Drug Delivery最新文献

The blood-brain barrier (BBB) is a protective barrier for brain safety, but it is also a major obstacle to the delivery of drugs to the cerebral parenchyma such as the hippocampus, hindering the treatment of central nervous system diseases such as Alzheimer's disease (AD). In this work, an anti-AD brain-targeted nanodrug delivery system by co-loading icariin (ICA) and tanshinone IIA (TSIIA) into Aniopep-2-modified long-circulating (Ang2-ICA/TSIIA) liposomes was developed. Low-density lipoprotein receptor-related protein-1 (LRP1) was a receptor overexpressed on the BBB. Angiopep-2, a specific ligand of LRP1, exhibited a high binding efficiency with LRP1. Additionally, ICA and TSIIA, drugs with neuroprotective effects are loaded into the liposomes, so that the liposomes not only have an effective BBB penetration effect, but also have a potential anti-AD effect. The prepared Ang2-ICA/TSIIA liposomes appeared narrow dispersity and good stability with a diameter of 110 nm, and a round morphology. Cell uptake observations, BBB models in vitro, and imaging analysis in vivo showed that Ang2-ICA/TSIIA liposomes not only penetrate the BBB through endocytosis, but also accumulate in N2a cells or brain tissue. The pharmacodynamic analysis in vivo demonstrated that Ang2-ICA/TSIIA liposomes could improve AD-like pathological features in APP/PS1 mice, including inhibiting neuroinflammation and oxidative stress, reducing apoptosis, protecting neurons, and improving cognitive function. Therefore, Ang2-ICA/TSIIA liposomes are considered a potentially effective therapeutic strategy for AD.

Plant-derived 5 α-reductase inhibitors, such as β-sitosterol and phytosterol glycosides, have been used to treat androgenic alopecia, but their oral absolute bioavailability is poor. This study aimed to develop a transdermal drug delivery system of β-sitosterol (BS) using a nanostructured lipid carrier (NLC) incorporated into polymeric microneedles (MN). Using a high-speed homogenization method, NLC was formulated variables were optimized by Box-Behnken statistical design. The optimized formulation of BS-loaded NLCs was incorporated into the chitosan-based MNs to prepare NLC-loaded polymeric MNs (NLC-MNs) and evaluated using testosterone induced alopecia rats. The cumulative amount of β-sitosterol associated with NLC- MN which penetrated the rat skin in-vitro was 3612.27 ± 120.81 μg/cm², while from the NLC preparation was 2402.35 ± 162.5 μg/cm². The steady state flux (J_ss) of NLC-MN was significantly higher than that of the optimized NLC formulation (P < 0.05). Anagen/telogen ratio was significantly affected by NLC and NLC-MN, which was 2.22 ± 0.34, 1.24 ± 0.18 respectively compared to 0.26 ± 0.08 for animal group treated with testosterone. The reversal of androgen-induced hair loss in animals treated with β-sitosterol was a sign of hair follicle dominance in the anagenic growth phase. However, NLC-MN delivery system has shown significant enhancement of hair growth in rats. From these experimental data, it can be concluded that NLC incorporated MN transdermal system have potential in effective treatment of androgenic alopecia.

The anti-hyperglycemic sodium glucose co-transporter 2 inhibitor Canagliflozin (CFZ) represents a recent antihyperglycemic modality, yet it suffers from low oral bioavailability. The current work aims to formulate CFZ-loaded transdermal nanostructured liquid crystal gel matrix (NLCG) to improve its therapeutic efficiency. Pre-formulation study included the construction of pseudoternary phase diagrams to explore the effect of two conventional amphiphiles against amphiphilic tri-block copolymer in the formulation of NLCG. The influence of different co-solvents was also investigated with the use of monooleine as the oil. Physical characterization, morphological examination and skin permeation were performed for the optimized formulations. The formula of choice was further investigated for skin irritation and chemical stability. Pharmacodynamic evaluation of the successful formula was conducted on hyperglycemic as well as normoglycemic mice. In addition, oral glucose tolerance test was conducted. Results revealed the supremacy of Poloxamer for stabilizing and maximizing liquid crystal gel (LCG) area percentage that reached up to 12.6%. CFZ-NLCG2 isotropic formula showed the highest permeation parameters; maximum flux value of 7460 μg/cm² h and Q₂₄ of 5327 μg/cm². Pharmacodynamic evaluation revealed the superiority of the antihyperglycemic activity of CFZ-NLCG2 in fasting mice and its equivalence in the oral glucose tolerance test (OGTT) compared to the oral one. The obtained results confirmed the success of CFZ-NLCG2 in the transdermal delivery of CFZ in therapeutically effective concentration compared to the oral route, bypassing first pass effect; in addition, eliminates the possible gastrointestinal side effects related to the inhibition of intestinal sodium glucose co-transporter (SGLT) and maximizes its selectivity to the desired inhibition of renal SGLT.

To realize the synergistic anti-tumor effect of chemotherapy and photodynamic therapy, the mono sulfide-modified docetaxel (DTX) prodrugs (DSD) provided by our laboratory and hematoporphyrin (HP) were used to physically prepare co-assembled nanoparticles (DSD/HP NPs) by nano-precipitation. For the first time, this study showed its characteristics, in vitro anti-tumor activity, pharmacokinetic behavior in rats, in vivo distribution, and pharmacodynamic effects on 4T1 tumor-bearing Bal b/c mice. DSD/HP NPs optimized by single-factor and response surface optimization had several distinct characteristics. First, it had dark purple appearance with particle size of 105.16 ± 1.24 nm, PDI of 0.168 ± 0.15, entrapment efficiency and drug loading of DSD and HP in DSD/HP NPs of 96.27 ± 1.03% and 97.70 ± 0.20%, 69.22 ± 1.03% and 20.03 ± 3.12%, respectively. Second, it had good stability and could release DTX and HP slowly in the media of pH 7.4 PBS with 10 mM DTT (H₂O₂). Moreover, DSD/HP NPs along with NiR treatment significantly inhibited 4T1 cells proliferation, and induced more reactive oxygen species and cells apoptosis. In vivo pharmacokinetic and pharmacodynamic studies showed that DSD/HP NPs could prolong the drug circulation time in rats, increase drug distribution in tumor site, obviously inhibit tumor growth, and decrease the exposure of drug to normal tissues. Therefore, DSD/HP NPs as a promising co-assembled nano-drug delivery system could potentially improve the therapeutic efficiency of chemotherapeutic drug and achieve better anti-tumor effects due to the combination of chemotherapy and photodynamic therapy.

Development of new approaches for oral delivery of an existing antiviral drug aimed to enhance its permeability and hence bioavailability. Ganciclovir (GC) is an antiviral drug that belongs to class III in biopharmaceutical classification. The encapsulation of poorly absorbed drugs within nanosized particles offers several characteristics to drug due to their acquired surface properties. In the following study, the solvent evaporation technique was used to incorporate GC, within elegant nanosize particles using cyclodextrin and shellac polymers for enhancing its permeability and release pattern. Formulation variables were optimized using 2³ full factorial design. The prepared formulations were assessed for yield, particle size, content, and micromeritics behavior. The optimized formula (F6) was identified through differential scanning calorimetry and Fourier transform infrared. In vitro release and stability were also assessed. Pharmacokinetic parameters of optimized nano GC solid dispersion particles (NGCSD-F6) were finally evaluated. The optimized formula (F6) showed a mean particle size of 288.5 ± 20.7 nm, a zeta potential of about 23.87 ± 2.27, and drug content 95.77 ± 2.1%. The in vitro drug release pattern of F6 showed an initial burst release followed by a sustained release over the next 12 h. The optimized formula showed accepted stability upon storage at room and refrigerator temperatures for 6 months with good flowing properties (Carr's index = 18.28 ± 0.44). In vivo pharmacokinetic study in rabbits revealed 2.2 fold increases in the bioavailability of GC compared with commercial convention tablets. The study affords evidence for the success of the solid dispersion technique under specified conditions in improvement of bioavailability of GC.

The antitumor immune response induced by chemotherapy has attracted considerable attention. However, the immunosuppressive tumor microenvironment hinders the immune activation effect of cancer chemotherapy. TGF-β plays a key role in driving tumor immunosuppression and can prevent effective antitumor immune response through multiple roles. In this study, a dual-responsive prodrug micelle (PAOL) is designed to co-deliver LY2109761 (a TGF-β receptor I/II inhibitor) and oxaliplatin (OXA, a conventional chemotherapy) to remodel tumor microenvironment and trigger immunogenic cell death (ICD) to induce antitumor immunity response. Under hypoxia tumor environment, the polyethylene glycol shell of the micelle cleavages, along with the release of LY2109761 and OXA prodrug. Cytotoxic effect of OXA is then activated by glutathione-mediated reduction in tumor cells and the activated OXA significantly enhances tumor immunogenicity and promotes intratumoral accumulation of cytotoxic T lymphocytes. Meanwhile, TGF-β blockade through LY2109761 reprograms tumor microenvironment by correcting the immunosuppressive state and regulating tumor extracellular matrix, which further maintaining OXA induced immune response. Therefore, due to the capability of boosting tumor-specific antitumor immunity, the bifunctional micelle presents markedly synergistic antitumor efficacies and provides a potent therapeutic strategy for chemoimmunotherapy of solid tumors.

Multidrug resistance (MDR), which is common in colorectal cancer (CRC), induces high mortality in patients. Due to its robust and selective apoptosis induction in some CRC cells with MDR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is attractive as a novel tool for CRC therapy. However, TRAIL is limited by its poor tumor-homing ability and inefficient apoptosis induction in CRC cells expressing low levels of death receptor (DR). Here, the tumor-homing RGR peptide (CRGRRST) was fused to TRAIL to produce RGR-TRAIL. Compared with TRAIL, RGR-TRAIL showed greater cell binding and cytotoxicity in CRC cells. In addition, RGR-TRAIL exerted significantly enhanced tumor uptake and growth suppression in mice bearing CRC tumor xenografts. Notably, RGR-TRAIL eradicated all tumor xenografts of DR-overexpressing COLO205 cells. However, TRAIL only showed mild tumor growth suppression under the same conditions, indicating that RGR fusion significantly increased the antitumor effect of TRAIL in DR-overexpressing CRC cells by improving tumor homing. Nevertheless, RGR fusion did not significantly enhance the antitumor effect of TRAIL in HT29 cells expressing low levels of DR. We found that DR expression in HT29 cells was enhanced by epidermal growth factor receptor (EGFR)-targeted photodynamic therapy (PDT). Moreover, both the in vitro and in vivo antitumor effects of RGR-TRAIL were significantly improved by combination with PDT. HT29 tumor xenografts (∼20%) were even eradicated by combination therapy. These results indicate that it is valuable to further evaluate the combination therapy of RGR-TRAIL and tumor-targeted PDT for clinical therapy of CRC with MDR.

Neointimal hyperplasia is a complex process after vascular interventions, acute platelet deposition and smooth muscle cell proliferation both contributed to this process. There are still no perfect solutions to solve this problem. Rivaroxaban is a novel anticoagulant that has been widely used in clinic, it has a good pharmacological effects both in vivo and in vitro. Chitosan microparticle rapamycin (MP-rapa) was fabricated, interspaces of polyglycolic acid (PGA) scaffold were used as a reservoir of MP-rapa, and the scaffold was coated with hyaluronic acid rivaroxaban (MP-rapa-riva). Scanning electronic microscopy (SEM) photographs were taken and water contact angles were measured, rat inferior vena cava (IVC) patch venoplasty model was used; patches were harvested at day 14 and examined by immunohistochemistry and immunofluorescence. SEM photographs showed the microparticles rapamycin were inside the interspace of the scaffold, hyaluronic acid rivaroxaban was also successfully coated onto the surface of the scaffold. There was a thinner neointima, fewer proliferating cell nuclear antigen (PCNA) positive cells, fewer macrophages in the MP-rapa and MP-rapa-riva grafts compared to the control PGA graft. The result showed that this scaffold with dual anticoagulation and antiproliferation functions can effectively inhibit venous neointimal hyperplasia, although this is an animal experiment, it showed promising potential clinical application in the future.

Although the etoposide and carboplatin (EP) combination strategy has been the first-line chemotherapy, patients with extensive-stage disease small-cell lung cancer (SCLC) still have poor survival outcomes. Our retrospective analysis revealed that 46 patients with SCLC only achieved medium overall survival (OS) of 11.6 months after treated by EP. Recently, it was demonstrated that combination therapy of PD1/PD-L1 immune checkpoint blocker and EP could significantly improve the OS of SCLC patients. However, the serious treatment-related toxicity leaded to a high rate of treatment-discontinuation or even death. In the present study, we have developed a novel TPP1-conjugated nanocomplex, abbreviated as TPP1NP-EP, which was co-loaded with carboplatin (CBP) and etoposide (VP16). The TPP1 was a PD-L1 targeting peptide and conjugated on the surface of nanocomplex by a matrix metalloproteinase (MMP-2/9)-cleavable peptide linker sequence PLGLAG. For dual-loading of CBP and VP16, the CBP was chemically conjugated with poly(ethylene glycol) (PEG)-poly(caprolactone) (PCL) by pH-sensitive hydrazone bond and the VP16 was physically encapsulated by emulsion-solvent evaporation method. In vitro and in vivo experiments demonstrated an excellent anti-tumor effect of TPP1NP-EP on SCLC and improved safety. In conclusion, the present study has provided a promising strategy for treatment of malignant SCLC.

Our study aimed to develop a self-microemulsifying drug delivery system for the poorly aqueous-soluble drug Coenzyme Q₁₀, to improve the dissolution and the oral bioavailability. Excipients were selected based on their Coenzyme Q₁₀ solubility, and their concentrations were set for the optimization of the microemulsion by using a D-optimal mixture design to achieve a minimum droplet size and a maximum solubility of Coenzyme Q₁₀ within 15 min. The optimized formulation was composed of an oil (omega-3; 38.55%), a co-surfactant (Lauroglycol® 90; 31.42%), and a surfactant (Gelucire^® 44/14; 30%) and exhibited a mean droplet size of 237.6 ± 5.8 nm and a drug solubilization (at 15 min) of 16 ± 2.48%. The drug dissolution of the optimized formulation conducted over 8 h in phosphate buffer medium (pH 6.8) was significantly higher when compared to that of the Coenzyme Q₁₀ suspension. A pharmacokinetic study in rats revealed a 4.5-fold and a 4.1-fold increase in the area under curve and the peak plasma concentration values generated by the optimized formulation respectively, as compared to the Coenzyme Q₁₀ suspension. A Coenzyme Q₁₀ brain distribution study revealed a higher Coenzyme Q₁₀ distribution in the brains of rats treated with the optimized formulation than the Coenzyme Q₁₀ suspension. Coenzyme Q₁₀-loaded self microemulsifying drug delivery system was successfully formulated and optimized by a response surface methodology based on a D-optimal mixture design and could be used as a delivery vehicle for the enhancement of the oral bioavailability and brain distribution of poorly soluble drugs such as Coenzyme Q₁₀.