactive in inhibiting prenylation in cultured osteoclasts while retaining high affinity for hydroxyapatite. ZOL-injected mice exhibit delayed tooth extraction wound healing with osteonecrosis relative to the untreated controls. 800CW-pRIS applied topically to the jaw one week before tooth extraction significantly reduces gingival oral barrier inflammation, improves extraction socket bone regeneration, and prevents development of osteonecrosis in ZOL-injected mice.ConclusionsTopical pre-treatment with 800CW-RIS in DNV is a promising approach to prevent the complication of abnormal oral wound healing associated with BRONJ while retaining the anti-resorptive benefit of legacy N-BP in appendicular or vertebrate bones.

Synthesis and evaluation of a multifunctional probe with a high affinity for prostate-specific membrane antigen (PSMA) and bone

Prostate cancer frequently metastasizes to the bone. Because patients with bone metastases suffer from skeletal-related events, the diagnosis and treatment of bone metastases in the early stage are important. In this study, to improve the sensitivity of detecting bone metastases in patients with prostate cancer, we designed, synthesized, and evaluated a multifunctional radiotracer, [67Ga]Ga-D11-PSMA-617 ([67Ga]3), with an undeca-aspartic acid as a bone-seeking moiety between [67Ga]Ga-DOTA and a prostate-specific membrane antigen (PSMA) ligand based on the lysine-urea-glutamate motif. [67Ga]3 showed a high affinity for hydroxyapatite and high uptake in PSMA-positive LNCaP cells. Moreover, in biodistribution experiments using tumor-bearing mice, [67Ga]3 exhibited high accumulation in the bone and PSMA-positive tumor although the accumulation of [67Ga]3 in the PSMA-positive tumor was lower than that of [67Ga]Ga-PSMA-617. This study provides valuable information for developing radiotheranostic probes combining multiple carriers with different mechanisms.

Development of local injectable, bone-targeting nanocarriers of triptolide for treatment of bone-only metastasis

Triptolide (TP) is known for its diverse pharmacological activities but also its delivery and toxicity issues. This study aimed at exploiting TP’s anticancer effects at lower risk of systemic toxicity by developing local-injectable “bone-targeting TP nanoparticle” (TPN) for bone-only metastasis treatment. The lipid/oil-based TPNs decorated with alendronate (ALE) achieved size of 70.4–111.2 nm with good dispersion stability. The drug encapsulation efficiency reached 97 % and drug release profiles were in biphasic, controlled manner lasting for 5 days in medium with serum proteins and calcium. TPNs were more cytotoxic than free TP against MDA-MB-231 breast cancer cells (IC50: 16.40 ± 0.80 nM vs 25.45 ± 1.83 nM, P < 0.05) but less cytotoxic against MC3T3-E1 osteoblasts (P < 0.05). When combined with paclitaxel or docetaxel, low dose TPN (containing 10 nM) significantly increased the effectiveness of the two chemotherapy drugs against MDA-MB-231 (IC50 values decreased from 7.3 nM to 2.5 nM for docetaxel; from 4.6 nM to 1.1 nM), indicating potent chemosensitization effects. Retardation of in vitro cancer cell migration by TPN was also observed in the standard scratch assay. ALE decoration significantly enhanced the TPN affinity for both calcium hydroxyapatite and porcine bone chip models, which led to enhancement in TP retention in the bones up to 8.1-fold versus free drug. Overall, TPN demonstrated good potential as a local-injectable, bone-targeted nanotherapy tailored for eradication of bone-only metastasis at reduced risk of systemic toxicity.

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.

Cytarabine delivered by CD44 and bone targeting redox-sensitive liposomes for treatment of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) remains a serious fatal disease for the patients and effective treatment strategies are urgently needed. Based on the characteristics of the AML, we developed the CD44 and bone targeting liposomes delivery system decorated with the redox-cleavable polymer. First, ALN-HA was obtained by amination between alendronate (ALN) and hyaluronic acid (HA), and cholesterol (Chol) was coupled by a disulfide linker (-SS-) with biological reducibility to obtain the goal polymer, ALN-HA-SS-Chol, decorated the liposomes loaded with the Cytarabine (AraC). ALN-HA-SS-AraC-Lip exhibited a spherical morphology with the diameter of 117.5 nm and expanded at the environment of 10 mM dithiothreitol. Besides, compared with other groups, ALN-HA-SS-AraC-Lip showed benign hydroxyapatite affinity in vitro and bone targeting in C57/BL6 mice, also, ALN-HA-SS-AraC-Lip exhibited encouraging antitumor which significantly reduced the white blood cell amount in bone marrow and blood smear caused by AML model, besides, the dual targeting liposomes also prolong the survival time of mice. In conclusion, the bone and CD44 dual targeting liposomes with redox sensitivity could target to the leukemia stem cells regions and then uptake by the tumor cells, which would be a valuable target for the treatment of the AML.

Decoration of Squalenoyl-Gemcitabine Nanoparticles with Squalenyl-Hydroxybisphosphonate for the Treatment of Bone Tumors.

Therapeutic perspectives of bone tumors such as osteosarcoma remain restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancer squalene‐based nanomedicine with bone affinity and retention capacity. A squalenyl‐hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1‐hydroxyl‐1,1‐bisphosphonate moiety to the squalene chain. This amphiphilic compound was inserted onto squalenoyl‐gemcitabine nanoparticles using the nanoprecipitation method. The co‐assembly led to nanoconstructs of 75 nm, with different morphology and colloidal properties. The presence of squalenyl‐hydroxybisphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite, a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient‐treated derived pediatric osteosarcoma cells. Further in vivo studies will shed light on the potential of these nanomedicines for the treatment of bone sarcomas.

Preparation and in vitro evaluation of doxorubicin loaded alendronate modified hollow gold nanoparticles for bone-targeted chemo-photothermal therapy

The treatment of malignant bone tumors (including primary bone tumors and metastatic bone tumors) has always been a clinical challenge. The purpose of this study is to design a bone-targeted nano-carrier with photothermal effect to achieve chemo-photothermal therapy (CPT), which allows the minimal use of photothermal agents and chemical drugs to target bone tumors. Alendronate modified hollow gold nanoparticles (HGNPs- ALN) were synthesized using mercapto polyethylene glycol carboxyl (SH-PEG2000-COOH) as the connecting arm, fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) data show that HGNPs-ALN with a particle size of about 80 nm has been successfully synthesized. The hydroxyapatite affinity experiment in vitro indicated that HGNPs-ALN exhibited a high affinity to bone. In addition, the temperature of HGNPs-ALN under near-infrared laser irradiation can rise to 53 °C, which can achieve effective photothermal therapy for bone tumors. Bone-targeted hollow gold nanoparticles (DOX@HGNPs-ALN) loaded with doxorubicin hydrochloride (DOX) were synthesized by one-pot method. By comparing the stability and drug loading of HGNPs-ALN, it was concluded that the optimal mass ratio of HGNPs-ALN (calculated by the amount of gold) to DOX was about 1:2. HGNPs-ALN and DOX@HGNPs-ALN both have good photothermal stability and photothermal transformation properties, and confirmed the safety of HGNPs on human osteosarcoma cells. MTT experiments showed that DOX@HGNPs-ALN had the strongest killing effect on MG-63 osteosarcoma cells under laser irradiation (the killing rate is about 65%). According to these results, it can be considered that DOX@HGNPs-ALN has the potential of CPT synergistic targeting therapy for bone tumors.