Smart Drug Delivery Vehicles Research Articles

Nanorobotics in Cancer Theropy

Nanorobotics is the technology of creating machines or robots at or close to the scale of a nanometre (10-9 metres), machines Constructed at the molecular level (nanomachines) may be used to cure the human body of its various ills.Traditionally nanotechnology dealt with design, synthesis and Application of materials along with devices at the nanometer scale. The application of nanotechnology in the field of health care and drug Delivery has come under great attention in recent times.Nanomaterials have a large surface area to Volume ratio and their physicochemical properties, such as Friction and interaction with other molecules, are distinct From equivalent materials at a larger scale. The most com-Mon use of nanotechnology in medicine has been in the Areas of developing novel therapeutic and imaging modal-Ities that have the potential to outperform the current state of The art in these areas. We will focus on the application of Nanotechnology to the development of smart drug deliv-Ery vehicles for cancer therapeutic applications. The most Common examples of these nanoscale delivery vehicles include polymeric nan Particles, dendrimers, nanoshells, liposomes, nucleic acid-Based nanoparticles, magnetic nanoparticles, and virus Nanoparticles. The following four types of nanorobotic systems have been developed and studied so far (a) large size nanomanipulators with nanoscale manipulation capability; (b) proicin- and DNA- hused bionanorobotic systems;c) Magnetically guided nano robotic system and d) bacterial based Nanorobotic etc.It can be used in many other applications.

PH-responsive polyacrylic acid (PAA)-carboxymethyl cellulose (CMC) hydrogel incorporating halloysite nanotubes (HNT) for controlled curcumin delivery

A pH-sensitive nanocomposite based on halloysite nanotubes (HNT) coated with polyacrylic acid (PAA)/carboxymethyl cellulose (CMC) hydrogel was synthesized for controlled delivery of curcumin (CUR) to MCF-7 cancer cells. Hazelnut oil was added to minimize the nanocomposite size and increase its uniformity via water/oil/water (W/O/W) double emulsion method. Likewise, Span 80 surfactant was incorporated to produce a nanoniosomal emulsion that increased the stability and retention of CUR as an anticancer drug. The molecular interactions between the nanocomposite components, its crystalline structure, surface morphology, size distribution and surface charge were analyzed through Fourier transformed infrared (FT-IR) spectroscopy, field emission-scanning electron microscope (FE-SEM), X-ray diffraction (XRD), dynamic light scattering (DLS) and zeta potential measurements, respectively. The resulting drug delivery system showed a 45% drug loading and an 87% encapsulation efficiency, which are amongst the highest values reported up to date for CUR nanocarriers. The zeta potential of the nanocomposite was about 36 mV, indicating good stability. A sustained drug release was observed, with 61% and 96% CUR released at pH 7.4 and 5.4 after 96 h, respectively, which confirms the pH-sensitivity of the developed nanocarrier. MTT assay demonstrated the strong toxicity of the nanocomposites against MCF-7 cancer cells. Also, 46% of cell death rate in the apoptotic phase was observed by flow cytometry. The results obtained herein support the great potential of PAA/CMC/HNT/CUR hydrogel nanocomposites as smart drug delivery vehicles for breast cancer treatment.

Acoustically-Activated Liposomal Nanocarriers to Mitigate the Side Effects of Conventional Chemotherapy with a Focus on Emulsion-Liposomes.

To improve currently available cancer treatments, nanomaterials are employed as smart drug delivery vehicles that can be engineered to locally target cancer cells and respond to stimuli. Nanocarriers can entrap chemotherapeutic drugs and deliver them to the diseased site, reducing the side effects associated with the systemic administration of conventional anticancer drugs. Upon accumulation in the tumor cells, the nanocarriers need to be potentiated to release their therapeutic cargo. Stimulation can be through endogenous or exogenous modalities, such as temperature, electromagnetic irradiation, ultrasound (US), pH, or enzymes. This review discusses the acoustic stimulation of different sonosensitive liposomal formulations. Emulsion liposomes, or eLiposomes, are liposomes encapsulating phase-changing nanoemulsion droplets, which promote acoustic droplet vaporization (ADV) upon sonication. This gives eLiposomes the advantage of delivering the encapsulated drug at low intensities and short exposure times relative to liposomes. Other formulations integrating microbubbles and nanobubbles are also discussed.

Exosomes as smart drug delivery vehicles for cancer immunotherapy.

Exosomes (Exos) as drug delivery vehicles have been widely used for cancer immunotherapy owing to their good biocompatibility, low toxicity, and low immunogenicity. Some Exos-based cancer immunotherapy strategies such as tuning of immunosuppressive tumor microenvironment, immune checkpoint blockades, and cancer vaccines have also been investigated in recent years, which all showed excellent therapeutic effects for malignant tumor. Furthermore, some Exos-based drug delivery systems (DDSs) for cancer immunotherapy have also undergone clinic trails, indicating that Exos are a promising drug delivery carrier. In this review, in order to promote the development of Exos-based DDSs in cancer immunotherapy, the biogenesis and composition of Exos, and Exos as drug delivery vehicles for cancer immunotherapy are summarized. Meanwhile, their clinical translation and challenges are also discussed. We hope this review will provide a good guidance for Exos as drug delivery vehicles for cancer immunotherapy.

Clickable and smart drug delivery vehicles accelerate the healing of infected diabetic wounds.

In this study, an adipic acid dihydrazide (ADH)/ tannic acid (TA)-grafted hyaluronic acid (HA)-based multifunctional hydrogel was synthesized through a spontaneous amino-yne click reaction and used to promote the improved healing of infected diabetic wounds. This hydrogel exhibited a range of beneficial properties such as tunable gelation time, adjustable mechanical properties, pH-sensitive response characteristics, excellent injectability, the ability to readily adhere to tissue, and ultra-intimate contact capabilities. Following the encapsulation of ultrasmall Ag nanoclusters (AgNCs) and deferoxamine loaded polydopamine/ hollow mesoporous manganese dioxide (PHMD, PDA/H-mMnO2@DFO) nanoparticles, the prepared hydrogel presented with robust antibacterial, anti-inflammatory, and pro-angiogenic properties and a desirable smart drug release profile. In this fabricated platform, PHMD was able to effectively alleviate localized oxidative stress and prolonged oxygen deprivation via the decomposition of endogenous H2O2 to produce O2. Further in vivo assays revealed that this hydrogel was capable of facilitating the healing of infected wounds through the sequential engagement of antibacterial, anti-inflammatory, and pro-angiogenic activities. Together, this synthesized clickable environmentally-responsive hydrogel offers great promise as a tool that can be applied to aid in the healing of chronically infected diabetic wounds and other inflammatory conditions.

Stimuli-Sensitive Linear-Dendritic Block Copolymer-Drug Prodrug as a Nanoplatform for Tumor Combination Therapy.

Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug-delivery vehicles. Herein, an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization is reported. The hydrophobic-dye-based photosensitizer chlorin e6 (Ce6) is employed for encapsulation in the prodrug nanoparticles (NPs) to obtain an LDBCs-based drug-delivery system (LD-DOX/Ce6) that offers a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 is degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggests that LD-DOX/Ce6 with laser irradiation treatment significantly induces apoptosis, DNA damage, and cell cycle arrest. The combination treatment can not only suppress tumor growth, but also significantly reduce tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis, and the hypoxia pathway. LD-DOX/Ce6 displays a synergistic chemo-photodynamic antitumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study demonstrates the potential of the biodegradable and tumor-microenvironment-responsive LDBCs as an intelligent multifunctional drug-delivery vehicle for high-efficiency cancer combination therapy.

A Lipid-Based Droplet Processor for Parallel Chemical Signals.

A key goal of bottom-up synthetic biology is to construct cell- and tissue-like structures. Underpinning cellular life is the ability to process several external chemical signals, often in parallel. Until now, cell- and tissue-like structures have been constructed with no more than one signaling pathway. Many pathways rely on signal transport across membranes using protein nanopores. However, such systems currently suffer from the slow transport of molecules. We have optimized the application of these nanopores to permit fast molecular transport, which has allowed us to construct a processor for parallel chemical signals from the bottom up in a modular fashion. The processor comprises three aqueous droplet compartments connected by lipid bilayers and operates in an aqueous environment. It can receive two chemical signals from the external environment, process them orthogonally, and then produce a distinct output for each signal. It is suitable for both sensing and enzymatic processing of environmental signals, with fluorescence and molecular outputs. In the future, such processors could serve as smart drug delivery vehicles or as modules within synthetic tissues to control their behavior in response to external chemical signals.

Multifunctional biomolecule nanostructures for cancer therapy.

Biomolecule-based nanostructures are inherently multifunctional and harbour diverse biological activities, which can be explored for cancer nanomedicine. The supramolecular properties of biomolecules can be precisely programmed for the design of smart drug delivery vehicles, enabling efficient transport in vivo, targeted drug delivery and combinatorial therapy within a single design. In this Review, we discuss biomolecule-based nanostructures, including polysaccharides, nucleic acids, peptides and proteins, and highlight their enormous design space for multifunctional nanomedicines. We identify key challenges in cancer nanomedicine that can be addressed by biomolecule-based nanostructures and survey the distinct biological activities, programmability and in vivo behaviour of biomolecule-based nanostructures. Finally, we discuss challenges in the rational design, characterization and fabrication of biomolecule-based nanostructures, and identify obstacles that need to be overcome to enable clinical translation.

Droplet Microfluidics for Tumor Drug-Related Studies and Programmable Artificial Cells.

Anticancer drug development is a crucial step toward cancer treatment, that requires realistic predictions of malignant tissue development and sophisticated drug delivery. Tumors often acquire drug resistance and drug efficacy, hence cannot be accurately predicted in 2D tumor cell cultures. On the other hand, 3D cultures, including multicellular tumor spheroids (MCTSs), mimic the in vivo cellular arrangement and provide robust platforms for drug testing when grown in hydrogels with characteristics similar to the living body. Microparticles and liposomes are considered smart drug delivery vehicles, are able to target cancerous tissue, and can release entrapped drugs on demand. Microfluidics serve as a high‐throughput tool for reproducible, flexible, and automated production of droplet‐based microscale constructs, tailored to the desired final application. In this review, it is described how natural hydrogels in combination with droplet microfluidics can generate MCTSs, and the use of microfluidics to produce tumor targeting microparticles and liposomes. One of the highlights of the review documents the use of the bottom‐up construction methodologies of synthetic biology for the formation of artificial cellular assemblies, which may additionally incorporate both target cancer cells and prospective drug candidates, as an integrated “droplet incubator” drug assay platform.

Membrane-cross-linked polymersomes with tumor pH-tunable selective permeability as intelligent nanoreactors and drug delivery vehicles

Stimuli-responsive polymersomes have attracted great attention not only as smart drug delivery vehicles but also as intelligent artificial nanoreactors. Herein, we develop a series of membrane-cross-linked (MCL) polymersomes with cross-linking density-mediated and tumor pH-tunable selective membrane permeability for stimuli-responsive drug delivery and controllable enzymatic reaction. The diblock copolymers consisting of poly(ethylene glycol) (PEG) and copolymerized with methacrylate monomers containing piperidine or coumarin moieties were synthesized and self-assembled into polymersomes that can encapsulate both small molecule doxorubicin hydrochloride (DOX) and large molecule glucose oxidase (GOD). After photo-cross-linking, the optimized cross-linking density and pH-responsive segments endow the polymersomes with superior stability and ultra pH-sensitive selective membranes permeability upon changing pH from 7.4 to 6.5. Drug release and enzymatic reaction are triggered by pH change via the enhanced membrane permeability of the polymersomes loading DOX and GOD. With diffusion of small molecules into or out of the polymersomes including DOX, glucose, and O2, the massively generated hydrogen peroxide (H2O2) under the catalysis of GOD and the released DOX can synergistically kill cancer cells. Thus, the polymersomes with the tumor pH-responsive and cross-linking density-mediated membrane permeability show promising applications as a unique platform for cancer therapy.

Hyaluronic Acid/Polylysine Composites for Local Drug Delivery: A Review

Site specific drug delivery systems (DDS) are usually developed to overcome the side effects of conventional ones (e.g. injections or oral ingestions), creating smart drug delivery vehicles characterized with greater efficiency, safety, predictable therapeutic response as well as controlled and prolonged drug release periods. DDS made of hyaluronic acid (HA) and poly-L-lysine (PLL) are promising candidates in the field of local drug delivery due to their high biocompatibility. Moreover, electrostatic attractions between negatively charged HA and positively charged PLL can be used to fabricate multilayer films, bilayer films and hydrogels, avoiding the application of toxic crosslinking agents. In this review, we report the preparation of HA/PLL composites exploiting their intrinsic properties, as well as developed composite application possibilities as controlled drug delivery systems in bone tissue, central nervous system and gene engineering.

Programmable Release of Berberine Chloride Hydrate from Shape Memory Fibers Prepared from Core-Sheath Wet-Spinning Technology.

Smart wet-spun fibers for highly programmable release of therapeutic drug have been rarely reported. Herein, thermalresponsive composite fibers were successfully prepared by core-sheath wet-spinning technology in present study. They consisted of a model drug of natural antibacterial berberine chloride hydrate (BCH) and a drug carrier of temperature responsive shape memory polyurethane (SMPU). The obtained composite fibers featured with well-controlled microscopic morphologies, exhibiting significantly enhanced thermal stability and superb mechanical properties. In vitro drug release test and corresponding release kinetics study were performed for investigation of BCH's release behavior. Results demonstrated that the release behaviors of BCH from the core-sheath fibers were pH-dependent, influenced by both diffusion from pore channels and the solubility of BCH in the release mediums, and BCH imbedded only in core part showed a longer release period compared with that in both core and sheath parts of the composite fibers. More importantly, the release rate of BCH can be simply controlled by changing the initial shapes of fibers through stretching and fixation of the stretched deformations. Furthermore, the antibacterial durability of the smart composites fibers was demonstrated and tracked according to the growth inhibition against both negative E. coli and positive S. aureus bacteria strains. All these results suggest that the developed composite fibers can be promising candidates as smart drug delivery vehicles for highly adjustable doses of target drugs towards practical applications.

Externally Addressable Smart Drug Delivery Vehicles: Current Technologies and Future Directions

Growing clinical evidence around the value of delivering drugs with pulsatile, user-controlled, or patient-specific kinetics has recently resulted in extensive efforts toward the design of new functional materials that can enable on-demand externally triggered drug release using noninvasive or minimally invasive stimuli such as temperature changes, magnetic fields, light, ultrasound, and/or electric fields. While substantial technical improvements have been made toward achieving longer-term and user-defined release kinetics from such materials (based principally on innovation in materials design and the development of various triggering modalities), clinical translation of such technologies remains in its infancy; specifically, multiple residual challenges exist around the chemical complexity, biological responses, and predictability of externally triggered release vehicles when used in vivo. In this perspective, we aim to outline major recent advances in the development of externally triggered drug deliv...

Nanofabrication based on DNA nanotechnology

Abstract Nanofabrication refers to manufacturing objects with nanometer dimensions. The evolution of DNA nanotechnology has brought new inspirations to this field, owing to the unprecedented programmability of DNA molecules. By combining with other components, DNA nanostructures can template the growth of heterogeneous materials, support delicate plasmonic devices, build smart drug delivery vehicles and detect biomolecular targets. This article focuses on key strategies for DNA-based nanofabrication and highlights recent developments in chemical reactions confined on DNA nanostructures, including metallization, mineralization and polymer coating. We also review applications based on DNA nanofabrication and propose perspective in this field.

Injectable antibacterial conductive hydrogels with dual response to an electric field and pH for localized “smart” drug release

Injectable hydrogels with multistimuli responsiveness to electrical field and pH as a drug delivery system have been rarely reported. Herein, we developed a series of injectable conductive hydrogels as “smart” drug carrier with the properties of electro-responsiveness, pH-sensitivity, and inherent antibacterial activity. The hydrogels were prepared by mixing chitosan-graft-polyaniline (CP) copolymer and oxidized dextran (OD) as a cross-linker. The chemical structures, morphologies, electrochemical property, swelling ratio, conductivity, rheological property, in vitro and in vivo biodegradation, and gelation time of hydrogels were characterized. The pH-responsive behavior was verified by drug release from hydrogels in PBS solutions with different pH values (pH = 7.4 or 5.5) in an in vitro model. As drug carriers with electric-driven release, the release rate of the model drugs amoxicillin and ibuprofen loaded within CP/OD hydrogels dramatically increased when an increase in voltage was applied. Both chitosan and polyaniline with inherent antibacterial properties endowed the hydrogels with excellent antibacterial properties. Furthermore, cytotoxicity tests of the hydrogels using L929 cells confirmed their good cytocompatibility. The in vivo biocompatibility of the hydrogels was verified by H&E staining. Together, all these results suggest that these injectable pH-sensitive conductive hydrogels with antibacterial activity could be ideal candidates as smart drug delivery vehicles for precise doses of medicine to meet practical demand. Statement of SignificanceStimuli-responsive or “smart” hydrogels have attracted great attention in the field of biotechnology and biomedicine, especially on designing novel drug delivery systems. Compared with traditional implantable electronic delivery devices, the injectable hydrogels with electrical stimuli not only are easy to generate and control electrical field but also could avoid frequent invasive surgeries that offer a new avenue for chronic diseases. In addition, designing a drug carrier with pH-sensitive property could release drug efficiently in targeted acid environment, and it could reinforce the precise doses of medicine. Furthermore, caused by opportunistic microorganisms and rapid spread of antibiotic-resistant microbes, infection is still a serious threat for many clinical utilities. To overcome these barriers, we designed a series of injectable antibacterial conductive hydrogels based on chitosan-graft-polyaniline (CP) copolymer and oxidized dextran (OD), and we demonstrated their potential as “smart” delivery vehicles with electro-responsiveness and pH-responsive properties for triggered and localized release of drugs.

Packaging DNA Origami into Viral Protein Cages.

The DNA origami technique is a widely used method to create customized, complex, spatially well-defined two-dimensional (2D) and three-dimensional (3D) DNA nanostructures. These structures have huge potential to serve as smart drug-delivery vehicles and molecular devices in various nanomedical and biotechnological applications. However, so far only little is known about the behavior of these novel structures in living organisms or in cell culture/tissue models. Moreover, enhancing pharmacokinetic bioavailability and transfection properties of such structures still remains a challenge. One intriguing approach to overcome these issues is to coat DNA origami nanostructures with proteins or lipid membranes. Here, we show how cowpea chlorotic mottle virus (CCMV) capsid proteins (CPs) can be used for coating DNA origami nanostructures. We present a method for disassembling native CCMV particles and isolating the pure CP dimers, which can further bind and encapsulate a rectangular DNA origami shape. Owing to the highly programmable nature of DNA origami, packaging of DNA nanostructures into viral protein cages could find imminent uses in enhanced targeting and cellular delivery of various active nano-objects, such as enzymes and drug molecules.

Glutathione responsive polymers and their application in drug delivery systems

Materials which respond to biological cues are the subject of intense research interest due to their possible application in smart drug delivery vehicles.

In situ formation of magnetopolymersomes via electroporation for MRI.

As the development of diagnostic/therapeutic (and combined: theranostic) nanomedicine grows, smart drug-delivery vehicles become ever more critical. Currently therapies consist of drugs tethered to, or encapsulated within nanoparticles or vesicles. There is growing interest in functionalising them with magnetic nanoparticles (MNPs) to target the therapeutics by localising them using magnetic fields. An alternating magnetic field induces remote heating of the particles (hyperthermia) triggering drug release or cell death. Furthermore, MNPs are diagnostic MRI contrast agents. There is considerable interest in MNP embedded vehicles for nanomedicine, but their development is hindered by difficulties producing consistently monodisperse MNPs and their reliable loading into vesicles. Furthermore, it is highly advantageous to "trigger" MNP production and to tune the MNP's size and magnetic response. Here we present the first example of a tuneable, switchable magnetic delivery vehicle for nanomedical application. These are comprised of robust, tailored polymer vesicles (polymersomes) embedded with superparamagnetic magnetite MNPs (magnetopolymersomes) which show good MRI contrast (R2* = 148.8 s−1) and have a vacant core for loading of therapeutics. Critically, the magnetopolymersomes are produced by a pioneering nanoreactor method whereby electroporation triggers the in situ formation of MNPs within the vesicle membrane, offering a switchable, tuneable magnetic responsive theranostic delivery vehicle.

Stimuli-responsive supramolecular micellar assemblies of cetylpyridinium chloride with cucurbit[5/7]urils

This article demonstrates, for the first time, construction of novel cucurbituril (CB)-adorned supramolecular micellar assemblies of a cationic surfactant, cetylpyridinium chloride (CPC), through noncovalent host-guest interactions. The distinct cation receptor features and cavity dimensions of the CB5 and CB7 homologues assert that the macrocyclic hosts remain complexed with the CPC monomers and take part in the micelle formation, a unique observation in contrast to that of the classical host, β-cyclodextrin. The cooperative contributions of the CB macrocycles in the micelle formation have been documented by the photochemical, surface tension, conductivity, DOSY NMR, and SANS measurements. The contrasting downward and upward shifts in the cmc of the CPC surfactant, respectively, with CB5 and CB7 hosts provide a unique opportunity for the controlled tuning of the micellization region for CPC from 0.57 to 1.6 mM, by using a combination of the macrocyclic hosts. The article also establishes the reversible response of these soft supramolecular micellar structures to thermal-stimuli, which projects their utility for on-demand smart drug-delivery vehicles.

PUA/PSS multilayer coated CaCO3 microparticles as smart drug delivery vehicles

Hybrid CaCO3 microparticles coated by sodium poly(styrene sulfonate) (PSS) and aliphatic poly(urethane-amine) (PUA) were developed as thermal-/pH-responsive drug delivery vehicles via LbL self-assembly technique. The DOX release from the CaCO3 microparticles was higher than 60% within 36h, whereas the value of PUA/PSS-coated microparticles was only 20%. The results demonstrated that the PUA/PSS multilayer coating could reduce the drug release rate and significantly assuage the initial burst release of DOX. In addition, the drug release of the hybrid microparticles was found to be thermal-/pH-dual responsive. More interestingly, more than 90% of DOX was released in 36h at pH2.1 and 55°C owing to the combined action of the dissolution of the CaCO3 core and the shrinkage of aliphatic PUA.