Preparation of injectable clopidogrel loaded submicron emulsion for enhancing physicochemical stability and anti-thrombotic efficacy.

Due to the superior safety and therapeutic efficacy, clopidogrel (CLP) has been widely used to prevent postoperative thrombosis. However, limitations of delayed absorption and metabolic activation of clopidogrel after oral administration hinder its clinic use for acute thrombosis treatment in percutaneous coronary intervention (PCI). Although clopidogrel aqueous injection systems were designed and developed, chemical instability under physiological condition or vascular irritation remains to be solved. In this study, we aim to prepare an injectable clopidogrel loaded submicron emulsion to overcome the drawbacks of conventional clopidogrel aqueous formulation and improve the antiplatelet aggregation effects. Results showed that this delivery system exerted inspiring features including uniform particle size, higher drug loading capacity and sustained drug release behavior. It can dramatically upgrade the formulation stability and prevent the drug degradation under sterilization or higher pH environments. No remarkable droplet size increase or drug content decrease was observed during storage. Compared to CLP tablet, the peak drug concentration (Cmax) and area under the curve (AUC) of CLP emulsion increased by 12.01-fold and 4.69-fold, respectively. Most importantly, it exerted excellent in vivo anti-thrombotic effect on numerous designed animal models. Conclusively, submicron emulsion is a promising delivery system for improving clopidogrel stability and anti-thrombotic efficacy.

Construction of Surface-Modified Polydopamine Nanoparticles for Sequential Drug Release and Combined Chemo-Photothermal Cancer Therapy.

Single chemotherapy often causes severe adverse effects and drug resistance to limit therapeutic efficacy. As a noninvasive approach, photothermal therapy (PTT) represents an attractive option for cancer therapy due to the benefits of remote control and precise treatment methods. Nanomedicines constructed with combined chemo-photothermal properties may exert synergistic effects and improved antitumor efficacy. In this study, we developed polydopamine (PDA)-coated nanoparticles grafted with folic acid (FA) and polyethylene glycol to transport doxorubicin (DOX) for targeted cancer therapy. The results showed that this delivery vehicle has a nanoscale particle size and narrow size distribution. No particle aggregation or significant drug leakage was observed during the stability test. This system presented excellent photothermal conversion capability under near-infrared light (NIR) laser irradiation due to the PDA layer covering. In vitro dissolution profiles demonstrated that sequential and triggered DOX release from nanoparticles was pH-, NIR irradiation-, and redox level-dependent and could be best fitted with the Ritger-Peppas equation. FA modification effectively promoted the intracellular uptake of nanoparticles by HepG2 cells and therefore significantly inhibited cell recovery and induced tumor cell apoptosis. Compared to the free DOX group, nanoparticles reduced the DOX concentration in the heart to avoid drug-related cardiotoxicity. More importantly, the in vivo antitumor efficacy results showed that compared with the single chemotherapy strategy, the nanoparticle group exerted combined and satisfactory tumor growth inhibition effects with good biocompatibility. In summary, this nanocarrier delivery system can organically combine chemotherapy and PTT to achieve effective and precise cancer treatment.

Folic Acid-Modified Erythrocyte Membrane Loading Dual Drug for Targeted and Chemo-Photothermal Synergistic Cancer Therapy.

To overcome the challenges of systemic toxicity and weak tumor selectivity caused by traditional antitumor drugs, numerous nanocarrier systems have been developed in recent decades, and their therapeutic effect has been improved to varying degrees. However, because of the drug resistance effect and metastasis involved in tumor recurrence, a single chemotherapy can no longer satisfy the diversified treatment needs. Recently, the application of chemotherapy in combination with thermotherapy as a synergistic approach has been proven to be more effective, and it provides a new strategy for cancer therapy. In this work, by utilizing the unique properties of erythrocytes, a surface-modified erythrocyte membrane was constructed as a novel nanocarrier system (DOX and ICG-PLGA@RBC nanoparticles, DIRNPs for short) for the simultaneous transportation of chemotherapeutic drugs (doxorubicin, DOX) and photothermal agents (indocyanine green, ICG) to achieve the effects of long-term circulation, active tumor targeting, and triggered drug release. The results indicated that DIRNPs have a nanoscale particle size of 158.4 nm with a narrow size distribution and a negative surface charge of -5.79 mV. No particle aggregation or remarkable drug leakage was observed during the 30 day storage test, and because of the excellent photothermal conversion ability of ICG, the local temperature of DIRNPs could dramatically increase from 33.7 to 49.8 °C in 10 min under near-infrared (NIR) laser irradiation. The in vitro drug dissolution data demonstrated that the DOX release from the DIRNPs was pH-dependent and NIR-triggered. Folic acid modifications of the erythrocyte membrane effectively facilitated the intracellular uptake of DIRNPs by HepG2 cells and, as a result, it significantly inhibited tumor cell growth, promoted reactive oxygen species levels, induced cell apoptosis, and restricted cell recovery and migration. In vivo pharmacokinetics and biodistribution studies indicated that the DIRNPs prolonged the half-life of DOX from 6.03 to 17.6 h and remarkably reduced the DOX level in the heart to avoid drug-related cardiotoxicity. More importantly, the DIRNPs exerted excellent in vivo antitumor efficacy against H22 tumors with superior safety. In conclusion, utilizing the advantageous properties of erythrocytes to construct a tumor-targeted biomimetic nanocarrier for codelivery of chemotherapeutics and photothermal agents to produce synergistic effects is considered an effective method for cancer therapy.