Cross‐Platform Comparison of Therapeutic Delivery from Multilamellar Lipid‐Coated Polymer Nanoparticles

Significant efforts have been invested in finding a delivery system that can encapsulate and deliver therapeutics. Core–shell polymer‐lipid hybrid nanoparticles have been studied as a promising platform because of their mechanical stability, narrow size distribution, biocompatibility, and ability to co‐deliver diverse drugs. Here, novel core–shell nanoparticles based on a poly(lactic‐co‐glycolic acid) (PLGA) core and multilamellar lipid shell are designed, where the lipid bilayers are crosslinked between the two adjacent bilayers (PLGA‐ICMVs). The cross‐platform performance of the nanoparticles to other polymer‐lipid hybrid platforms is examined, including physicochemical characteristics, ability to encapsulate a variety of therapeutics, biocompatibility, and functionality as a vaccine delivery platform. Differential abilities of nanoparticle systems to encapsulate distinct pharmaceutics are observed, which suggest careful consideration of the platform chosen depending on the therapeutic agent and desired function. The novel PLGA‐ICMV platform herein demonstrates great potential in stably encapsulating water‐soluble agents and therefore is an attractive platform for therapeutic delivery.     

Gas phase behavior of radical cations of perfluoroalkyl‐1,2,4‐triazines: an experimental and theoretical study

Electron ionization mass spectrometry and low‐energy collision‐induced decomposition reactions occurring in a tridimensional ion trap, together with density functional theory (DFT) calculations on neutrals, even‐ and odd‐electron cations, have been used to study the gas‐phase ion chemistry of a series of perfluoroalkyl‐1,2,4‐triazines. Loss of oxygen, due to thermal degradation occurring before ionization, likely involving the hydroxylamino group, has been observed. Compounds having a carbonyl group at position 6 of the triazine ring fragment in the source by elimination of NO followed by HF or CO. The decomposition pathways occurring due to CID experiments have shown interesting features depending on the nature and structure of precursor ions. Most of them involve elimination of endocyclic atoms, thereby producing contraction of the original six‐membered ring or formation of acyclic structures. DFT (B3LYP/6‐31G(d,p)) calculations have been used for evaluating structure, stability and properties of neutral and ionic species involved in gas‐phase processes. In particular, it has been calculated that in the molecular ion the unpaired electron is mainly located on the exocyclic nitrogen, while the positive charge is on the C(6) carbon atom. Copyright © 2009 John Wiley & Sons, Ltd.     

A pH‐Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P‐Glycoprotein‐Mediated Multidrug Resistance

Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P‐glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT‐11) and a NO‐releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp‐mediated MDR reversal agent. The site‐specific drug release and the NO‐reduced Pgp‐mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell‐killing threshold, eventually inducing its antitumor activity. These results reveal that this pH‐responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.     

Supramolecular Host‐Inhibited Excited‐State Proton Transfer and Fluorescence Switching of the Anti‐Cancer Drug,Topotecan

The effect of cucurbit[7]uril (CB[7]) nano‐caging on the photophysical properties, particularly excited‐state proton transfer (ESPT) reaction, of an eminent anti‐cancer drug, topotecan (TPT), is demonstrated through steady‐state and time‐resolved fluorescence measurements. TPT in water (pH 6) exists exclusively as the cationic form (C) in the ground state. However, the drug emission mainly comes from the excited‐state zwitterionic form (Z*) of TPT, and is attributed to water‐assisted ESPT between the 10‐hydroxyl group and water, which leads to the transformation of C* to Z* of TPT. In the presence of CB[7], it is found that selective encapsulation of the C form of TPT results in the formation of a 1:1 inclusion complex (CB[7]:TPT), and the ESPT process is inhibited by this encapsulation process. As a result, C* becomes the dominant emitting species in the presence of CB[7] rather than Z*, and fluorescence switching takes place from green to blue. Time‐resolved studies also support the existence of CB[7]‐encapsulated cationic species as the major emitting species in the presence of the macrocyclic host. Semi‐empirical quantum chemical calculations are employed to gain insight into the molecular picture of orientation of TPT in the inclusion complex. It is clearly seen from the optimised structure of 1:1 CB[7]:TPT inclusion complex that both 10‐hydroxyl and 9‐dimethylaminomethylene groups of TPT lie partly inside the cavity, and thereby inhibit the excited‐state transformation of C* to Z* by the ESPT process. Finally, controlled release of the drug is achieved by means of fluorescence switching by introducing NaCl, which is rich in cells, as an external stimulus.     

Small Targeted Cytotoxics: Current State and Promises from DNA‐Encoded Chemical Libraries

The targeted delivery of potent cytotoxic agents has emerged as a promising strategy for the treatment of cancer and other serious conditions. Traditionally, antibodies against markers of disease have been used as drug‐delivery vehicles. More recently, lower molecular weight ligands have been proposed for the generation of a novel class of targeted cytotoxics with improved properties. Advances in this field crucially rely on efficient methods for the identification and optimization of organic molecules capable of high‐affinity binding and selective recognition of target proteins. The advent of DNA‐encoded chemical libraries allows the construction and screening of compound collections of unprecedented size. In this Review, we survey developments in the field of small ligand‐based targeted cytotoxics and show how innovative library technologies will help develop the drugs of the future.     

Photo‐Degradable,Protein–Polyelectrolyte Complex‐Coated,Mesoporous Silica Nanoparticles for Controlled Co‐Release of Protein and Model Drugs

The fabrication of photo‐degradable, protein–polyelectrolyte complex (PPC)‐coated, mesoporous silica nanoparticles (MSNs) and their controlled co‐release of protein and model drugs is reported. Random copolymers composed of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), and a photolabile o‐nitrobenzyl‐containing monomer, 5‐(2′‐(dimethylamino)ethoxy)‐2‐nitrobenzyl methacrylate (DENBMA), are first anchored onto the MSNs and then quaternary aminated, to obtain positively charged P(OEGMA‐co‐TENBMA) which exhibits photo‐induced charge conversion characteristics. PPCs consisting of P(OEGMA‐co‐TENBMA) and the protein bovine serum albumin (BSA) are utilized as capping agents for the nanopores of the MSNs. Upon UV irradiation, charge conversion of P(OEGMA‐co‐TENBMA) can lead to the disruption of PPCs on MSNs and co‐release of BSA and rhodamine B by electrostatic repulsion.     

Azobenzene Polyesters Used as Gate‐Like Scaffolds in Nanoscopic Hybrid Systems

The synthesis and characterisation of new capped silica mesoporous nanoparticles for on‐command delivery applications is reported. Functional capped hybrid systems consist of MCM‐41 nanoparticles functionalised on the external surface with polyesters bearing azobenzene derivatives and rhodamine B inside the mesopores. Two solid materials, Rh‐PAzo8‐S and Rh‐PAzo6‐S, containing two closely related polymers, PAzo8 and PAzo6, in the pore outlets have been prepared. Materials Rh‐PAzo8‐S and Rh‐PAzo6‐S showed an almost zero release in water due to steric hindrance imposed by the presence of anchored bulky polyesters, whereas a large delivery of the cargo was observed in the presence of an esterase enzyme due to the progressive hydrolysis of polyester chains. Moreover, nanoparticles Rh‐PAzo8‐S and Rh‐PAzo6‐S were used to study the controlled release of the dye in intracellular media. Nanoparticles were not toxic for HeLa cells and endocytosis‐mediated cell internalisation was confirmed by confocal microscopy. Furthermore, the possible use of capped materials as a drug‐delivery system was demonstrated by the preparation of a new mesoporous silica nanoparticle functionalised with PAzo6 and loaded with the cytotoxic drug camptothecin (CPT‐PAzo6‐S). Following cell internalisation and lysosome resident enzyme‐dependent gate opening, CPT‐PAzo6‐S induced CPT‐dependent cell death in HeLa cells.     

Gelatin‐Alginate Gels and Their Enzymatic Modifications: Controlling the Delivery of Small Molecules

The release of molecules entrapped within biogels is dictated by diffusion laws. Innovative biogel architectures are conceived and tested to control small molecule delivery from gelatin gels. The ionic interactions modulate the release of small molecules. Alginate is then added to gelatin gels and further hydrolyzed; the influence of viscosity is discussed. Next, various mixed gels are compared, such as a gelatin‐alginate IPN and the original architecture of an alginate gel entrapped in a gelatin gel with or without a polysaccharidase. The relative influence of ionic interactions and diffusional constraints on the delivery of small charged molecules is explored, and a solution for controlling diffusion is proposed for any situation.

     

Inorganic Metal Hydroxide Nanoparticles for Targeted Cellular Uptake Through Clathrin‐Mediated Endocytosis

Layered double hydroxides (LDHs) are biocompatible materials which can be used as drug‐delivery nanovehicles. In order to define the optimum size of LDH nanoparticles for efficient cellular uptake and drug‐delivery pathway, we prepared different sized LDH nanoparticles with narrow size distribution by modulating the crystal growth rate, and labelled each LDH particle with a fluorophore using a silane coupling reaction. The cellular uptake rate of LDHs was found to be highly dependent on particle size (50>200≥100>350 nm), whose range of 50 to 200 nm was selectively internalized into cells through clathrin‐mediated endocytosis with enhanced permeability and retention. Our study clearly shows that not only the particle size plays an important role in the endocytic pathway and processing, but also the size control of LDH nanoparticles results in their targeted uptake to site‐specific clathrin‐mediated endocytosis. This result provides a new perspective for the design of LDH nanoparticles with maximum ability towards targeted drug delivery.     

pH‐Disintegrable Polyelectrolyte Multilayer‐Coated Mesoporous Silica Nanoparticles Exhibiting Triggered Co‐Release of Cisplatin and Model Drug Molecules

We report on the fabrication of pH‐disintegrable polyelectrolyte multilayer‐coated mesoporous silica nanoparticles (MSN) capable of triggered co‐release of cisplatin and model drug molecules. The outer polyelectrolyte multilayer was assembled from permanently cationic polyelectrolyte, poly(allyl amine hydrochloride) (PAH), and negatively charged polyelectrolyte, P(DMA‐co‐TPAMA), consisting of N,N‐dimethylacrylamide (DMA) and 3,4,5,6‐tetrahydrophthalic anhydride‐functionalized N‐(3‐aminopropyl)methacrylamide (TPAMA) monomer units, which exhibits pH‐induced charge conversion characteristics. Thus, the subtle alteration of solution pH from 7.4 to ≈5–6 can lead to the disintegration of outer polyelectrolyte multilayers, accompanied with the co‐release of cisplatin and RhB.

     

Supramolecular Gels by Design: Towards the Development of Topical Gels for Self‐Delivery Application

Following a supramolecular synthon approach, simple salt formation has been employed to gain access to a series of supramolecular gelators derived from the well‐known non‐steroidal anti‐inflammatory drug (NSAID) ibuprofen. A well‐studied gel‐inducing supramolecular synthon, namely primary ammonium monocarboxylate (PAM), has been exploited to generate a series of PAM salts by reacting ibuprofen with various primary amines. Remarkably, all of the salts ( S1 – S7 ) thus synthesized proved to be good to moderate gelators of various polar and nonpolar solvents. Single‐crystal and powder X‐ray diffraction studies established the existence of the PAM synthons in the gel network, confirming the efficacy of the supramolecular synthon approach employed. Most importantly, the majority of the salts ( S2 , S3 , S6 , and S7 ) were capable of gelling methyl salicylate (MS), an important ingredient found in many commercial topical gels. In vitro experiments (MTT and PGE₂ assays) revealed that all of the salts (except S3 and S7 ) were biocompatible (up to 0.5 mm concentration), and the most suited one, S6 , displayed anti‐inflammatory ability as good as that of the parent drug ibuprofen. A topical gel of S6 with methyl salicylate and menthol was found to be suitable for delivering the gelator drug in a self‐delivery fashion in treating skin inflammation in mice. Histological studies, including immunohistology, were performed to further probe the role of the gelator drug S6 in treating inflammation. Cell imaging studies supported cellular uptake of the gelator drug in such biomedical application.     

Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose‐coated polymeric nanocarriers, which can be bound by glucose transporter‐1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose‐ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non‐coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose‐modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.     

Transporting and Shielding Photosensitisers by Using Water‐Soluble Organometallic Cages: A New Strategy in Drug Delivery and Photodynamic Therapy

Skin photosensitivity remains one of the main limitations in photodynamic therapy. In this Concept article a strategy to overcome this limitation is described, in which the photosensitizer is hidden inside the hydrophobic cavity of a water‐soluble organometallic cage. The metallacage not only protects the photosensitizer from light, it also facilitates its delivery to cancer cells.     

Use of Three‐Dimensional Arterial Models To Predict the In Vivo Behavior of Nanoparticles for Drug Delivery

Nanomaterials have been widely used for applications in biomedical fields and could become indispensable in the near future. However, since it is difficult to optimize in vivo biological behavior in a 3D environment by using a single cell in vitro, there have been many failures in animal models. In vitro prediction systems using 3D human‐tissue models reflecting the 3D location of cell types may be useful to better understand the biological characteristics of nanomaterials for optimization of their function. Herein we demonstrate the potential ability of 3D engineered human‐arterial models for in vitro prediction of the in vivo behavior of nanoparticles for drug delivery. These models enabled optimization of the composition and size of the nanoparticles for targeting and treatment efficacy for atherosclerosis. In vivo experiments with atherosclerotic mice suggested excellent biological characteristics and potential treatment effects of the nanoparticles optimized in vitro.     

Encapsulation of Pyrene‐Functionalized Poly(benzyl ether) Dendrons into a Water‐Soluble Organometallic Cage

Two generations of lipophilic pyrenyl functionalized poly(benzyl ether) dendrimers (P₁ and P₂) have been synthesized. The thermal properties of the two functionalized dendrimers have been investigated, and the pyrenyl group of the dendritic molecules encapsulated in the arene–ruthenium metalla‐cage, [Ru₆(p‐cymene)₆(tpt)₂(donq)₃]⁶⁺ ([ 1 ]⁶⁺) (tpt=2,4,6‐tri(pyridin‐4‐yl)‐1,3,5‐triazine; donq=5,8‐dioxydo‐1,4‐naphthoquinonato). The host–guest properties of [P₁⊂ 1 ]⁶⁺ and [P₂⊂ 1 ]⁶⁺ were studied in solution by NMR and UV/Vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water‐soluble host–guest systems was evaluated on human ovarian cancer cells.     

Enhancing Tumor Cell Response to Chemotherapy through the Targeted Delivery of Platinum Drugs Mediated by Highly Stable,Multifunctional Carboxymethylcellulose‐Coated Magnetic Nanoparticles

The fabrication of nanoparticles using different formulations, and which can be used for the delivery of chemotherapeutics, has recently attracted considerable attention. We describe herein an innovative approach that may ultimately allow for the selective delivery of anticancer drugs to tumor cells by using an external magnet. A conventional antitumor drug, cisplatin, has been incorporated into new carboxymethylcellulose‐stabilized magnetite nanoparticles conjugated with the fluorescent marker Alexa Fluor 488 or folic acid as targeting agent. The magnetic nanocarriers possess exceptionally high biocompatibility and colloidal stability. These cisplatin‐loaded nanoparticles overcome the resistance mechanisms typical of free cisplatin. Moreover, experiments aimed at the localization of the nanoparticles driven by an external magnet in a medium that mimics physiological conditions confirmed that this localization can inhibit tumor cell growth site‐specifically.