Controlled Cargo Release Research Articles

Triggering multiple modalities of cell death via dual-responsive nanomedicines to address the narrow therapeutic window of β-lapachone

The clinical translation of the anticancer drug β-lapachone (LAP) has been limited by the narrow therapeutic window. Stimuli-responsive anticancer drug delivery systems have gained tremendous attention in recent years to alleviate adverse effects and enhance therapeutic efficacy. Here, we report a dual pH- and enzyme-responsive nanocarrier to address the above issue of LAP. In detail, the epigallocatechin gallate (EGCG) and ferric ions were employed to engineer nanoscale ferric ion-polyphenol complexes where LAP was physically encapsulated therein. The coordination bond between Fe3+ and the catechol moiety of EGCG was sensitive to the low pH, enabling the triggered cargo release in the acidic endosomes/lysosomes. Afterward, the released LAP was activated by the overexpressed NAD(P)H: quinone oxidoreductase 1 (NQO1) and ferroptosis suppressor protein 1 (FSP1) in the tumor cells, followed by the generation of reactive oxygen species (ROS), and the induction of oxidative stress and apoptotic cell death. Meanwhile, EGCG could upregulate gasdermin E (GSDME), and ferric ions were involved in the Fenton reaction. Hence, EGCG and ferric ions could sensitize the toxicity of LAP through the induction of multiple cell death pathways (e.g., pyroptosis, ferroptosis, apoptosis, and necroptosis). The current work enlarged the LAP’s therapeutic window via controlled cargo release and vehicle sensitization.

Synthesis and Controlled Cargo Release of Novel Photoresponsive Polysiloxane‐Based Single‐Chain Nanoparticles

AbstractHerein, a novel, highly branched and photoresponsive polysiloxane is synthesized and studied. The polymer is photoconstructed into a single‐chain nanoparticle loaded with Nile Red and Metformin. Through the photoreversible [2+2] mechanism of the polymer's pendant coumarin moieties, the nanoparticles are de‐crosslinked, and their cargo molecules released. A study of the kinetics of release is undertaken in different solvents, providing insight into the relationship between the cargo's molecular structure and that of the polymer chain. On the whole, this report's study introduces new controlled release and cationic ring‐opening polymerization concepts while providing the first example of a single‐chain polymer nanoparticle based on a photoresponsive polysiloxane.

Nanomedicine‐Enabled Mild Photothermal Therapy Strategies for Enhanced Antitumor Treatment

Photothermal therapy (PTT) has emerged as a promising approach for tumor ablation utilizing hyperthermia offers several advantages, including non‐invasiveness, spatiotemporal controllability, and notable therapeutic efficacy. However, the clinical application of PTT is challenged by the heat diffusion. To address this, mild PTT (mPTT) has gained attention as an alternative strategy, operating at temperatures below 45 °C, with remarkable antitumor effects and minimal thermal damage to nearby normal tissues. Despite these benefits, the expression of heat shock proteins (HSPs) induces thermal resistance, which limits the therapeutic potential and practical implementation of mPTT. Nanomedicines have emerged as a solution to overcome these challenges, offering improved solubility, prolonged circulation time, enhanced tumor accumulation, and controlled cargo release, surpassing the capabilities of small molecular HSP inhibitors. Herein, it has been aimed to discuss the current landscape of photothermal agents, elucidate the underlying mechanisms of mPTT, highlight the benefits of mPTT in combination therapy, and explore the potential of nanomedicines to enhance mPTT efficacy. Additionally, future directions for the development of mPTT are presented and the challenges that are needed to be addressed are identified, with the aim of encouraging further research contributions to advance mPTT toward clinical applications.

DNA Crosslinked Mucin Hydrogels Allow for On-Demand Gel Disintegration and Triggered Particle Release.

Whereas hydrogels created from synthetic polymers offer a high level of control over their stability and mechanical properties, their biomedical activity is typically limited. In contrast, biopolymers have evolved over billions of years to integrate a broad range of functionalities into a single design. Thus, biopolymeric hydrogels can show remarkable capabilities such as regulatory behavior, selective barrier properties, or antimicrobial effects. Still, despite their widespread use in numerous biomedical applications, achieving a meticulous control over the physical properties of macroscopic biopolymeric networks remains a challenge. Here, a macroscopic, DNA-crosslinked mucin hydrogel with tunable viscoelastic properties that responds to two types of triggers: temperature alterations and DNA displacement strands, is presented. As confirmed with bulk rheology and single particle tracking, the hybridized base pairs governing the stability of the hydrogel can be opened, thus allowing for a precise control over the hydrogel stiffness and even enabling a full gel-to-sol transition. As those DNA-crosslinked mucin hydrogels possess tunable mechanical properties and can be disintegrated on demand, they can not only be considered for controlled cargo release but may also serve as a role model for the development of smart biomedical materials in applications such as tissue engineering and wound healing.

Electrostatic loading and photoredox-accelerated release of antibiotics from oligoviologen-crosslinked hydrogels using red light

Hydrogel drug delivery is the subject of an ever-expanding industry where delivery occurs by numerous methods, many of them passive in nature. On-command, stimuli-driven release, particularly using light to initiate spatiotemporal, controlled release of cargo is a more attractive approach than passive release methods. Here, we report a novel method for electrostatically loading negatively charged dye and antibiotic cargo in biocompatible, oligoviologen-crosslinked hydrogels equipped with an integrated Aza-boron-dipyrromethene (Aza-BODIPY) photocatalyst. Following loading, the release of the electrostatically bound cargos can be accelerated upon irradiation with red light (660 nm) through a photoinduced electron transfer (PET) process that reduced the oligoviologen subunits. A free radical polymerization method was used to fabricate the hydrogels with a hydroxyethyl acrylate backbone, co-crosslinked by a viologen hexamer (6V-St•12Cl) and Aza-BODIPY derivative. Irradiation of the Aza-BODIPY photocatalyst led to a reduction of the viologen subunits to their monoradical cation oxidation state via PET. The photocatalyst was regenerated in situ in a triethanolamine (TEOA) solution, which served as a sacrificial reductant. Negatively charged dye (i.e., methyl orange, MO) was electrostatically loaded into the hydrogel through counteranion metathesis, followed by irradiation with red light to release the dye as the subunits of the viologen crosslinker lost positive charges (i.e., V2+ to V●+). Controlled release of the dye was tracked by UV/Vis absorption spectroscopy, yielding up to 74 % of cargo released in 75 h. Negatively charged antibiotic cargo (i.e., nalidixic acid) was then electrostatically loaded into and released from hydrogels by the same method. Controlled release of the drug was tracked by agar diffusion and liquid broth microdilution antibacterial susceptibility assays, where bacterial growth inhibition was recorded, confirming the same release trends observed for the dye cargo.

Current Principles, Challenges, and New Metrics in pH-Responsive Drug Delivery Systems for Systemic Cancer Therapy.

The paradigm of drug delivery via particulate formulations is one of the leading ideas that enable overcoming limitations of traditional chemotherapeutic agents. The trend toward more complex multifunctional drug carriers is well-traced in the literature. Nowadays, the prospectiveness of stimuli-responsive systems capable of controlled cargo release in the lesion nidus is widely accepted. Both endogenous and exogenous stimuli are employed for this purpose; however, endogenous pH is the most common trigger. Unfortunately, scientists encounter multiple challenges on the way to the implementation of this idea related to the vehicles' accumulation in off-target tissues, their immunogenicity, the complexity of drug delivery to intracellular targets, and finally, the difficulties in the fabrication of carriers matching all imposed requirements. Here, we discuss fundamental strategies for pH-responsive drug delivery, as well as limitations related to such carriers' application, and reveal the main problems, weaknesses, and reasons for poor clinical results. Moreover, we attempted to formulate the profiles of an "ideal" drug carrier in the frame of different strategies drawing on the example of metal-comprising materials and considered recently published studies through the lens of these profiles. We believe that this approach will facilitate the formulation of the main challenges facing researchers and the identification of the most promising trends in technology development.

Tailored Beta-Lapachone Nanomedicines for Cancer-Specific Therapy.

Nanotechnology shows the power to improve efficacy and reduce the adverse effects of anticancer agents. As a quinone-containing compound, beta-lapachone (LAP) is widely employed for targeted anticancer therapy under hypoxia. The principal mechanism of LAP-mediated cytotoxicity is believed due to the continuous generation of reactive oxygen species with the aid of NAD(P)H: quinone oxidoreductase 1 (NQO1). The cancer selectivity of LAP relies on the difference between NQO1 expression in tumors and that in healthy organs. Despite this, the clinical translation of LAP faces the problem of narrow therapeutic window that is challenging for dose regimen design. Herein, the multifaceted anticancer mechanism of LAP is briefly introduced, the advance of nanocarriers for LAP delivery is reviewed, and the combinational delivery approaches to enhance LAP potency in recent years are summarized. The mechanisms by which nanosystems boost LAP efficacy, including tumor targeting, cellular uptake enhancement, controlled cargo release, enhanced Fenton or Fenton-like reaction, and multidrug synergism, are also presented. The problems of LAP anticancer nanomedicines and the prospective solutions are discussed. The current review may help to unlock the potential of cancer-specific LAP therapy and speed up its clinical translation.

Bioderived Lipoic Acid-Based Dynamic Covalent Nanonetworks of Poly(disulfide)s: Enhanced Encapsulation Stability and Cancer Cell-Selective Delivery of Drugs.

Dynamic covalent poly(disulfide)-based cross-linked nanoaggregates, termed nanonetworks (NNs), endowed with pH- and redox-responsive degradation features have been fabricated for stable noncovalent encapsulation and triggered cargo release in a controlled fashion. A bioderived lipoic acid-based Gemini surfactant-like amphiphilic molecule was synthesized for the preparation of nanoaggregates. It self-assembles by a entropy-driven self-assembly process in aqueous milieu. To further stabilize the self-assembled nanostructure, the core was cross-linked by ring-opening disulfide exchange polymerization (RODEP) of 1,2-dithiolane rings situated inside the core of the nanoaggregates. The cross-linked nanoaggregates, i.e., nanonetwork, are found to be stable in the presence of blood serum, and also, they maintain the self-assembled structure even below the critical aggregation concentration (CAC) as probed by dynamic light scattering (DLS) experiments. The nanonetwork showed almost 50% reduction in guest leakage compared to that of the nanoaggregates as shown by the release profile in the absence of stimuli, suggesting high encapsulation stability as evidenced by the fluorescence resonance energy transfer (FRET) experiment. The decross-linking of the nanonetwork occurs in response to redox and pH stimuli due to disulfide reduction and β-thioester hydrolysis, respectively, thus empowering disassembly-mediated controlled cargo release up to ∼87% for 55 h of incubation. The biological evaluation of the doxorubicin (DOX)-loaded nanonetwork revealed environment-specific surface charge modulation-mediated cancer cell-selective cellular uptake and cytotoxicity. The benign nature of the nanonetwork toward normal cells makes the system very promising in targeted drug delivery applications. Thus, the ease of synthesis, nanonetwork fabrication reproducibility, robust stability, triggered drug release in a controlled fashion, and cell-selective cytotoxicity behavior, we believe, will make the system a potential candidate in the development of robust materials for chemotherapeutic applications.

Nanoscale metallic‐organic frameworks as an advanced tool for medical applications: Challenges and recent progress

Recently, metal‐organic frameworks (MOFs) have received a lot of interest for application in many fields ranging from catalysis, energy storage, and gas sensing to chemosensory and biomedicine owed to their flexible composition, tunable porosity, and easy functionalization ability. In particular, nanoscale MOFs have been broadly investigated as carriers for the delivery of therapeutics to cancerous organs owed to their high encapsulating capacity and controlled cargo release, versatility, biodegradability, and good biocompatibility. Several methods such as solvothermal, mechanochemical, electrochemical, microwave, and ultrasound have been utilized to fabricate MOFs via custom‐made synthesis. Many efforts have been made to functionalize MOFs through “post‐synthetic modification,” by adjusting the nature, size, and charge of the linkers or tuning its main components. Herein, a comprehensive literature review on recent papers dealing with drug‐loaded MOFs for the detection and treatment of cancer as well as bacterial, fungal, and viral infections is presented. Different types of MOFs applied as carriers in drug delivery systems and biosensing platforms are described. Furthermore, perspectives and challenges for future research in the field, particularly for cancer therapy, are discussed. Thus, very limited literature is available on in vitro and in vivo toxicity of nanoscale MOFs. Besides, their biological stability and long‐term safety are crucial factors that should be further investigated. Based on the reviewed papers, zeolite imidazolate framework (ZIF) and Materials of Institute Lavoisier (MIL) families have been the main focus for drug delivery and diagnosis applications, respectively, while many types of MOFs have exhibited antibacterial and antifungal properties regardless of their cargo.

Co-crystal nanoarchitectonics as an emerging strategy in attenuating cancer: Fundamentals and applications.

Cancer ranks as the second foremost cause of death in various corners of the globe. The clinical uses of assorted anticancer therapeutics have been limited owing to the poor physicochemical attributes, pharmacokinetic performance, and lethal toxicities. Various sorts of co-crystals or nano co-crystals or co-crystals-laden nanocarriers have presented great promise in targeting cancer via improved physicochemical attributes, pharmacokinetic performance, and reduced toxicities. These systems have also demonstrated the controlled cargo release and passive targeting via enhanced permeation and retention (EPR) effect. In addition, regional delivery of co-crystals via inhalation and transdermal route displayed remarkable potential in targeting lung and skin cancer effectively. However, more research is required on the use of co-crystals in cancer and their commercialization. The present review mainly emphasizes co-crystals as emerging avenues in the treatment of various cancers by modulating the physicochemical and pharmacokinetic attributes of approved anticancer therapeutics. The worth of co-crystals in cancer treatment, computational paths in the co-crystals screening, diverse experimental techniques of co-crystals fabrication, and sorts of co-crystals and their noteworthy applications in targeting cancer are also discussed. Besides, the game changer approaches like nano co-crystals and co-crystals-laden nanocarriers, and co-crystals in regional delivery in cancer are also explained with reported case studies. Furthermore, regulatory directives for pharmaceutical co-crystals and their scale-up, and challenges are also highlighted with concluding remarks and future initiatives. In essence, co-crystals and nano co-crystals emerge to be a promising strategy in overwhelming cancers through improving anticancer efficacy, safety, patient compliance, and reducing the cost.

Tunable enzymatically degradable hydrogels for controlled cargo release with dynamic mechanical properties.

Here, we designed enzymatically degradable hydrogels with tunable mesh sizes and crosslinking points to evaluate the effectiveness of network structure estimations in predicting dynamic mechanical properties and cargo retention or release. Poly(ethylene glycol) (PEG) hydrogels were prepared through a thiol-ene click reaction between four- or eight-arm PEG functionalized with vinyl sulfone and cysteine residues of collagenase-degradable peptides to create well-defined, homogenous, and robust materials with a range of mesh sizes estimated from the elasticity theory or Flory-Rehner theory. Time-dependent changes in mechanical properties associated with hydrogel degradation, i.e., dynamics of storage modulus, which is determined by the relationship between the hydrogel mesh and enzyme sizes, were characterized. The shear modulus G' decreased by enzyme addition, and the degradation rate decreased with the initial crosslinking density of the hydrogel. The degradation rate could also be controlled with the reactivity of peptide sequences against collagenase. With these findings, the retention and release of FITC-dextran were successfully controlled by tuning the mesh size and degradability of the hydrogel. This report provides useful insights for designing hydrogels as cell scaffolds or functional molecular delivery matrices with tunable dynamic mechanical properties and the resulting release of loaded drugs or proteins.

All-Aqueous, Surfactant-Free, and pH-Driven Nanoformulation Methods of Dual-Responsive Polymer Nanoparticles and their Potential use as Nanocarriers of pH-Sensitive Drugs.

All-aqueous, surfactant-free, and pH-driven nanoformulation methods to generate pH- and temperature-responsive polymer nanoparticles (NPs) are described. Copolymers comprising a poly(methyl methacrylate) (PMMA) backbone with a few units of 2-(dimethylamino)ethyl methacrylate (DMAEMA) are solubilized in acidic buffer (pH 2.0) to produce pH-sensitive NPs. Copolymers of different molar mass (2.3-11.5kgmol-1 ) and DMAEMA composition (7.3-14.2mol%) are evaluated using a "conventional" pH-driven nanoformulation method (i.e., adding an aqueous polymer solution (acidic buffer) into an aqueous non-solvent (basic buffer)) and a robotized method for pH adjustment of polymer dispersions. Dynamic light scattering, zeta-potential (ζ), and sedimentation-diffusion analysessuggest the formation of dual-responsive NPs of tunable size (from 20 to 110nm) being stable for at least 28 days in the pH and temperature intervals from 2.0 to 6.0 and 25 to 50°C, respectively. Ultraviolet-visible spectroscopic experiments show that these NPs can act as nanocarriers for the pH-sensitive dipyridamole drug, expanding its bioavailability and potential controlled release as a function of pH and temperature. These approaches offer alternative strategies to prepare stimuli-responsive NPs, avoiding the use of harmful solvents and complex purification steps, and improving the availability of biocompatible polymer nanoformulations for specific controlled release of pH-sensitive cargos.

Metabolite-Responsive Liposomes Employing Synthetic Lipid Switches Driven by Molecular Recognition Principles.

The ability to exert control over lipid properties, including structure, charge, function, and self-assembly characteristics is a powerful tool that can be implemented to achieve a wide range of biomedical applications. Examples in this arena include the development of caged lipids for controlled activation of signaling properties, metabolic labeling strategies for tracking lipid biosynthesis, lipid activity probes for identifying cognate binding partners, approaches for in situ membrane assembly, and liposome triggered release strategies. In this Account, we describe recent advancements in the latter area entailing the development of stimuli-responsive liposomes through programmable changes to lipid self-assembly properties, which can be harnessed to drive the release of encapsulated contents toward applications including drug delivery. We will focus on an emerging paradigm involving liposomal platforms that are sensitized toward chemical agents ranging from metal cations to small organic molecules that exhibit dysregulation in disease states. This has been achieved by developing synthetic lipid switches that are designed to undergo programmed conformational changes upon the recognition of specific target analytes. These structural alterations are leveraged to perturb the packing of lipids within the membrane and thereby drive the release of encapsulated contents.We provide an overview of the inspiration, design, and characterization of liposomes that selectively respond to wide-ranging target analytes. This series of studies began with the development of calcium-responsive liposomes utilizing a lipid switch inspired by sensors including indo-1. Following this successful demonstration, we next showed that the selectivity of the lipid switch could be altered among different metal cations by producing a liposomal platform for which release is induced through zinc binding. Our next goal was to develop metabolite-responsive liposomes in which switching is driven by molecular recognition events involving phosphorylated small molecules. In this work, screening of lipid switches designed to interact with phosphorylated metabolites led to the identification of liposomal formulations that selectivity release contents in the presence of adenosine triphosphate (ATP). Finally, we were able to modulate the metabolite selectivity by rationally designing a modified lipid switch structure that is activated through complexation of inositol-(1,4,5)-trisphosphate (IP3). These projects show the progression of our approaches for liposome release triggered by molecular recognition principles, building from ion-responsive lipid switches to structures that are activated by small molecules. These "smart" liposomal platforms provide an important addition to the toolbox for controlled cargo release since they respond to ions or small molecules that are commonly overproduced by diseased cells.

Stabilizing Entropically Driven Self-Assembly of Self-Immolative Polyurethanes in Water: A Strategy for Tunable Encapsulation Stability and Controlled Cargo Release

Stimuli-responsive amphiphilic polymer assemblies are of great interest in the area of targeted drug delivery applications as they can sequester guest molecules in one set of conditions and release them under another. Hence, developing a strategy of molar mass controlled synthesis, in-depth understanding of the thermodynamics of the self-assembly process, stabilization, and triggered guest release in a controlled fashion would be highly anticipated in the field of drug delivery applications. As polymer molar mass has a significant impact on the self-assembly process or material property of polymers, we focused on a methodology of controlled molar mass polyurethane synthesis using recycled plastic waste and synthesized a series of self-immolative amphiphilic polyurethanes of varying molar masses and polydispersity indexes. All of the polymers were equipped with periodically grafted triethyleneglycol monomethyl ether as a pendant, a redox-responsive disulfide bond, a tertiary amine, and an aromatic moiety on the backbone. In aqueous milieu, these polymers are found to form entropically driven nanoassemblies (ΔS > 0), which were further stabilized by supramolecular cross-linking via the synergistic effect of π–π stacking (aromatic moiety), H-bonding (urethane functionality), and hydrophobic interactions, which eventually amplifies the guest encapsulation stability. A guest release profile in the presence of a redox environment shows ∼65% release in a controlled fashion. Furthermore, the tertiary amine on the polymer backbone leads to the formation of positively charged nanoassemblies at the tumor-relevant pH (pH ∼ 6.5–6.8), which could potentially enhance the cellular uptake of nanocarriers in tumor cells. Thus, a strategy for molar mass controlled polyurethane synthesis, understanding the effect of polymer molar mass on thermodynamics of self-assembly, establishing a stable micellar nanostructure endowed with environment-specific surface charge modulation, and controlled guest release, we believe, will significantly contribute to the development of robust chemotherapeutics.

Targeting necroptosis as an alternative strategy in tumor treatment: From drugs to nanoparticles.

Over last decades, most antitumor therapeutic strategies have focused on apoptosis, however, apoptosis resistance and immunological silence usually led to treatment failure. In this sense, triggering other programmed cell death such as necroptosis may achieve a better therapeutic efficacy and has gained widespread attentions in tumor therapy. Studies in this field have identified several types of necroptosis modulators and highlighted the therapeutic potential of necroptotic cell death in cancer. Nanoparticles further provide possibilities to improve therapeutic outcomes as an efficient drug delivery system, facilitating tumor targeting and controlled cargo release. Furthermore, some nanoparticles themselves can trigger/promote programmed necrosis through hyperthermia, ultrasound and autophagy blockage. These investigations have entered necroptosis for consideration as a promising strategy for tumor therapy, though numerous challenges remain and clinical applications are still distant. In this review, we would briefly introduce molecular mechanism and characteristics of necroptosis, and then summarize recent progress of programmed necrosis and their inducers in tumor therapy. Furthermore, the antitumor strategies that take advantages of nanoparticles to induce necroptosis are also discussed.

Yield‐Stress and Creep Control Depot Formation and Persistence of Injectable Hydrogels Following Subcutaneous Administration

AbstractHydrogels that can be injected into the body using standard needles or catheters enable a minimally invasive strategy to prolong local delivery of therapeutic cargo. In particular, physically cross‐linked hydrogels exhibit shear‐thinning and self‐healing behaviors enabling facile injectability and depot formation upon administration. While prior efforts to characterize these systems have focused on injectability and cargo release behaviors, prediction of cargo release in the body often assumes these materials form a depot rather than spreading out upon administration. Here, it is evaluated how hydrogel rheology correlates with depot formation and persistence following subcutaneous administration in mice with two physiochemically distinct, physically cross‐linked hydrogel systems. Calcium‐alginate and polymer‐nanoparticle hydrogel systems exhibit variable mechanical behaviors across several rheological properties (stiffness, viscoelasticity, yield stress, and creep). By relating measured rheological properties to depot formation and persistence time following subcutaneous administration, it is identified that yield stress is predictive of initial depot formation while creep is predictive of depot persistence for these two gel systems. Indeed, only materials with yield stresses >25 Pa form robust depots, and reduced creep correlates with longer depot persistence. These findings provide predictive insights into design considerations for hydrogel technologies capable of extended controlled release of therapeutic cargo.

β-Lactamase-Responsive Hydrogel Drug Delivery Platform for Bacteria-Triggered Cargo Release

Antibiotic resistance is a growing public health threat that complicates the treatment of infections. β-Lactamase enzymes, which hydrolyze the β-lactam ring present in many common antibiotics, are a major cause of this resistance and are produced by a broad range of bacterial pathogens. Here, we developed hydrogels that degrade specifically in the presence of β-lactamases and β-lactamase-producing bacteria as a platform for bacteria-triggered drug delivery. A maleimide-functionalized β-lactamase-cleavable cephalosporin was used as a crosslinker in the fabrication of hydrogels through end-crosslinked polymerization with multiarm thiol-terminated poly(ethylene glycol) macromers via Michael-type addition. We demonstrated that only hydrogels containing the responsive crosslinker were degraded by β-lactamases and β-lactamase-producing bacteria in vitro and in an ex vivo porcine skin infection model. Fluorescent polystyrene nanoparticles, encapsulated in the hydrogels as model cargo, were released at rates that closely tracked hydrogel wet mass loss, confirming β-lactamase-triggered controlled cargo release. Nonresponsive hydrogels, lacking the β-lactam crosslinker, remained stable in the presence of β-lactamases and β-lactamase-producing bacteria and exhibited no change in mass or nanoparticle release. Furthermore, the responsive hydrogels remained stable in non-β-lactamase enzymes, including collagenases and lipases. These hydrogels have the potential to be used as a bacteria-triggered drug delivery system to control unnecessary exposure to encapsulated antimicrobials, which can provide effective infection treatment without exacerbating resistance.

Triggered azobenzene-based prodrugs and drug delivery systems.

Azobenzene-based molecules show unique trans-cis isomerization upon ultraviolet light irradiation, which induce the change of polarity, crystallinity, stability, and binding affinity with pharmacological target. Moreover, azobenzene is the substrate of azoreductase that is often overexpressed in many pathological sites, e.g. hypoxic solid tumor. Therefore, azobenzene can be a multifunctional molecule in material science, pharmaceutical science and biomedicine because of its sensitivity to light, hypoxia and certain enzymes, hence showing potential application in site-specific smart therapy. Herein we focus on the employment of azobenzene and its derivatives for engineering triggered prodrugs and drug delivery systems, and provide an overview of photoswitchable azo-based prodrugs, the associated problems regarding the reversible isomerization and tissue penetration of ultraviolet (UV) light, as well as the potential solutions. We also present the advance of azo-bearing delivery vehicles wherein azobenzene acts as the linker, capping agent, and building block, and discuss the corresponding mechanisms for controlled cargo release, endocytosis enhancement and sensitization of free radical cancer therapy.

Tailoring Niosomes- Implications for Controlled Cargo Release and Function as Nanoreactors.

Nonionic surfactant vesicles (Niosomes) were prepared using polyoxyethylene alkyl ether (Brij 58).The impact of variation of the Brij: cholesterol molar ratio on the niosomal structure was studied. Fluorescence studies performed with the membrane probe 1,6-Diphenyl-1,3,5-triene (DPH) gave important insight on the bilayer integrity of the niosomes in response to environmental perturbations. The aim of the work being assessment of the efficacy of the niosomes as "drug release vehicles", release studies were performed with a xanthene dye Carboxyfluorescein (CF). Further, the vesicles were used as nanoreactors for the synthesis of gold nanoparticles (GNPs) as it is often useful to house nanoparticles in biological /biomimicking environments. Stable, spherical GNPs of diameter 6-10 nm were formed in these vesicles. As the vesicular bilayer mimics the cell membrane, the present work is relevant to the use of the GNPs for diagnostic and therapeutic purpose. It has also been established that fluorescence resonance energy transfer (FRET) effectively occurs between DPH and CF in the niosomes. The FRET studies provide important insight on the location of dyes within the vesicles thus indicating the prospective applications of this fluorescence technique for tracking the location of probes in biomimicking systems which maybe extrapolated to in vivo biological systems in future.

Designer membraneless organelles sequester native factors for control of cell behavior.

Subcellular compartmentalization of macromolecules increases flux and prevents inhibitory interactions to control biochemical reactions. Inspired by this functionality, we sought to build designer compartments that function as hubs to regulate the flow of information through cellular control systems. We report a synthetic membraneless organelle platform to control endogenous cellular activities through sequestration and insulation of native proteins. We engineer and express a disordered protein scaffold to assemble micron size condensates and recruit endogenous clients via genomic tagging with high-affinity dimerization motifs. By relocalizing up to ninety percent of a targeted enzymes to synthetic condensates, we efficiently control cellular behaviors, including proliferation, division, and cytoskeletal organization. Further, we demonstrate multiple strategies for controlled cargo release from condensates to switch cells between functional states. These synthetic organelles offer a powerful and generalizable approach to modularly control cell decision-making in a variety of model systems with broad applications for cellular engineering.