Size,shape,charge and“stealthy”surface:Carrier properties affect the drug circulation time in vivo

The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.

Application of sialic acid/polysialic acid in the drug delivery systems

The properties of modified biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At the same time,SA modification of the drugs/carriers can enhance the uptake of tumor cell and retention in brain;PSA modifi-cation can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modified drugs/carriers in the blood,thus achieving active targeting effect.These properties offer a variety of opportunities for applications in drug delivery systems.This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modified small molecule drugs,proteins and carriers in drug delivery systems.

Effect of Qiming Granule(芪明颗粒) on Retinal Blood Circulation of Diabetic Retinopathy:A Multicenter Clinical Trial

Objective： To objectively assess the effect of Qiming Granule （芪明颗粒） in the treatment of diabetic retinopathy （DR） by fluorescence fundus angiography （FFA）. Methods： In a multi-center, randomized, parallel controlled clinical trial, patients with DR were randomly assigned to the control group （calcium dobesilate capsule） and the test group （Qiming Granule）. Changes in the retinal blood circulation time were recorded by FFA after 3 months of medication. Results： Significant reduction was observed in the retinal arterio-venous circulation time （AVCT） in both groups （P〈0.01）, the value was 7.635 ± 3.149 s before treatment and 5.165 ±3.382 s after treatment in the treated group, and 7.737±3.413 s and 5.313±3.472 s in the control group respectively. Qiming Granule also reduced the arm-to-retinal circulation time （ARCT, P〈0.05）. The value was 17.867± 3.872 s before treatment and 15.643 ± 4.648 s after treatment in the treated group, and 17.217 ± 3.833 s and 16.312± 3.613 s in the control group （P〉0.05） respectively. The ARCT in the tested group was reduced, with a statistically significant difference post-medication （P〈0.01）. Conclusion： As a Chinese medicine complex prescription, Qiming Granule may alleviate retinal hypoxia and ischemia by increasing retinal blood flow and improving the blood circulation.

A lipophilic prodrug of Danshensu:preparation,characterization,and in vitro and in vivo evaluation

Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu(DSS), palmitoyl Danshensu(PDSS), was synthesized with the aim to improve its oral bioavailability and prolong its half-life. The in vitro experiments were carried out to evaluate the physicochemical properties and stability of PDSS. Although the solubility of PDSS in water was only 0.055 mg·mL^(-1), its solubility in Fa SSIF and Fe SSIF reached 4.68 and 9.08 mg·mL^(-1), respectively. Octanol-water partition coefficient(log P) was increased from-2.48 of DSS to 1.90 of PDSS. PDSS was relatively stable in the aqueous solution in pH range from 5.6 to 7.4. Furthermore, the pharmacokinetics in rats was evaluated after oral administration of PDSS and DSS. AUC and t1/2 of PDSS were enhanced up to 9.8-fold and 2.2-fold, respectively, compared to that of DSS. Cmax was 1.67 ± 0.11 μg·mL^(-1) for PDSS and 0.81 ± 0.06 μg·m L-1 for DSS. Thus, these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug.

Poly(L-glutamic acid)-cisplatin nanoformulations with detachable PEGylation for prolonged circulation half-life and enhanced cell internalization

PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect,which consequently improves the intratumoral accumulation.However,cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG,which limits their therapeutic effect.To this end,we designed and prepared two kinds of poly(L-glutamic acid)-cisplatin(PLG-CDDP)nanoformulations with detachable PEG,which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization.The extracellular pH(pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride(CDM)-derived amide bond and matrix metalloproteinases-2/9(MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG,yielding pHe-responsive PEG-pHe-PLG and MMP-sensitive PEG-MMP-PLG.The corresponding smart nanoformulations PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin(CDDP).The circulation half-lives of PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt,respectively.Upon reaching tumor tissue,PEG on the surface of nanomedicines was detached as triggered by pHe or MMP,which increased intratumoral CDDP retention,enhanced cell uptake,and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer(HGSOC)mouse model,indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.