Triggered Drug Release Research Articles

NanoBioMaterials: Advanced Research Outlines New Horizons for Basic and Applied Science

Nanobiomaterials are nanostructured materials implemented in a wide range of biomedical applications, including nanostructured ceramics, polymers, lipids, metals, composites, nucleic acids, self-assembled materials, and macromolecules. Emerging technologies outline novel experimental tools for characterizing nanostructured biomaterials' behavior in cells and the whole organism for numerous applications, including drug delivery, medical diagnostics, surgery, and tissue engineering. Thus, NanoBioMaterials represent a new class of materials designed to interact intrinsically with biological substances to achieve a precise biological outcome. This Special Issue of the IJC presents various approaches of outstanding young researchers from Israel's universities to develop and study novel materials and their implications for biology. The biological targets of these materials vary, including imaging of the brain and treatment of cancerous tumors and modulating plants' physical properties. The manuscripts describe new manipulations of molecules and matter by employing innovative chemical approaches, such as microfluidics' and nanotechnology. Combined, integrating these material-biology interfaces allows the improved discovery of new biological targets and new drugs. The ability to form targeted nanoscale medicines and test them in organ-on-chip scenarios promises improved therapeutic accuracy, reduced use of animals, and rapid clinical implementation. To achieve these goals, the integration of chemical, biological, and computational capabilities are required. These studies require research groups that are interdisciplinary by their nature. The value of work at the interface of nanotechnology, materials, and biology is immense, generating fundamental understandings regarding how our body responds to engineered materials. Next-generation materials are designed to become biomimetic for better tissue integration. Furthermore, experimental trial and error processes are shortened by taking a lesson from Nature, adapting natural principles, and leveraging them to develop new therapeutic and diagnostic materials. The list of new materials includes bioadhesives that adhere to wet environments with minimal toxicity, and materials that degrade to safe biproducts which, in turn, are secreted or metabolized by the body. Engineering also allows these systems to respond to internal or external cues that trigger drug release with spatio-temporal accuracy. Precision at the nanoscale allows to reduce side effects and focus the therapeutic activity to the site that most renders treatment. In summary, the use of nanobiomaterials is becoming more common in modern life. Nanobiomaterials exhibit distinctive biophysical characteristics, including mechanical, electrical, and optical properties, making them suitable for various in vitro and in vivo biological applications. This special issue of the IJC provides insight into cutting-edge research conducted in Young and Emerging Scientific Stars laboratories in Israel's universities. These young researchers hold great promise to make a transformative leap in the field of NanoBioMaterials.

Polar Lipid Fraction E from Sulfolobus acidocaldarius and Dipalmitoylphosphatidylcholine Can Form Stable yet Thermo-Sensitive Tetraether/Diester Hybrid Archaeosomes with Controlled Release Capability.

Archaeosomes have drawn increasing attention in recent years as novel nano-carriers for therapeutics. The main obstacle of using archaeosomes for therapeutics delivery has been the lack of an efficient method to trigger the release of entrapped content from the otherwise extremely stable structure. Our present study tackles this long-standing problem. We made hybrid archaeosomes composed of tetraether lipids, called the polar lipid fraction E (PLFE) isolated from the thermoacidophilic archaeon Sulfolobus acidocaldarius, and the synthetic diester lipid dipalmitoylphosphatidylcholine (DPPC). Differential polarized phase-modulation and steady-state fluorometry, confocal fluorescence microscopy, zeta potential (ZP) measurements, and biochemical assays were employed to characterize the physical properties and drug behaviors in PLFE/DPPC hybrid archaeosomes in the presence and absence of live cells. We found that PLFE lipids have an ordering effect on fluid DPPC liposomal membranes, which can slow down the release of entrapped drugs, while PLFE provides high negative charges on the outer surface of liposomes, which can increase vesicle stability against coalescence among liposomes or with cells. Furthermore, we found that the zeta potential in hybrid archaeosomes with 30 mol% PLFE and 70 mol% DPPC (designated as PLFE/DPPC(3:7) archaeosomes) undergoes an abrupt increase from −48 mV at 37 °C to −16 mV at 44 °C (termed the ZP transition), which we hypothesize results from DPPC domain melting and PLFE lipid ‘flip-flop’. The anticancer drug doxorubicin (DXO) can be readily incorporated into PLFE/DPPC(3:7) archaeosomes. The rate constant of DXO release from PLFE/DPPC(3:7) archaeosomes into Tris buffer exhibited a sharp increase (~2.5 times), when the temperature was raised from 37 to 42 °C, which is believed to result from the liposomal structural changes associated with the ZP transition. This thermo-induced sharp increase in drug release was not affected by serum proteins as a similar temperature dependence of drug release kinetics was observed in human blood serum. A 15-min pre-incubation of PLFE/DPPC(3:7) archaeosomal DXO with MCF-7 breast cancer cells at 42 °C caused a significant increase in the amount of DXO entering into the nuclei and a considerable increase in the cell’s cytotoxicity under the 37 °C growth temperature. Taken together, our data suggests that PLFE/DPPC(3:7) archaeosomes are stable yet potentially useful thermo-sensitive liposomes wherein the temperature range (from 37 to 42–44 °C) clinically used for mild hyperthermia treatment of tumors can be used to trigger drug release for medical interventions.

Mechanisms for Tuning Engineered Nanomaterials to Enhance Radiation Therapy of Cancer.

Engineered nanomaterials that produce reactive oxygen species on exposure to X‐ and gamma‐rays used in radiation therapy offer promise of novel cancer treatment strategies. Similar to photodynamic therapy but suitable for large and deep tumors, this new approach where nanomaterials acting as sensitizing agents are combined with clinical radiation can be effective at well‐tolerated low radiation doses. Suitably engineered nanomaterials can enhance cancer radiotherapy by increasing the tumor selectivity and decreasing side effects. Additionally, the nanomaterial platform offers therapeutically valuable functionalities, including molecular targeting, drug/gene delivery, and adaptive responses to trigger drug release. The potential of such nanomaterials to be combined with radiotherapy is widely recognized. In order for further breakthroughs to be made, and to facilitate clinical translation, the applicable principles and fundamentals should be articulated. This review focuses on mechanisms underpinning rational nanomaterial design to enhance radiation therapy, the understanding of which will enable novel ways to optimize its therapeutic efficacy. A roadmap for designing nanomaterials with optimized anticancer performance is also shown and the potential clinical significance and future translation are discussed.

Hyperthermia and Temperature-Sensitive Nanomaterials for Spatiotemporal Drug Delivery to Solid Tumors.

Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using spatiotemporal drug release by means of nanoparticles with the capacity for content release triggered by internal or external stimuli. Among different stimuli, interests for application of external heat, hyperthermia, is growing. Advanced technology, ease of application and most importantly high level of control over applied heat, and as a result triggered release, and the adjuvant effect of hyperthermia in enhancing therapeutic response of chemotherapeutics, i.e., thermochemotherapy, make hyperthermia a great stimulus for triggered drug release. Therefore, a variety of temperature sensitive nano-carriers, lipid or/and polymeric based, have been fabricated and studied. Importantly, in order to achieve an efficient therapeutic outcome, and taking the advantages of thermochemotherapy into consideration, release characteristics from nano-carriers should fit with applicable clinical thermal setting. Here we introduce and discuss the application of the three most studied temperature sensitive nanoparticles with emphasis on release behavior and its importance regarding applicability and therapeutic potentials.

Drug-induced hierarchical self-assembly of poly(amino acid) for efficient intracellular drug delivery

As a potent anticancer drug, gambogic acid (GA) suffers from its poor water solubility and low chemical stability and shows a limited clinical outcome. To address this problem, we report here a simple and effective strategy to immobilize and deliver GA using a reducible diblock poly(amino acid) as a model. The electrostatic interaction between GA and polymer enables a high drug loading content up to 53.6 %. Moreover, the drug complexation induces a micelle-to-vesicle transformation, combined with a conformation transition from random coil to α-helix. The hierarchically assembled drug nanocomplexes can serve as a smart carrier for efficient cell internalization and triggered release of multiple drugs under intracellular acidic and reductive conditions, resulting in a synergistic antitumor efficacy in vitro. This work provides a new insight into the drug-carrier interaction and a facile nanoplatform for drug delivery applications.

Design of circular-ring film embedded contact lens for improved compatibility and sustained ocular drug delivery

Contact lenses are ideal medical devices to sustain the release of ophthalmic drugs. However, the incorporation of drug loaded system can cause visual obstruction and poor oxygen/light permeability which restrict the application of contact lens for long-term wearing. Inspired by the physiological structure of our human eyes, we assume a circular-ring type inner layer embedded CLs might be a good solution to address the above-mentioned problems. In this study, taking betaxolol hydrochloride (BH) as a model drug, its complex with ion exchange resin was used as a carrier for adjusting drug loading amount, which is being dispersed into circular-ring shape Eudragit® S100 film as an inner layer, silicone-based hydrogel as the outer layer. Influence of resin particle size and drug/S100 ratio on drug release profiles was investigated. It was demonstrated that using resin as a carrier can not only increase drug loading amount but also sustain drug release, with the drug release rate well-tuned by either changing particle size of the resin or S100 ratio. Meanwhile S100 can well function as a pH-triggered drug release matrix, with limited drug leakage in the storage medium. Light transmittance of over 97% was achieved in the novel circular-ring layer-embedded CLs. Oxygen permeability coefficient (Dk) of the circular-ring film embedded CLs was 31.1 ± 3.7 barrer, similar to that of pure CLs. The sustained drug release behavior of this circular-ring embedded CLs was also well demonstrated in vivo. A level A IVIVC between in vitro drug release and in vivo drug concentration in tear fluid of the circular-ring embedded CLs was established. In conclusion, this circular-ring embedded contact lens is very promising for ophthalmic drug delivery with enhanced compatibility, sustained and pH triggered drug release characteristics.

Electroresponsive Alginate-Based Hydrogels for Controlled Release of Hydrophobic Drugs.

Stimuli-responsive biomaterials have attracted significant attention for the construction of on-demand drug release systems. The possibility of using external stimulation to trigger drug release is particularly enticing for hydrophobic compounds, which are not easily released by simple diffusion. In this work, an electrochemically active hydrogel, which has been prepared by gelling a mixture of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) and alginate (Alg), has been loaded with curcumin (CUR), a hydrophobic drug with a wide spectrum of clinical applications. The PEDOT/Alg hydrogel is electrochemically active and organizes as segregated PEDOT- and Alg-rich domains, explaining its behavior as an electroresponsive drug delivery system. When loaded with CUR, the hydrogel demonstrates a controlled drug release upon application of a negative electrical voltage. Comparison with the release profiles obtained applying a positive voltage and in the absence of electrical stimuli indicates that the release mechanism dominating this system is complex because of not only the intermolecular interactions between the drug and the polymeric network but also the loading of a hydrophobic drug in a water-containing delivery system.

Thermoresponsive magnetic/polymer composite nanoparticles for biomedical applications

Thermoresponsive magnetic/polymer composite nanoparticles (MPCNPs) possess unique properties for combined simultaneous application of magnetically induced targeted delivery of drugs to tumors, hyperthermia, controlled drug discharge and magnetic resonance imaging (MRI). In this regard, magnetic nanoparticles (MNPs), in particular Fe3O4 and γ-Fe2O3, are important because of their apparent biocompatibility and exclusive size-dependent qualities. Thermoresponsive polymers deliver controlled drug release, which is induced by the temperature above their lower critical solution temperature (LCST). Incorporation of MNPs into the thermoresponsive polymers structure provide combined benefits: (i) the magnetic component acts as heat source by means of magnetically assisted heating, which triggers drug release; (ii) preferential accumulation of drug loaded MPCNPs to the targeted locations is achieved by utilizing an external magnetic field; (iii) imaging and diagnostic can be done by MRI. In this article, formulation of a drug delivery system, based on ion γ-Fe2O3 MNPs and thermoresponsive polymer Poly(N-isopropylacrylamide) (PNIPAM) is presented. γ-Fe2O3 MNPs were synthesized by wet chemical method and γ-Fe2O3–PNIPAM composite nanoparticles were made by dispersion free-radical mechanism through polymerization of NIPAM. The synthesized MPCNPs were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), thermo gravimetric analysis (TGA) and vibrating sample magnetometry (VSM). Anti-cancer drug, doxorubicin, was loaded into MPCNPs. The drug release profile was studied in-vitro under the influence of magnetically assisted heating conditions, when therapeutically substantial quantity of drug was released. Therefore, multimodal approach (magnetic drug targeting, simultaneous hyperthermia and controlled drug release) of cancer treatment by using anti-cancer drug loaded thermoresponsive magnetic/polymer composite nanoparticles can improve the efficacy of present cancer treatment.

A Redox-Responsive, In-Situ Polymerized Polyplatinum(IV)-Coated Gold Nanorod as An Amplifier of Tumor Accumulation for Enhanced Thermo-Chemotherapy

It remains a major challenge to develop an effective therapeutic system based on gold nanorods (GNRs) for cancer therapy. Herein, we developed a redox-responsive, in-situ polymerized polyplatinum(IV)-coated gold nanorod (GNR@polyPt(IV)) with coupling of the near-infrared (NIR)-induced hyperthermal effect and redox-triggered drug release in one therapeutic platform as an amplifier of tumor accumulation through mild hyperthermia for enhanced synergistical thermo-chemotherapy. After in-situ polymerized with 2-methacryloyloxy ethyl phosphorylcholine (MPC) and Pt(IV) complex-based prodrug monomer (PPM) onto the surface of GNRs, the nanosized GNR@polyPt(IV) exhibited the advantages of high drug encapsulation efficiency, triggered drug release, and reduced side effect. As demonstrated by thermal imaging and photoacoustic imaging in vitro and in vivo, this GNR@polyPt(IV) exhibited an excellent NIR-associated hyperthermal effect and outstanding capacity of tumor accumulation. Importantly, under a mild hyperthermia process, the vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were upregulation, resulting in angiogenic vessel around the tumor. Combination with accelerated blood flow and angiogenesis by mild hyperthermia, a dramatic increase of drug accumulation in tumor could be realized after systematic administration. As a result, this amplification fashion of tumor accumulation would contribute the GNR@polyPt(IV) to inhibit tumor progression effectively. Such a facile and simple methodology for enhanced therapeutic effect based on GNRs holds great promises for cancer therapy with further development.

An overview on Pharmacokinetics of Polymeric Nanoparticles Intended for Oral Delivery

Polymeric nanoparticles are investigated as drug delivery devices to overcome physicochemical and pharmacokinetic (PK) problems. Many drugs were found to be drug-like during the pharmacological screening. However, all of them cannot make it to the market due to toxicity and poor bio-availability. The advent of nanoparticles has opened a new window of research where poorly soluble drugs are made useful. Nanoparticles have also been developed for favourable pharmacokinetics to avoid toxicity and side effects, to target the desired site of action and to provide triggered drug release. Poorly soluble drugs can be entrapped, encapsulated, coated or chemically bound in nanoparticles to deliver the drugs. Generally, in standard drug delivery, devices carry the drug until the gastrointestinal tract (GIT) and the drug is released, but the tool never expected to be entering the blood. However, in polymeric nanoparticles, sometimes the drug is being carried to the blood and the site of action. Polymeric nanoparticles release the drug in the gastrointestinal tract (GIT) or enter the GIT through various pathways to appear in the bloodstream. In this review, we discuss the fate of polymeric nanoparticles made up of biodegradable polymers after they are administered through the oral route. Key words: Nanoparticle, Pharmacokinetics, Drug delivery, Polymer, Oral route.

Self-Assembled Peptide-Based Biocomposites for Near-Infrared Light Triggered Drug Release to Tumor Cells.

Peptide-based nanomaterials are increasingly gaining popularity due to their specificity, biocompatibility, and biodegradability. In this work, a new multi-layered peptide-based biocomposite for targeting MCF-7 breast cancer cells is developed. The amphipathic Fluorenylmethyloxycarbonyl (Fmoc)-Leu-Ser peptide is synthesized, which is conjugated to a tumor-targeting peptide sequence Gly-Cys-Gly-Asn-Ser to form Fmoc-L-S-G-C-G-N-S (FLS) assemblies. To the FLS assemblies, gold nanorods are then attached to develop drug delivery vehicles (DDVs). The DDVs are entrapped with the anti-cancer drug fulvestrant. Entrapment efficiency is found to be 50.6%. Release studies indicate that irradiating the gold nanorod bound DDVs at NIR wavelength (785nm) increases drug release by fourfold compared to assemblies that are not irradiated. These results also show higher cytotoxicity and lower cell invasion due to photo-triggered drug release. Furthermore, distinct actin cytoskeletal changes are observed. Such novel peptide-based gold nanorod bound DDVs demonstrate potential in dual targeting of MCF-7 breast cancer cells.

Pharmacokinetics of Polymeric Nanoparticles Intended for Oral Delivery

Polymeric nanoparticles are investigated as drug delivery devices to overcome physicochemical and pharmacokinetic (PK) problems. Many drugs were found to be drug-like during the pharmacological screening. However, all of them cannot make it to the market due to toxicity and poor bio-availability. The advent of nanoparticles has opened a new window of research where poorly soluble drugs are made useful. Nanoparticles have also been developed for favourable pharmacokinetics to avoid toxicity and side effects, to target the desired site of action and to provide triggered drug release. Poorly soluble drugs can be entrapped, encapsulated, coated or chemically bound in nanoparticles to deliver the drugs. Generally, in standard drug delivery, devices carry the drug until the gastrointestinal tract (GIT) and the drug is released, but the tool never expected to be entering the blood. However, in polymeric nanoparticles, sometimes the drug is being carried to the blood and the site of action. Polymeric nanoparticles release the drug in the gastrointestinal tract (GIT) or enter the GIT through various pathways to appear in the bloodstream. In this review, we discuss the fate of polymeric nanoparticles made up of biodegradable polymers after they are administered through the oral route. Key words: Nanoparticle, pharmacokinetics, drug delivery, polymer, oral route.

Polydopamine-Mesoporous Silica Core-Shell Nanoparticles for Combined Photothermal Immunotherapy.

Cancer immunotherapy involves a cascade of events that ultimately leads to cytotoxic immune cells effectively identifying and destroying cancer cells. Responsive nanomaterials, which enable spatiotemporal orchestration of various immunological events for mounting a highly potent and long-lasting antitumor immune response, are an attractive platform to overcome challenges associated with existing cancer immunotherapies. Here, we report a multifunctional near-infrared (NIR)-responsive core-shell nanoparticle, which enables (i) photothermal ablation of cancer cells for generating tumor-associated antigen (TAA) and (ii) triggered release of an immunomodulatory drug (gardiquimod) for starting a series of immunological events. The core of these nanostructures is composed of a polydopamine nanoparticle, which serves as a photothermal agent, and the shell is made of mesoporous silica, which serves as a drug carrier. We employed a phase-change material as a gatekeeper to achieve concurrent release of both TAA and adjuvant, thus efficiently activating the antigen-presenting cells. Photothermal immunotherapy enabled by these nanostructures resulted in regression of primary tumor and significantly improved inhibition of secondary tumor in a mouse melanoma model. These biocompatible, biodegradable, and NIR-responsive core-shell nanostructures simultaneously deliver payload and cause photothermal ablation of the cancer cells. Our results demonstrate potential of responsive nanomaterials in generating highly synergistic photothermal immunotherapeutic response.

Graphene-laden hydrogels: A strategy for thermally triggered drug delivery.

The synthesis of graphene-based materials has attracted considerable attention in drug delivery strategies. Indeed, the conductivity and mechanical stability of graphene have been investigated for controlled and tunable drug release via electric or mechanical stimuli. However, the design of a thermo-sensitive scaffold using pristine graphene (without distortions related to the oxidation processes) has not been deeply investigated yet, although it may represent a promising approach for several therapeutic treatments. Here, few-layer graphene was used as a nanofiller in a hydrogel system with a thermally tunable drug release profile. In particular, varying the temperature (25°C, 37°C and 44°C), responsive drug releases were noticed and hypothesized depending on the formation and perturbation of π-π interactions involving graphene, the polymeric matrix and the model drug (diclofenac). As a result, these hybrid hydrogels show a potential application as thermally triggered drug release systems in several healthcare scenarios.

Use of Ferritin Capped Mesoporous Silica Nanoparticles for Redox and pH Triggered Drug Release In Vitro and In Vivo

AbstractMesoporous silica nanoparticles (MSNs) functionalized with redox‐sensitive or pH‐sensitive nanovalves for doxorubicin delivery and release by using recombinant human H chain ferritin (HFn) as a cap have been designed and fabricated. In both cases, transmission electron microscope observatory, dynamic light scattering change, Fourier transform infrared spectra examination, thermogravimetric analysis show that HFn can be chemically bonded to MSNs while retaining its ability to target transferrin receptor 1 (TfR1). Cargo loading and release studies demonstrate that HFn is an efficient capping agent, blocking the pores of MSN preventing cargo molecules from diffusing out, and is responsive to redox stimuli or pH changes. More importantly, HFn can not only cap the MSNs, but also enables targeted cargo delivery to malignant cells by binding to the TfR1 that has been overexpressed in various tumors, which can be reflected by the cell viability and fluorescence microscope analysis results comparing with cyclodextrin as the capping agent and TfR1 blocking assay. The in vivo study reveals the excellent efficacy of doxorubicin loaded and HFn capped MSNs on suppression of tumor growth. The new developed drug delivery system features mutually benefit and mutually support, providing strategy for achieving specific‐site therapeutics delivery systems.

A dual mode nanophotonics concept for in situ activation of brain immune cells using a photoswitchable yolk-shell upconversion nanoformulation

Here, we introduce a nanophotonics concept for optically triggered activation of microglia. Specifically, we synthesized a yolk-shell structured mesoporous silica coated core-shell upconverting nanoparticles (UCNP@ysSiO2). The nanoparticles are loaded with microglia activators-bacterial lipopolysaccharide (LPS) together with indocyanine green (ICG), and then capped with β-cyclodextrin (CD) via selective affinity of this compound to photoswitchable azobenzene (Azo). Upon exposure to NIR light, and subsequent trans- to cis photoisomerization of the Azo group induced by the upconversion light, dissociation of β-CD produces the release of LPS. The released LPS activates microglia through a toll-like receptor 4 mediated pathway, while ICG excited by its absorption of the 800 nm upconversion light, produces local heating, thus synergistically activating microglia through heat shock proteins. We propose that the controlled activation of microglia with deep tissue penetrating NIR triggered drug release, may provide a new strategy for in situ treatment of many brain diseases.

PH‐Responsive Polymer–Drug Conjugate: An Effective Strategy to Combat the Antimicrobial Resistance

AbstractAn urgent need for developing new antimicrobial approaches has emerged due to the imminent threat of antimicrobial‐resistant (AMR) pathogens. Bacterial infection can induce a unique microenvironment with low pH, which can be employed to trigger drug release and activation. Here, a pH‐responsive polymer–drug conjugate (PDC) capable of combating severe infectious diseases and overcoming AMR is reported. The PDC is made of a unique biodegradable and biocompatible cationic polymer Hex‐Cys‐DET and streptomycin, a model antibiotic. The two components show strong antimicrobial synergy since the polymer can induce pores on the bacterial wall/membrane, thus significantly enhancing the transport of antibiotics into the bacteria and bypassing the efflux pump. The PDC is neutralized for enhanced biocompatibility under physiological conditions but becomes positively charged while releasing the antibiotic in infected tissues due to the low pH. Additionally, the polymer contains disulfide bonds in its main chain, which makes it biodegradable in mammalian cells and thus reducing the cytotoxicity. The PDC can effectively penetrate bacterial biofilms and be taken up by mammalian cells, thereby minimizing biofilm‐induced AMR and intracellular infections. The PDC exhibits remarkable antimicrobial activity in three in vivo infection models, demonstrating its broad‐spectrum antimicrobial capability and great potency in eliminating AMR infections.

Controlled drug delivery with nanoassemblies of redox-responsive prodrug and polyprodrug amphiphiles

Self-assembled nanostructures are highly promising for controlled delivery of therapeutic and diagnostic agents. However, for conventional drug delivery nanosystems, there exist some intrinsic limitations such as low drug-loading contents, premature and burst release, nanocarrier matrix-associated toxicity and immunogenicity, and poor shelf stability. To address these issues, the covalent integration of active drug molecules into prodrug and polyprodrug amphiphiles and fabrication of self-delivery nanomedicines via controlled molecular self-assembly have emerged as a new paradigm. Moreover, it is crucial to achieve on-demand and selective activation of prodrugs and polyprodrugs in a spatiotemporally controlled manner, thus considerably reducing the occurrence of systemic toxicities. In this context, dynamic variations of reductive/oxidative (redox) milieu across normal and pathological tissues, cells, and cytoplasmic compartments provide accessible biochemical stimuli for triggered release of intact drugs. In this review, we highlight recent progresses on emerging applications of redox-activatable nanostructures self-assembled from prodrug and polyprodrug amphiphiles.

Magnetothermal Multiplexing for Selective Remote Control of Cell Signaling.

Magnetic nanoparticles have garnered sustained research interest for their promise in biomedical applications including diagnostic imaging, triggered drug release, cancer hyperthermia, and neural stimulation. Many of these applications make use of heat dissipation by ferrite nanoparticles under alternating magnetic fields, with these fields acting as an externally administered stimulus that is either present or absent, toggling heat dissipation on and off. Here, we motivate and demonstrate an extension of this concept, magnetothermal multiplexing, in which exposure to alternating magnetic fields of differing amplitude and frequency can result in selective and independent heating of magnetic nanoparticle ensembles. The differing magnetic coercivity of these particles, empirically characterized by a custom high amplitude alternating current magnetometer, informs the systematic selection of a multiplexed material system. This work culminates in a demonstration of magnetothermal multiplexing for selective remote control of cellular signaling in vitro.

Matrix Metalloproteinase-Responsive Mesoporous Silica Nanoparticles Cloaked with Cleavable Protein for "Self-Actuating" On-Demand Controlled Drug Delivery for Cancer Therapy.

The tumour site-specific stimulus responsiveness of smart drug delivery systems gives a unique system for effective therapeutic delivery with reduced toxic effects of conventional chemotherapeutic drugs. In this work, matrix metalloproteinase-2 (MMP-2)-responsive mesoporous silica nanoparticles (MSNs) were synthesized and assessed for "self-actuating" on-demand controlled drug delivery for cancer therapy. MMPs are members of protease enzymes that are generally overexpressed in cancerous tissues in all stages of cancer. MSNs have attracted significant consideration as a potential delivery system because of their robust and versatile physicochemical properties suitable to deliver the therapeutic payload. Cisplatin (Cis) was used as a model drug, which was incorporated into MSNs to evaluate targeting of lung cancer cells and their release kinetics. In this delivery system, collagen was coated on the surface of Cis-loaded MSNs (Cis-MSN) to form a capping layer, resulting in collagen-coated MSNs (Cis-col-MSN). Under normal cell conditions, a collagen-capping coat efficiently forbids the release of Cis molecules from Cis-col-MSN. The tumor microenvironment would lead to augmented drug release because of the uncapping of collagen from MSN pores due to the presence of overexpressed MMP-2 enzyme and the ensuing controlled drug release. MMP-responsive experiments have shown augmented enzyme triggered drug release. The cellular uptake and cytocompatibility studies in A549 adenocarcinomic lung cancer cell lines demonstrated that this nanocarrier could be efficiently endocytosed in 24 h and have shown favorable biocompatibility with the cells. Cytotoxicity results of Cis-col-MSN demonstrated dose-dependent toxicity. The efficacy of the Cis-col-MSN significantly enhanced with the supplementation of MMP-2 enzyme with increasing concentrations in the cell culture milieu. The efficacy of formulation was attributed to significantly enhance reactive oxygen species, cell cycle arrest, and apoptosis. It is expected that Cis-col-MSN promises a pragmatic approach to constructing an "on-demand" smart drug delivery system to deliver a therapeutic payload at the tumor site only.