Neovascularization-directed bionic eye drops for noninvasive renovation of age-related macular degeneration

The current treatment of wet age-related macular degeneration (wAMD) relies on monthly intravitreal or intravenously injection of vascular endothelial growth factor (VEGF) inhibitor or photodynamic (PDT) agents to inhibit choroidal neovascularization. However, traumatic local therapy and exogenous long-distance fundus drug delivery often lead to secondary eye damage, low treatment efficiency, and immunogenic inflammation. Herein, inspired by the natural neovascular targeting ability of endogenous low-density lipoproteins (LDL), a noninvasive bionic nano-eye-drop with enhanced ocular penetrability and lesion recognizability is developed for enabling the PDT treatment of wAMD. Verteporfin (VP) as a laser-induced PDT agent is protected inside the hydrophobic core of reconstituted LDL (rLDL) vectors. 5-carboxyfluorescein (FAM) conjugated ste-penetratin (PEN, a transmembrane peptide) is anchored on the surface of the rLDL carrier, which enabled the nanoparticles (PEN-rLDL-VP) to cross the blood-retina barrier to realizing visual therapy. Following instillation, PEN-rLDL-VP can effectively deliver VP into neovascular that overexpress LDL receptors, which can respond to laser-induced PDT. Only with a single dose of the eye-drop and laser-induced PDT, the VEGF and proinflammatory intercellular adhesion molecule-1 (ICAM-1) proteins are significantly down-regulated in vivo, which implicates the neovascular inhibition and inflammation alleviation. This study presents an attractive non-invasive strategy for the PDT of wAMD

Supersaturation induced by Itraconazole/Soluplus® micelles provided high GI absorption in vivo

To investigate the effect of supersaturation induced by micelle formation during dissolution on the bioavailability of itraconazole (ITZ)/Soluplus® solid dispersion. Solid dispersions prepared by hot melt extrusion (HME) were compressed into tablets directly with other excipients. Dissolution behavior of ITZ tablets was studied by dissolution testing and the morphology of micelles in dissolution media was studied using transmission electron microscopy (TEM). Drug transferring from stomach into intestine was simulated to obtain a supersaturated drug solution. Bioavailability studies were performed on the ITZ tablets and Sporanox® in beagle dogs. The morphology of micelles in the dissolution media was observed to be spherical in shape, with an average size smaller than 100 nm. The supersaturated solutions formed by Soluplus® micelles were stable and no precipitation took place over a period of 180 min. Compared with Sporanox®, ITZ tablets exhibited a 2.50-fold increase in the AUC(0–96) of ITZ and a 1.95-fold increase in its active metabolite hydroxyitraconazole (OH-ITZ) in the plasma of beagle dogs. The results obtained provided clear evidence that not only the increase in the dissolution rate in the stomach, but also the supersaturation produced by micelles in the small intestine may be of great assistance in the successful development of poorly water-soluble drugs. The micelles formed by Soluplus® enwrapped the molecular ITZ inside the core which promoted the amount of free drug in the intestinal cavity and carried ITZ through the aqueous boundary layer (ABL), resulting in high absorption by passive transportation across biological membranes. The uptake of intact micelles through pinocytosis together with the inhibition of P-glycoprotein-mediated drug efflux in intestinal epithelia contributed to the absorption of ITZ in the gastrointestinal tract. These results indicate that HME with Soluplus®, which can induce supersaturation by micelle formation, may be of great assistance to the successful development of poorly water-soluble drugs

Self-Assembled Micelles Composed of Doxorubicin Conjugated Y-Shaped PEG-Poly(glutamic acid)2 Copolymers via Hydrazone Linkers

In this work, micelles composed of doxorubicin-conjugated Y-shaped copolymers (YMs) linked via an acid-labile linker were constructed. Y-shaped copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin)2 and linear copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin) were synthesized and characterized. Particle size, size distribution, morphology, drug loading content (DLC) and drug release of the micelles were determined. Alterations in size and DLC of the micelles could be achieved by varying the hydrophobic block lengths. Moreover, at fixed DLCs, YMs showed a smaller diameter than micelles composed of linear copolymers (LMs). Also, all prepared micelles showed sustained release behaviors under physiological conditions over 72 h. DOX loaded in YMs was released more completely, with 30% more drug released in acid. The anti-tumor efficacy of the micelles against HeLa cells was evaluated by MTT assays, and YMs exhibited stronger cytotoxic effects than LMs in a dose- and time-dependent manner. Cellular uptake studied by CLSM indicated that YMs and LMs were readily taken up by HeLa cells. According to the results of this study, doxorubicin-conjugated Y-shaped PEG-(polypeptide)2 copolymers showed advantages over linear copolymers, like assembling into smaller nanoparticles, faster drug release in acid, which may correspond to higher cellular uptake and enhanced extracellular/intracellular drug release, indicating their potential in constructing nano-sized drug delivery systems

Improving Breviscapine Oral Bioavailability by Preparing Nanosuspensions, Liposomes and Phospholipid Complexes

Breviscapine (BVP), a flavonoid compound, is widely used in the treatment of cardiovascular and cerebrovascular diseases; however, the low oral bioavailability and short half-life properties limit its application. The aim of this study was to investigate the three preparations for improving its oral bioavailability: nanosuspensions (BVP-NS), liposomes (BVP-LP) and phospholipid complexes (BVP-PLC). In vitro and in vivo results suggested that these three could all significantly improved the cumulative released amount and oral bioavailability compared with physical mixture, in which BVP-PLC was the most optimal preparation with the relative bioavailability and mean retention time of 10.79 ± 0.25 (p p < 0.01), respectively. Furthermore, the influence of drug-lipid ratios on the in vitro release and pharmacokinetic behavior of BVP-PLC was also studied and the results showed that 1:2 drug-lipid ratio was the most satisfactory one attributed to the moderate-intensity interaction between drug and phospholipid which could balance the drug loading and drug release very well

Improving Breviscapine Oral Bioavailability by Preparing Nanosuspensions, Liposomes and Phospholipid Complexes

Breviscapine (BVP), a flavonoid compound, is widely used in the treatment of cardiovascular and cerebrovascular diseases; however, the low oral bioavailability and short half-life properties limit its application. The aim of this study was to investigate the three preparations for improving its oral bioavailability: nanosuspensions (BVP-NS), liposomes (BVP-LP) and phospholipid complexes (BVP-PLC). In vitro and in vivo results suggested that these three could all significantly improved the cumulative released amount and oral bioavailability compared with physical mixture, in which BVP-PLC was the most optimal preparation with the relative bioavailability and mean retention time of 10.79 &plusmn; 0.25 (p &lt; 0.01) and 471.32% (p &lt; 0.01), respectively. Furthermore, the influence of drug-lipid ratios on the in vitro release and pharmacokinetic behavior of BVP-PLC was also studied and the results showed that 1:2 drug-lipid ratio was the most satisfactory one attributed to the moderate-intensity interaction between drug and phospholipid which could balance the drug loading and drug release very well

Schematic illustration of DTX-PCL-PEG-SMLP micelles targeted to PSMA.

<p>Schematic illustration of DTX-PCL-PEG-SMLP micelles targeted to PSMA.</p

Synthetic representation of the chemical reaction for preparation of PCL-PEG-SMLP copolymer.

<p>Synthetic representation of the chemical reaction for preparation of PCL-PEG-SMLP copolymer.</p

In vitro cytotoxicity determination of different concentrations of DSD, DTX-PMs1 and DTX-PMs2 in LNCaP cells and PC3 cells after incubation for 48 h, 72 h, respectively, using MTT assay.

<p>(*) significantly different from DSD; (#) significantly different from PMs1; (n = 5). Note: *P<0.01, ^#P<0.01.</p