We report a novel hybrid polyamidoamine (PAMAM) dendrimer hydrogel/poly(lactic-co-glycolic acid) (PLGA) nanoparticle platform (HDNP) for codelivery of two antiglaucoma drugs, brimonidine and timolol maleate. This platform was not cytotoxic to human corneal epithelial cells. Cellular uptake of Nile red-encapsulating PLGA nanoparticles was significantly increased by dendrimer hydrogel. A prolonged residence time of nanoparticles was demonstrated through investigation of FluoSpheres loaded into dendrimer hydrogel. Both brimonidine and timolol maleate were slowly released in vitro over a period of 28-35 days. Following topical administration of one eye drop (30 μL of 0.7% w/v brimonidine and 3.5% w/v timolol maleate) in normotensive adult Dutch-belted male rabbits, the HDNP formulation resulted in a sustained and effective IOP reduction (18% or higher) for 4 days. Furthermore, the HDNP maintained significantly higher concentrations of brimonidine in aqueous humor and cornea as well as timolol maleate in the aqueous humor, cornea, and conjunctiva up to 7 days as compared to saline, DH, and PLGA nanoparticle dosage forms, without inducing ocular inflammation or discomfort. Histological analysis of the cornea and conjunctiva did not reveal any morphological or structural changes. Our work demonstrated that this new platform is capable of enhancing drug bioavailability and sustaining effective IOP reduction over an extended period of time. This newly developed platform can greatly reduce dosing frequency of topical formulations, thus, improving long-term patient compliance and reducing enormous societal and economic costs. Given its high structural adaptability, many other chronic ocular diseases would benefit from long-lasting drug delivery of this new platform.
Cell membrane-camouflaged nanoparticles have appeared as a promising platform to develop active tumor targeting nanomedicines. To evade the immune surveillance, we designed a composite cell membrane-camouflaged biomimetic nanoplatform, namely, leutusome, which is made of liposomal nanoparticles incorporating plasma membrane components derived from both leukocytes (murine J774A.1 cells) and tumor cells (head and neck tumor cells HN12). Exogenous phospholipids were used as building blocks to fuse with two cell membranes to form liposomal nanoparticles. Liposomal nanoparticles made of exogenous phospholipids only or in combination with one type of cell membrane were fabricated and compared. The anticancer drug paclitaxel (PTX) was used to make drug-encapsulating liposomal nanoparticles. Leutusome resembling characteristic plasma membrane components of the two cell membranes were examined and confirmed in vitro. A xenograft mouse model of head and neck cancer was used to profile the blood clearance kinetics, biodistribution, and antitumor efficacy of the different liposomal nanoparticles. The results demonstrated that leutusome obtained prolonged blood circulation and was most efficient accumulating at the tumor site (79.1 ± 6.6% ID per gram of tumor). Similarly, leutusome composed of membrane fractions of B16 melanoma cells and leukocytes (J774A.1) showed prominent accumulation within the B16 tumor, suggesting the generalization of the approach. Furthermore, PTX-encapsulating leutusome was found to most potently inhibit tumor growth while not causing systemic adverse effects.
Central nervous system (CNS) diseases represent the largest and fastest growing area of unmet medical need. Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis. With the aid of nanoparticles of high specificity and multifunctionality, such as dendrimers and quantum dots, therapeutics, imaging agents, and diagnostic molecules can be delivered to the brain across the blood-brain barrier (BBB), enabling considerable progress in the understanding, diagnosis, and treatment of CNS diseases. Nanoparticles used in the CNS for drug delivery, imaging, and diagnosis are reviewed, as well as their administration routes, toxicity, and routes to cross the BBB. Future directions and major challenges are outlined.
Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal H19 represents a noninvasive biomarker and potential therapeutic target for cholestatic diseases. (Hepatology 2018).
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