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Journal: Journal of controlled release : official journal of the Controlled Release Society


trans-Epithelial delivery of medication across the vagina has proven successful for administration of small, lipophilic molecules such as sex steroids. However, little information is available regarding the vaginal delivery of larger and more polar molecules that currently require parenteral administration reflecting the bias that vaginal epithelium is a barrier to absorption of larger molecular weight (MW) molecules. Six healthy women underwent administration of 18 or 36mg of leuprolide, a GnRH agonist and a larger MW peptide, via a novel ethylene vinyl acetate (EVA) ring transvaginal drug delivery system (TVDS). Serum levels rose within 8h following insertion: low dose at 310pg/ml and high dose at 1220pg/ml, i.e. levels typically following parenteral injections of leuprolide. GnRHa biological activity was validated by secretion of gonadotropins and sex steroids. These results demonstrate that the non-keratinized vaginal epithelium permits a rapid absorption of a biologically active peptide and that there is significant potential for a novel TVDS to deliver peptides and possibly other macromolecules therapeutically.

Concepts: Pharmacology, Childbirth, Molecule, Peptide, Reproductive system, Cervix, Human sexuality, Vagina


This review provides the first comprehensive overview of the use of both nanoparticles and nanofibers for topical drug delivery. Researchers have explored the use of nanotechnology, specifically nanoparticles and nanofibers, as drug delivery systems for topical and transdermal applications. This approach employs increased drug concentration in the carrier, in order to increase drug flux into and through the skin. Both nanoparticles and nanofibers can be used to deliver hydrophobic and hydrophilic drugs and are capable of controlled release for a prolonged period of time. The examples presented provide significant evidence that this area of research has - and will continue to have - a profound impact on both clinical outcomes and the development of new products.

Concepts: Time, Pharmacology, Drug, Chemical properties, Nanomaterials, Drugs, Topical, Route of administration


The delivery of therapeutics to the brain is greatly hampered by the blood-brain barrier (BBB). The use of nanoparticles that can cross the BBB via the process of receptor-mediated transcytosis at blood-brain barrier endothelial cells seems a promising strategy to transport therapeutics into the brain. To screen for suitable nanocarriers, and to study the process of transcytosis, a cultured polarized monolayer of brain microvascular endothelial cells on an extracellular matrix-coated porous membrane filter is widely used as an in vitro BBB model. However, due to the adhesion of numerous types of nanoparticles to the membrane filter and within the filter pores, such a model is unsuitable for the quantification of transendothelial delivery of nanoparticles. Hence, there is a pressing need for a filter-free in vitro BBB model. Ideally, the model is inexpensive and easy to use, in order to allow for its wide use in nanomedicine and biology laboratories around the world. Here, we developed a filter-free in vitro BBB model that consists of a collagen gel covered with a monolayer of brain microvascular endothelial (hCMEC/D3) cells. The paracellular leakage of differently sized dextrans and the transcellular transport of LDL were measured to demonstrate the validity of the filter-free model. Finally, the transendothelial delivery of fluorescently-labelled PEG-P(CL-g-TMC) polymersomes that were functionalized with GM1-targeting peptides was assessed by fluorescence spectroscopy measurement of the luminal, cellular, and abluminal parts of the filter-free BBB model. Our data confirm the effectiveness of the G23 peptide to mediate transport of polymersomes across the BBB and the suitability of this filter-free in vitro model for quantification of nanoparticle transcytosis.


This article presents BEPO®, an in situ forming depot (ISFD) technology mediated by a solvent-exchange mechanism. The matrix of the in situ formed drug delivery depot is composed of the combination of a diblock (DB) and a triblock (TB) polyethylene glycol-polyester copolymer. This combination offers a broad capability to tune the release of a wide variety of drugs to the desired pharmacokinetics. The work described in the present article demonstrates that the delivery rate and profile can be adjusted by changing the composition of either TB or DB or the relative ratio between them, among other parameters. It has been shown that the polymeric composition of the formulation has a substantial impact on the solvent exchange rate between the organic solvent and the surrounding aqueous medium which subsequently determines the internal structure of the resulting depot and the delivery of the therapeutic cargo. This has been demonstrated studying the in vitro release of two model molecules: bupivacaine and ivermectin. Formulations releasing these drugs have been administered to animal models to show the possibility of delivering therapeutics from weeks to months by using BEPO® technology.


Immunologic graft rejection is one of the main causes of short and long-term graft failure in corneal transplantation. Steroids are the most commonly used immunosuppressive agents for postoperative management and prevention of corneal graft rejection. However, steroids delivered in eye drops are rapidly cleared from the surface of the eye, so the required frequency of dosing for corneal graft rejection management can be as high as once every 2h. Additionally, these eye drops are often prescribed for daily use for 1year or longer, which can result in poor patient compliance and steroid-related side effects. Here, we report a biodegradable nanoparticle system composed of Generally Regarded as Safe (GRAS) materials that can provide sustained release of corticosteroids to prevent corneal graft rejection following subconjunctival injection provided initially during transplant surgery. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing dexamethasone sodium phosphate (DSP) exhibited a size of 200nm, 8wt.% drug loading, and sustained drug release over 15days in vitro under sink conditions. DSP-loaded nanoparticles provided sustained ocular drug levels for at least 7days after subconjunctival administration in rats, and prevented corneal allograft rejection over the entire 9-week study when administered weekly. In contrast, control treatment groups that received weekly injections of either placebo nanoparticles, saline, or DSP in solution demonstrated corneal graft rejection accompanied by severe corneal edema, neovascularization and opacity that occurred in ≤4weeks. Local controlled release of corticosteroids may reduce the rate of corneal graft rejection, perhaps especially in the days immediately following surgery when risk of rejection is highest and when typical steroid eye drop administration requirements are particularly onerous.

Concepts: Immune system, Surgery, Immunology, Eye, Cornea, Organ transplant, Corneal transplantation, Transplantation medicine


Successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that activation of immune cells through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or Nod-like receptors (NLRs) may be critical. Among PRRs, the use of TLR ligands as adjuvants is already largely described whereas the use of NLRs ligands remains largely unexplored. As activation of intracytoplasmic NLRs is able to induce proinflammatory molecules, the added value of encapsulation of Nod1 and Nod2 receptor ligands into Poly(Lactic Acid) (PLA) biodegradable nanocarriers to modulate their immune properties on human dendritic cells (DCs) maturation has been evaluated. Their ability to induce systemic immune responses in mice was also measured and compared to free ligands and the Alum adjuvant. Nod ligands encapsulated into PLA NPs were efficiently taken up by DCs and subsequently induced a strong up-regulation of maturation markers and the enhancement of proinflammatory cytokine secretion by DCs. Furthermore, co-injection of encapsulated Nod-ligands with PLA particles carrying Gag p24 HIV-1 antigen allowed a 100 fold increase in antibody responses in comparison to Alum. These results suggest that encapsulation of Nod ligands into PLA-NPs could be an effective way to improve vaccine efficiency.

Concepts: Immune system, Antibody, Protein, Innate immune system, Toll-like receptor, Receptor, Pattern recognition receptor, Immunologic adjuvant


Over the past three decades, taxanes represent one of the most important new classes of drugs approved in oncology. Paclitaxel (PTX), the prototype of this class, is an anti-cancer drug approved for the treatment of breast and ovarian cancer. However, notwithstanding a suitable premedication, present-day chemotherapy employing a commercial preparation of PTX (Taxol®) is associated with serious side effects and hypersensitivity reactions. Liposomes represent advanced and versatile delivery systems for drugs. Generally, both in vivo mice tumor models and human clinical trials demonstrated that liposomal PTX formulations significantly increase a maximum tolerated dose (MTD) of PTX which outperform that for Taxol®. Liposomal PTX formulations are in various stages of clinical trials. LEP-ETU (NeoPharm) and EndoTAG®-1 (Medigene) have reached the phase II of the clinical trials; Lipusu® (Luye Pharma Group) has already been commercialized. Present achievements in the preparation of various liposomal formulations of PTX, the development of targeted liposomal PTX systems and the progress in clinical testing of liposomal PTX are discussed in this review summarizing about 30years of liposomal PTX development.

Concepts: Pharmacology, Clinical trial, Cancer, Metastasis, Oncology, Chemotherapy, Taxane, Doxorubicin


In the current study, core-crosslinked polymeric micelles (DEX-PMs) loaded with three different DEX derivatives designed to display different drug release kinetics, were evaluated for cancer therapy and compared to another effective nanomedicine formulation (long-circulating liposomes encapsulating dexamethasone, LCL-DEX). Pharmacokinetic studies with both radiolabeled dexamethasone and polymer showed that these polymeric systems have long circulating half-lives and may accumulate at the tumor site to a higher extent than liposomes. The in vitro drug release profiles and circulating drug levels in the blood stream show that DEX-PMs with dexamethasone covalently entrapped via a sulfone ester-containing linker (DMSL2) have prolonged circulation time and intermediate drug release kinetics compared to the other polymeric DEX-releasing systems. Furthermore, as the free dexamethasone circulating levels were similar when administered as DMSL2-PM or LCL-DEX, these systems were evaluated simultaneously for antitumor efficacy in B16F10 melanoma bearing mice. The corticosteroid-targeted systems inhibited tumor growth to a similar extent and both increased survival compared to free drug. Recently antitumor efficacy of targeted formulations has been correlated with a systemic effect: a decrease of white blood cell count. In this study all three polymeric systems, liposomes as well as free drug had similar effects on the number of circulating white blood cells, although white blood cell counts recovered faster in the group receiving free drug. In conclusion, corticosteroid-targeting with a polymeric system or a liposomal system translates in similar therapeutic effects. The proven high versatility of the PM with possible optimization and adjustment of the drug release to that required by the therapeutic application, clearly demonstrates the potential of these systems for the treatment of chronic inflammatory diseases including cancer.

Concepts: Immune system, White blood cell, Monocyte, Lymphocyte, Blood, Bone marrow, Leukemia, Complete blood count


We report on hydrogen-bonded layer-by-layer (LbL) films as a robust, reusable platform for temperature-triggered “on-demand” release of drugs. Films with high drug loading capacity, temperature-controlled on-off drug release, and stability at physiological conditions were enabled by assembly of tannic acid (TA) with temperature-responsive block copolymer micelles (BCMs), which were pre-formed by heating solutions of a neutral diblock copolymer, poly(N-vinylpyrrolidone)-b-poly(N-isopropylacrylamide) (PVPON-b-PNIPAM), to a temperature above the lower critical solution temperature (LCST) of PNIPAM. The BCM/TA films exhibited temperature-triggered swelling/deswelling transitions at physiological conditions (swelling ratios of 1.75 and 1.2 at 37 °C and 20 ºC, respectively). A model drug, doxorubicin (DOX) was incorporated into the film at a high drug-to-matrix ratio (~9.3 weight % of DOX per film mass), with a total loading capacity controlled by the film thickness. At 37 ºC, DOX was efficiently retained within the hydrophobic BCM cores of BCM/TA films, whereas exposure to a lower temperature (20 ºC) triggered fast DOX release. While neither bare BCM-containing films nor films loaded with DOX showed cytotoxicity at 37 °C, drug released from films at lower temperature exhibited high potency against breast cancer cells. Repeated on/off drug release was demonstrated with 1.5-μm-thick DOX-loaded films, allowing at least three 30-min cooling cycles with consistent DOX (~12-16 % of loaded DOX released for each cycle) released over a 4-day period. Despite significant stress associated with multiple swelling/deswelling cycles, films maintained their structural integrity in PBS, and each film could be repeated by loaded with drug more than 15 times with only ~7% loss in film thickness and no obvious changes in reloading capacity or release profiles. This work presents the first proof-of-concept utility of temperature-responsive BCM-containing films for repeated on-demand release of a drug.

Concepts: Cancer, Breast cancer, Polymer, Copolymer, Doxorubicin, Lower critical solution temperature, Upper critical solution temperature, Poly(N-isopropylacrylamide)


Polymeric hydrogels typically release their drug payload rapidly due to their high water content and the diffusivity for drug molecules. This study proposes a multimaterial system to sustain the release by covering the hydrogel with a poly(alkyl-2-cyanoacrylate) [PACA]-based film, which should be formed by an in situ polymerization on the hydrogel surface initiated upon contact with water. A series of PACA-hydrogel hybrid systems with increasing PACA side chain hydrophobicity was prepared using physically crosslinked alginate films and hydrophilic diclofenac sodium as model hydrogel/drug system. Successful synthesis of PACA at the hydrogel surface was confirmed and the PACA layer was identified to be most homogeneous for poly(n-butyl-2-cyanoacrylate) on both the micro- and nanolevel. At the same time, the diclofenac release from the hybrid systems was substantially sustained from ~ 1 d for unmodified hydrogels up to >14 d depending on the type of PACA employed as diffusion barrier. Overall, in situ polymerized PACA films on hydrogels may be widely applicable to various hydrogel matrices, different matrix sizes as well as more complex shaped hydrogel carriers.

Concepts: Water, Polymer, Polymer chemistry, Monomer, Polyethylene, Elastomer, Branching, Polymerization