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Ultralow molecular weight (ULAAW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.

Heparin analogs can serve as potent anticoagulants, but heterogeneous structures in some preparations and lack of antidote for others can complicate treatments. A chemoenzymatic method that prevents reversible epimerization now enables reversible application of defined constructs in cells and mice. Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs.

Purpose This study tests the hypothesis that pegylated dendrimeric micelles prolong the half-life of low molecular weight heparin (LMWH) and increase the drug's pulmonary absorption, thereby efficacious in preventing deep vein thrombosis (DVT) in a rodent model. Materials and Methods Pegylated PAMAM dendrimer was synthesized by conjugating G3 PAMAM dendrimer with methyl ester of polyethylene glycol 2000 (PEG-2000). Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) spectra and thin layer chromatography (TLC) were used to evaluate the identity and purity of pegylated dendrimer. The particle size distributions of the formulations were measured by using a Nicomp Zeta meter, and drug entrapment efficiency was studied by azure A assay. The efficacy of pegylated dendrimers in enhancing pulmonary absorption, prolonging drug half-life, and preventing DVT was studied in a rodent model. Results FTIR, NMR and TLC data confirmed that PAMAM dendrimer was conjugated to PEG-2000. The entrapment efficiency of LMWH in PEG-dendrimer micelles was about 40%. Upon encapsulation of LMWH, the particle size of PEG-dendrimer micelles increased from 11.7 to 17.1 nm. LMWH entrapped in PEG-dendrimer produced a significant increase in pulmonary absorption and the relative bioavailability of the formulation was 60.6% compared to subcutaneous LMWH. The half-life of the PEG-dendrimer-based formulation was 11.9 h, which is 2.4-fold greater than the half-life of LMWH in a saline control formulation. When the formulation was administered at 48-h intervals, the efficacy of LMWH encapsulated in pegylated dendrimers in reducing thrombus weight in a rodent model was very similar to that of subcutaneous LMWH administered at 24-h intervals. Conclusions Pegylated PAMAM dendrimer could potentially be used as a carrier for pulmonary delivery of LMWH for the long-term management of DVT.

High-efficiency treatment for tumor is not easy to achieve owing to the existence of metastasis, which remains the arch-criminal of most tumor deaths. Conventional chemotherapy exhibits insufficient inhibitory efficiency on tumor metastasis and more powerful strategies to conquer metastatic tumors are urgently needed. In this study, a rational chemoimmunotherapy strategy was adopted to treat highly aggressive melanoma based on a newly developed multifunctional nanoplatform. Firstly, immunoadjuvant cytosine-phosphate-guanine oligonucleotides (CpG ODNs) were used to boost the doxorubicin (DOX)-elicited immune responses, which synergistically suppressed tumor growth and metastasis. And the anti-metastatic low molecular weight heparin (LMWH) was also integrated, thus multiple anti-metastatic effects to against tumor metastasis were achieved. G4 PAMAM was serving as the main support to conjugate DOX by pH-sensitive hydrazone bond (PPD) and the synthesized conjugates were confirmed by H-NMR spectra, IR spectra and HRMS. Immunoadjuvant CpG ODNs were loaded by electrostatic adsorption to formulate PPD/CpG. After the coating of anti-metastatic LMWH, the designed LMWH/PPD/CpG was fabricated and characterized. The platelets-related and platelets-unrelated anti-metastatic mechanisms were investigated on B16F10 the immune activation effects, anti-tumor and anti-metastatic efficacy of LMWH/PPD/CpG were evaluated on a B16F10 melanoma xenograft model. DOX elicited tumor-specific immune responses by ICD, and the immunological effects could be further promoted by CpG ODNs, exhibiting enhanced maturation of dendritic cells (DCs) and increased level of cytolytic T lymphocytes (CTLs) . Owing to the coating of LMWH, the platelets-induced epithelial-mesenchymal-like transition of tumor cells was hindered and the actin cytoskeletal arrangement of tumor cells was affected, thus the migration ability of tumor cells was further inhibited. This multifunctional nanoplatform showed enhanced treatment efficiency on melanoma primary tumor and pulmonary metastasis. The immune activation and multiple anti-metastatic effects of LMWH/PPD/CpG establish a novel therapeutic strategy for melanoma. This anti-metastatic nanoplatform could be broadly applied for the co-delivery of other nucleic acids and chemotherapeutic drugs to treat highly aggressive tumors.

Inflammatory factors and reactive oxygen species (ROS) are risk factors for atherosclerosis. Many existing therapies use ROS-sensitive delivery systems to alleviate atherosclerosis, which achieved certain efficacy, but cannot eliminate excessive ROS. Moreover, the potential biological safety concerns of carrier materials through chemical synthesis cannot be ignored. Herein, an amphiphilic low molecular weight heparin- lipoic acid conjugate (LMWH-LA) was used as a ROS-sensitive carrier material, which consisted of injectable drug molecules used clinically, avoiding unknown side effects. LMWH-LA and curcumin (Cur) self-assembled to form LLC nanoparticles (LLC NPs) with LMWH as shell and LA/Cur as core, in which LMWH could target P-selectin on plaque endothelial cells and competitively block the migration of monocytes to endothelial cells to inhibit the origin of ROS and inflammatory factors, and LA could be oxidized to trigger hydrophilic-hydrophobic transformation and accelerate the release of Cur. Cur released within plaques further exerted anti-inflammatory and antioxidant effects, thereby suppressing ROS and inflammatory factors. We used ultrasound imaging, pathology and serum analysis to evaluate the therapeutic effect of nanoparticles on atherosclerotic plaques in apoe −/− mice, and the results showed that LLC showed significant anti-atherosclerotic effects. Our finding provided a promising therapeutic nanomedicine for the treatment of atherosclerosis.

The aim of this study was to first evaluate whether the chitosan hydrochloride-genipin crosslinking reaction is influenced by factors such as time, and polymer/genipin concentration, and second, to develop crosslinked drug loaded microspheres to improve the control over drug release. Once the crosslinking process was characterized as a function of the factors mentioned above, drug loaded hydrochloride chitosan microspheres with different degrees of crosslinking were obtained. Microspheres were characterized in terms of size, morphology, drug content, surface charge and capacity to control in vitro drug release. Clarithromycin, tramadol hydrochloride, and low molecular weight heparin (LMWH) were used as model drugs. The obtained particles were spherical, positively charged, with a diameter of 1–10 μm. X-Ray diffraction showed that there was an interaction of genipin and each drug with chitosan in the microspheres. In relation to the release profiles, a higher degree of crosslinking led to more control of drug release in the case of clarithromycin and tramadol. For these drugs, optimal release profiles were obtained for microspheres crosslinked with 1 mM genipin at 50 ºC for 5 h and with 5 mM genipin at 50 ºC for 5 h, respectively. In LMWH microspheres, the best release profile corresponded to 0.5 mM genipin, 50 ºC, 5 h. In conclusion, genipin showed to be eligible as a chemical-crosslinking agent delaying the outflow of drugs from the microspheres. However, more studies in vitro and in vivo must be carried out to determine adequate crosslinking conditions for different drugs.

The primary challenges in the tissue engineering of small-diameter artificial blood vessels include inadequate mechanical properties and insufficient anticoagulation capabilities. To address these challenges, urea-pyrimidone (Upy)-based polyurethane elastomers (PIIU-B) were synthesized by incorporating quadruple hydrogen bonding within the polymer backbone. The synthesis process employed poly(L-lactide-ε-caprolactone) (PLCL) as the soft segment, while di-(isophorone diisocyanate)-Ureido pyrimidinone (IUI) and isophorone diisocyanate (IPDI) were utilized as the hard segment. The resulting PIIU-B small-diameter artificial blood vessel with a diameter of 4 mm was fabricated using the electrospinning technique, achieving an optimized IUI/IPDI composition ratio of 1:1. Enhanced by multiple hydrogen bonds, the vessels exhibited a robust elastic modulus of 12.45 MPa, an extracellular matrix (ECM)-mimetic nanofiber morphology, and a high porosity of 41.31%. Subsequently, the PIIU-B vessel underwent dual-functionalization with low-molecular-weight heparin and gelatin via ultraviolet (UV) crosslinking (designated as PIIU-B@LHep/Gel), which conferred superior biocompatibility and exceptional anticoagulation properties. The study revealed improved anti-platelet adhesion characteristics as well as a prolonged activated partial thromboplastin time (APTT) of 157.2 s and thrombin time (TT) of 64.2 s in vitro. Following a seven-day subcutaneous implantation, the PIIU-B@LHep/Gel vessel exhibited excellent biocompatibility, evidenced by complete integration with the surrounding peri-implant tissue, significant cell infiltration, and collagen formation in vivo. Consequently, polyurethane-based artificial blood vessels, reinforced by multiple hydrogen bonds and dual-functionalized with heparin and gelatin, present as promising candidates for vascular tissue engineering.

We produced low-molecular-weight heparin/protamine nanoparticles (LMW-H/P NPs) as a carrier for heparin-binding growth factors, such as fibroblast growth factor-2 (FGF-2). A mixture of low-molecular-weight heparin (MW: about 5000 Da, 6.4 mg/mL) and protamine (MW: about 3000 Da, 10 mg/mL) at a ratio of 7:3 (vol:vol) yields a dispersion of microparticles (1-6 microm in diameter). In this study, diluted low-molecular-weight heparin solution in saline (0.32 mg/mL) mixed with diluted protamine (0.5 mg/mL) at a ratio at 7:3 (vol:vol) resulted in soluble nanoparticles (112.5 +/- 46.1 nm in diameter). The generated NPs could be then stabilized by adding 2 mg/mL dextran (MW: 178-217 kDa) and remained soluble after lyophilization of dialyzed LMW-H/P NP solution. We then evaluated the capacity of LMW-H/P NPs to protect activity of FGF-2. Interaction between FGF-2 and LMW-H/P NPs substantially prolonged the biological half-life of FGF-2. Furthermore, FGF-2 molecules were protected from inactivation by heat and proteolysis in the presence of LMW-H/P NPs.

Intravenous injection of protamine sulfate or quarternized chitosan derivative to guinea pigs after injection of 70 aIIa U/kg non-fractionated heparin shortened plasma clotting time (shown by partial activated thromboplastin time, thrombin time, and prothrombin time). Intravenous injection of protamine sulfate or quarternized chitosan derivative to guinea pigs after injection of 1 mg/kg (100 aXa U/kg) low-molecular-weight heparin (clexane) led to shortening of plasma clotting time in the ReaClot Heparin test and to prolongation of plasma amidolytic activity in the factor Xa chromogenic substrate test.