Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).

Stimuli-responsive nanocarriers for drug delivery

Polylactic acid is proving to be a viable alternative to petrochemical-based plastics for many applications It is produced from renewable resources and is biodegradable, decomposing to give H2O, CO2, and humus, the black material in soil In addition, it has unique physical properties that make it useful in diverse applications including paper coating, fibers, films, and packaging (see Figure)

Polylactic Acid Technology

Interaction of spherical particles with cells and within animals has been studied extensively, but the effects of shape have received little attention. Here we use highly stable, polymer micelle assemblies known as filomicelles to compare the transport and trafficking of flexible filaments with spheres of similar chemistry. In rodents, filomicelles persisted in the circulation up to one week after intravenous injection. This is about ten times longer than their spherical counterparts and is more persistent than any known synthetic nanoparticle. Under fluid flow conditions, spheres and short filomicelles are taken up by cells more readily than longer filaments because the latter are extended by the flow. Preliminary results further demonstrate that filomicelles can effectively deliver the anticancer drug paclitaxel and shrink human-derived tumours in mice. Although these findings show that long-circulating vehicles need not be nanospheres, they also lend insight into possible shape effects of natural filamentous viruses.

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Shape effects of filaments versus spherical particles in flow and drug delivery.

Sasidharan Swarnalatha Lucky,†,§ Khee Chee Soo,‡ and Yong Zhang*,†,§,∥ †NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore 117456 ‡Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore 169610 Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore 117576 College of Chemistry and Life Sciences, Zhejiang Normal University, Zhejiang, P. R. China 321004

Nanoparticles in photodynamic therapy.

The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,Llactide-co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (~200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less

Nonviral Vectors for Gene Delivery

Micellar carriers based on block copolymers of poly(ε-caprolactone) and poly(ethylene glycol) for doxorubicin delivery

Magnetite-Loaded Polymeric Micelles as Ultrasensitive Magnetic-Resonance Probes†

Low water solubility, rapid phagocytic and renal clearance, and systemic toxicity represent three major barriers that limit the therapeutic use of many hydrophobic antitumor agents such as doxorubicin (DOXO) and paclitaxel. Various drugdelivery systems, among which polymeric micelles have emerged as a very important system, have been developed to overcome these limitations and deliver various drugs with remarkable in vitro and in vivo success. 3] Polymeric micelles are nanoscopic (10 to 100 nm) colloidal particles self-assembled from amphiphilic block or graft copolymers in aqueous media. The hydrophobic core of the micelles is a carrier compartment that accommodates antitumor drugs, and the shell consists of a brushlike protective corona that stabilizes the nanoparticles in aqueous solution. The basic requirements for polymeric micelles in drug-delivery applications include high drug-loading capacity, biodegradability, long blood circulation times, and controllable drug-release profiles. Research on micelles has been greatly advanced in the

cRGD-functionalized polymer micelles for targeted doxorubicin delivery.

Although the utilization of polymeric micelles has demonstrated great potential in delivering anticancer drugs, this technique is facing tremendous challenges. In particular, polymeric micelles usually show a drug-release profile that is not in favor of achieving optimal drug availability inside tumor cells. That is, a “burst release” of up to 20–30 % of the encapsulated drug within several hours post micelle formation, followed by a slow diffusional drug release lasting for many days. The premature burst release leads to drug loss in micelle storage and blood circulation. Meanwhile, the secondstage slow drug release results in low intracellular drug availability insufficient for killing cancer cells. Therefore, development of delivery systems with better drug-release properties is still of great importance. One of the most promising strategies is to construct polymeric micelles that respond to specific stimulation, such as light exposure, enzymatic degradation, redox reaction, or change in pH or temperature. Acid-triggered rapid release of drugs can be achieved inside tumor tissue (pH below 6.8) or lysosomal compartments (pH about 5.0) of cancer cells by using micelles of copolymers bearing pH-sensitive blocks, such as poly(lhistidine) and poly(b-amino ester). Nevertheless, these pH-sensitive micelles were not designed to avoid the premature burst release of drugs. In addition, supramolecular nanoassemblies de-micellize when the polymer concentration drops below the critical micelle concentration (CMC), which is another underlying cause for the loss of drugs during blood circulation. Recently, covalent crosslinking of the core or shell of selfassembled polymeric micelles has emerged as a viable strategy to prevent de-micellization-associated drug loss. 11] Among various approaches, the utilization of disulfide-containing reversible crosslinkers is of particular importance, owing to the fact that the disulfide bond is reducible and therefore can be cleaved by glutathione (GSH), a thiol-containing oligopeptide predominantly found inside cells (up to the millimolar scale). Indeed, shell-crosslinked micelles (SCMs) obtained using disulfide-containing agents have demonstrated great potential for specifically releasing the loaded cargos inside cells. 13] In spite of their potential in reducing premature drug leakage, these SCMs cannot rapidly release drugs inside cells because drug release from their nonsensitive cores still follows a diffusion-controlled mechanism. Herein, we describe the first example of a highly packed interlayer-crosslinked micelle (HP-ICM) with reduction and pH dual sensitivity, which comprises a polyethylene glycol (PEG) corona to stabilize the particles, a highly compressed pH-sensitive partially hydrated core to load anticancer drugs, and a disulfide-crosslinked interlayer to tie up the core against expansion at neutral pH. The HP-ICM was stable and drug leakage free in a neutral pH environment without reducing agent. However, when the HP-ICM was internalized into cells and trapped inside lysosomes featuring low pH ( 5) and enriched reducing agent (GSH), the pH-sensitive core was unpacked and thus erupted to burst release the anticancer drug (Figure 1). The reductionand pH-sensitive interlayer-crosslinked micelle with partially hydrated core was prepared from a triblock copolymer of monomethoxy polyethylene glycol (mPEG), 2-mercaptoethylamine (MEA)-grafted poly(laspartic acid) (PAsp(MEA)), and 2-(diisopropylamino)ethylamine (DIP)-grafted poly(l-aspartic acid) (PAsp(DIP)). The copolymer was synthesized by ring-opening polymerization of b-benzyl l-aspartate N-carboxy-anhydride (BLA-NCA) in combination with click and aminolysis reactions (see the Supporting Information, Figure S1). So far, most reported shell-crosslinked nanoparticles have been based on polyacrylate or polyacrylamide. 14] We chose biodegradable polypeptide as the copolymer backbone in consideration of biocompatibility requirements in drug delivery. Poly(BLA) aminolysis with MEA and DIP introduced the crosslinkable thiol and pH-sensitive tertiary amino groups onto the middle and end blocks of the copolymer, respectively. NMR and FTIR analyses confirmed the chemical structures of the polymers (see the Supporting Information, Figures S3–S6). Gel permeation chromatography measurements also evidenced the successful synthesis of mPEG[*] Dr. J. Dai, S. Lin, Dr. D. Cheng, Prof. X. Shuai PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering Sun Yat-sen University, Guangzhou 510275 (China) E-mail: shuaixt@mail.sysu.edu.cn

Xintao Shuai

Papers

Micellar carriers based on block copolymers of poly(ε-caprolactone) and poly(ethylene glycol) for doxorubicin delivery

Magnetite-Loaded Polymeric Micelles as Ultrasensitive Magnetic-Resonance Probes†

cRGD-functionalized polymer micelles for targeted doxorubicin delivery.

Interlayer-Crosslinked Micelle with Partially Hydrated Core Showing Reduction and pH Dual Sensitivity for Pinpointed Intracellular Drug Release

The depolymerization of chitosan: effects on physicochemical and biological properties