Multifunctional Drug Delivery Vehicles Research Articles

Actively Targeting Redox-Responsive Multifunctional Micelles for Synergistic Chemotherapy of Cancer.

Stimuli-responsive polymeric micelles decorated with cancer biomarkers represent an optimal choice for drug delivery applications due to their ability to enhance therapeutic efficacy while mitigating adverse side effects. Accordingly, we synthesized a digoxin-modified novel multifunctional redox-responsive disulfide-linked poly(ethylene glycol-b-poly(lactic-co-glycolic acid) copolymer (Bi(Dig-PEG-PLGA)-S2) for the targeted and controlled release of doxorubicin (DOX) in cancer cells. Within the micellar aggregate, the disulfide bond confers redox responsiveness, while the presence of the digoxin moiety acts as a targeting agent and chemosensitizer for DOX. Upon self-assembly in aqueous solution, Bi(Dig-PEG-PLGA)-S2 formed uniformly distributed spherical micelles with a hydrodynamic diameter (D h ) of 58.36 ± 0.78 nm and a zeta potential of -24.71 ± 1.01 mV. The micelles exhibited desirable serum and colloidal stability with a substantial drug loading capacity (DLC) of 6.26% and an encapsulation efficiency (EE) of 83.23%. In addition, the release of DOX demonstrated the redox-responsive behavior of the micelles, with approximately 89.41 ± 6.09 and 79.64 ± 6.68% of DOX diffusing from DOX@Bi(Dig-PEG-PLGA)-S2 in the presence of 10 mM GSH and 0.1 mM H2O2, respectively, over 96 h. Therefore, in HeLa cell lines, DOX@Bi(Dig-PEG-PLGA)-S2 showed enhanced intracellular accumulation and subsequent apoptotic effects, attributed to the targeting ability and chemosensitization potential of digoxin. Hence, these findings underscore the promising characteristics of Bi(Dig-PEG-PLGA)-S2 as a multifunctional drug delivery vehicle for cancer treatment.

Hollow Nanooxidase Enhanced Phototherapy Against Solid Tumors.

Although phototherapy has attracted extensive attention in antitumor field in recent years, its therapeutic effect is usually unsatisfactory because of the complexity and variability of the tumor microenvironment (TME). Herein, we report novel CoSn(OH)6@CoOOH hollow carriers with oxidase properties that can enhance phototherapy. Hollow CoSn(OH)6@CoOOH nanocubes (NCs) with a particle size of ∼160 nm were synthesized via a two-step process of coprecipitation and etching. These NCs can react with O2 to generate singlet oxygen without hydrogen peroxide and consume glutathione, and their hollow structure can be utilized to carry drug molecules. After loading indocyanine green (ICG) and 1,2-bis(2-(4,5-dihydro-1H-imidazol-2-yl)propan-2-yl) diazene dihydrochloride (AIPH), the resulting nanosystem (HCIA) exhibited enhanced phototherapy effects through the catalytic activity of oxidase, production of alkyl radicals, and consumption of glutathione. Cell and mouse experiments showed that HCIA combined with near-infrared laser irradiation significantly inhibited the growth of 4T1 tumors. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that PI3K-Akt and MAPK signaling pathways were highly relevant to this therapeutic system. Such hollow NCs with oxidase activity have considerable potential for the design of multifunctional drug delivery vehicles for tumor therapy.

PH-responsive Mannose-modified ferrocene Metal-Organic frameworks with rare earth for Tumor-targeted synchronous Chemo/Chemodynamic therapy

The combination of chemodynamic therapy (CDT) and chemotherapy is a promising strategy to achieve enhanced anticancer effects. Metal-organic frameworks (MOFs), as multifunctional drug delivery vehicles, have received extensive attention in the biomedical field. Carbohydrate has excellent biocompatibility and targeting ability, which can be used as a targeting ligand due to a specific recognition with glycoprotein receptors that overexpress on cancer cell membranes. Herein, the pH-responsive mannose-modified ferrocene MOFs with rare earth metal were synthesized via coordination-driven self-assembly of 1,1′-Ferrocenedicarboxylic acid and ytterbium chloride. Subsequently, DOX@Fc-MOFs-Mann nanoparticles (NPs) were obtained by loading doxorubicin (DOX) and modifying mannose (Mann), where DOX@Fc-MOFs-Mann NPs were able to precisely target HepG2 cells via mannose receptor and slowly decompose in the acidic environment of tumor to release ferrocene, DOX, and Yb3+. Fe2+ in ferrocene effectively activated Fenton reaction to produce high levels of reactive oxygen species (ROS) for irreversible induction of cell apoptosis or necroptosis. Combined with the chemotherapy (CT) ability of DOX, Yb3+ further induced cell death through its own toxicity to successfully achieved the rare earth metal synergistic CDT and CT combination therapy. This synergistic CDT and CT strategy not only opens up new horizons for rare earth metals in biomedical applications but also provides new inspiration into the construction of glycosyl-modified MOFs.

Targeted Drug Delivery Using Graphene Quantum Dots: Approaches, Limitations and Future Perspectives.

This mini-review centers on the framework of GQDs to function as a drug delivery system (DDS), that is both target-specific and efficient. Researchers exploit GQDs for the unique pharmacokinetic properties they possess, that make them an ideal multi-functional drug delivery vehicle. We cannot enhance the therapeutic efficacy of drugs merely by focusing on drug delivery mechanisms. The conjugation of the drug with GQD allows more flexibility in controlling the kinetics and circulation time of drug in the body, the characteristic which is highly regarded in modern therapeutics. GQDs possess properties such as enhanced water solubility, lower cytotoxicity, tunable photoluminescence properties, larger specific surface area, large surface to volume ratio, and ease of surface functionalization, which make them highly effective drug molecular loading cores. Also, the review addresses the various methods of synthesis of GQDs, that include top-down and bottom-up approaches; top-down modes being more feasible and advantageous. The review touches on the various modes of GQD drug-loaded delivery- release systems (DDRS). The review also addresses the limitations associated with drug delivery using GQDs. Insufficient information about the translocation of GQDs limits their application in biomedical field and make it difficult for GQD-based carriers to pass clinical trials. Through this review, we look to summarize the important concepts of drug delivery using GQDs, and their biomedical applications and scope in nanomedicine in foreseeable future

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.

Clickable biocompatible brush polymers as a versatile platform toward development of multifunctional drug delivery vehicles

Clickable polymers have been gaining attention in the biomedical field because of their ability to carry various functional moieties, including drugs, imaging agents, and cell targeting ligands made by highly efficient click-reaction chemistry. In particular, brush polymers formed by the conjugation of polyethylene glycol (PEG) to clickable polymers are very promising for developing advanced drug delivery systems because of the enhanced water-solubility, biocompatibility, and so-called “stealth” capabilities. Recently, we developed and patented a clickable brush polymer PEAMO-g-PEG by the ring-opening polymerization of an alkyne-substituted oxetane monomer following the conjugation of PEG via Cu(I)-catalyzed azide-alkyne cycloaddition click reaction. The clickable brush polymer has excellent water solubility and biocompatibility as well as flexibility for coupling therapeutic drugs and other multi-modality entities. A novel chronotherapeutic polymeric drug for brain cancer therapy was then developed using the brush polymer platform as an example of this technology. The anticancer drug camptothecin primarily targeting proliferating cells was coupled to the PEAMO polymer and delivered to mouse brain via intra-tumoral delivery resulting in significantly improved survival. In this perspective, we review and discuss this new drug delivery platform with an in-depth discussion of its structural features, properties, and therapeutic applications. Future directions and possible utilization of this platform for novel formulations are also elaborated upon.

ERK-Peptide-Inhibitor-Modified Ferritin Enhanced the Therapeutic Effects of Paclitaxel in Cancer Cells and Spheroids.

Rational design of a drug delivery system with enhanced therapeutic potency is critical for efficient tumor chemotherapy. Many protein-based drug delivery platforms have been designed to deliver drugs to target sites and improve the therapeutic efficacy. In this study, paclitaxel (PTX) molecules were encapsulated within an apoferritin nanocage-based drug delivery system with the modification of an extracellular-signal-regulated kinase (ERK) peptide inhibitor at the C-terminus of ferritin (HERK). Apoferritin is an endogenous nano-sized spherical protein which has the ability to specially bind to a majority of tumor cells via interacting with transferrin receptor 1. The ERK peptide inhibitor is a peptide which can disrupt the interaction of MEK with ERK in the mitogen-activated protein kinase/ERK pathway. By combining the targeted delivery effect of ferritin and the inhibitory effect of the ERK peptide inhibitor, the newly fabricated ferritin carrier nanoparticle HERK could still be taken up by tumor cells, and it displayed higher cell cytotoxicity than the parent ferritin. After loading with PTX, HERK-PTX displayed a favorable anticancer effect in human breast cancer cells MDA-MB-231 and lung carcinoma cells A549. The remarkable inhibitory effect on MDA-MB-231 tumor spheroids was also identified. These results indicated that the constructed HERK nanocarrier is a promising multi-functional drug delivery vehicle to enhance the therapeutic effect of drugs in cancer therapy.

Self-assembled dipeptide nanospheres as single component based delivery vehicle for ampicillin and doxorubicin

Effective delivery of therapeutic agents encounters many challenges such as uncontrolled drug release, low bioavailability of drugs, degradation of drugs in the intestinal transit and non-biocompatibility of the delivery vehicle. Thus, in the quest for advance drug delivery system, self-assembled dipeptide (Fmoc-L-Trp-L-Phe-OCH3) nanospheres (SPNS) were generated in aqueous medium with size ranging between 100 and 400 nm. The SPNS were examined for the presence of hydrophobic and hydrophilic domains which was followed by drug loading analysis (ampicillin and doxorubicin) into SPNS using HPLC. Further, SPNS demonstrated pH triggered morphological alterations leading to controlled release of loaded therapeutics. Additionally, SPNS exhibited low cytotoxicity and exceptional stability against enzymatic degradation. The system was further analyzed for in vitro cellular internalization of therapeutics. Thus, outcome of this analysis indicated that SPNS acts as single component, multifunctional drug delivery vehicle by addressing critical issues such as effective drug loading, pH responsive controlled release, biocompatibility, and stability against enzymatic degradation.

Copper Nanocluster-Doped Luminescent Hydroxyapatite Nanoparticles for Antibacterial and Antibiofilm Applications.

Novel strategies in the field of nanotechnology for the development of suitable multifunctional drug delivery vehicles have been pursued with promising upshots. Luminescent copper nanocluster-doped hydroxyapatite nanoparticles (HAP NPs) were synthesized and applied for the delivery of antibacterial drug kanamycin. The negatively charged doped HAP NPs could electrostatically interact with the positively charged kanamycin. The kanamycin-loaded doped HAP NPs showed pronounced activity in the case of Gram-negative bacteria compared to that in Gram-positive bacteria. Upon interaction with the bacteria, kanamycin could probably generate harmful agents such as hydroxyl radical that leads to bacterial cell damage. After being incorporated with copper nanoclusters (Cu NCs), the doped HAP NPs were applied for the bioimaging of bacterial cells. The biocompatibility of doped HAP NPs was also studied in HeLa cells. As compared to copper nanoclusters, the doped HAP NPs showed excellent biocompatibility even at higher concentrations of copper. The kanamycin-loaded doped HAP NPs were further applied toward Pseudomonas aeruginosa biofilm eradication. Thus, the as-synthesized copper nanocluster-doped HAP NPs were applied as nanocarriers for antibiotic drug delivery, bioimaging, and antibiofilm applications.

Core-shell noble-metal@zeolitic-imidazolate-framework nanocarriers with high cancer treatment efficiency in vitro.

Core-shell Au@zeolitic-imidazolate-framework-8 (ZIF-8) nanostructures are reported as a nanocarrier with both a high drug payload and high cancer treatment efficiency in vitro. Impressively, when used as multifunctional drug delivery vehicles, such core-shell Au@ZIF-8 nanostructures not only exhibit light- and pH-controlled drug release properties, but also provide two synergetic therapeutic modes for cancer treatment, resulting in 98% cell-killing activity after 30 min light irradiation followed by 24 h incubation even though HeLa cells are treated only by Au@ZIF-8 nanostructures loaded with 10 μM doxorubicin hydrochloride. All these results demonstrate the promising applications of this type of core-shell nanostructure in biomedical fields.

Side effects-avoided theranostics achieved by biodegradable magnetic silica-sealed mesoporous polymer-drug with ultralow leakage

The development of drug delivery vehicles without side effects to normal physiological tissues represents an urgent challenge for safety and effective nanomedicine. Herein, a multifunctional drug delivery vehicle with ultralow leakage was presented, containing an ordered mesoporous resin as a polymer core and homogeneous Fe nanodots-doped silica as the biodegradable shell. In this core-shell structure, the Fe-doped silica shell acts as a compact inorganic cap to seal doxorubicin into the mesoporous polymer cores, but also serves as a superparamagnetic agent for magnetic targeting and magnetic resonance imaging (MRI). Importantly, the caps can be opened via Fe extraction-induced degradation to slowly release the loaded drug under the acidic tumor environment, while achieving ultralow drug leakage under normal in vivo blood circulation (physiological environment). This unique core-shell nanospheres with ultralow drug leakage were demonstrated to achieve side effects-avoided targeting chemotherapy guided by MRI with improved therapeutic outcomes, which showing great potential for efficient cancer theranostics.

Ultrasound-Triggered Destruction of Folate-Functionalized Mesoporous Silica Nanoparticle-Loaded Microbubble for Targeted Tumor Therapy.

A multifunctional drug delivery vehicle, which combines the active targeted mesoporous silica nanoparticle (MSN) and microbubble (MB) drug delivery system, is proposed and fabricated. The resulting delivery vehicle integrates the merits of high drug loading capacity, multitargeting, and ultrasound-guided releasing. Folate (FA), which serves as an active ligand, is modified to the surface of MSN (MSN-FA) to enhance cell membrane translocation. MSN-FA is loaded with tanshinone IIA (TAN), then encapsulated in a microbubble (denoted as MSN-FA-TAN-MB) for more precise tumor targeting. The conjunction between FA and MSN is confirmed by fourier transform infrared spectroscopy (FTIR). The characteristics and morphology of MSN-FA-TAN-MB are investigated by confocal microscopy and transmission electron microscopy. In vitro cytotoxicity and cellular uptake studies of MSN-FA-TAN-MB are conducted on A549 and HeLa tumor cells. FA-facilitated MSN-FA-TAN uptake is shown by HeLa cells that overexpress FA receptors via a FA-receptor-mediated endocytosis mechanism. The ultrasound response property of MSN-FA-TAN-MB is also verified. MSN-FA-TAN-MB shows significant antitumor efficacy in vivo with the assistance of FA, MB, and an external ultrasound irradiation. Thus, this multifunctional vehicle may provide a novel strategy for tumor targeting and imaging in tumor therapy.

Multistage vector (MSV) therapeutics

One of the greatest challenges in the field of medicine is obtaining controlled distribution of systemically administered therapeutic agents within the body. Indeed, biological barriers such as physical compartmentalization, pressure gradients, and excretion pathways adversely affect localized delivery of drugs to pathological tissue. The diverse nature of these barriers requires the use of multifunctional drug delivery vehicles that can overcome a wide range of sequential obstacles. In this review, we explore the role of multifunctionality in nanomedicine by primarily focusing on multistage vectors (MSVs). The MSV is an example of a promising therapeutic platform that incorporates several components, including a microparticle, nanoparticles, and small molecules. In particular, these components are activated in a sequential manner in order to successively address transport barriers.

Emerging therapeutic delivery capabilities and challenges utilizing enzyme/protein packaged bacterial vesicles.

Nanoparticle-based therapeutics are poised to play a critical role in treating disease. These complex multifunctional drug delivery vehicles provide for the passive and active targeted delivery of numerous small molecule, peptide and protein-derived pharmaceuticals. This article will first discuss some of the current state of the art nanoparticle classes (dendrimers, lipid-based, polymeric and inorganic), highlighting benefits/drawbacks associated with their implementation. We will then discuss an emerging class of nanoparticle therapeutics, bacterial outer membrane vesicles, that can provide many of the nanoparticle benefits while simplifying assembly. Through molecular biology techniques; outer membrane vesicle hijacking potentially allows for stringent control over nanoparticle production allowing for targeted protein packaged nanoparticles to be fully synthesized by bacteria.

Gold nanoparticle surface functionalization: a necessary requirement in the development of novel nanotherapeutics.

With several gold nanoparticle-based therapies currently undergoing clinical trials, these treatments may soon be in the clinic as novel anticancer agents. Gold nanoparticles are the subject of a wide ranging international research effort with preclinical studies underway for multiple applications including photoablation, diagnostic imaging, radiosensitization and multifunctional drug-delivery vehicles. These applications require an increasingly complex level of surface modification in order to achieve efficacy and limit off-target toxicity. This review will discuss the main obstacles in relation to surface functionalization and the chemical approaches commonly utilized. Finally, we review a range of recent preclinical studies that aim to advance gold nanoparticle treatments toward the clinic.

A new poly(propylene imine) dendron as potential convenient building-block in the construction of multifunctional systems

The synthesis of a novel third generation poly(propylene imine) dendron (PPI dendron) is described herein. The dendritic focal point was attached to a tetraethylene glycol spacer that was terminated with a Tmob-protected thiol in order to both avoid any side-reaction during functionalization of dendritic branches as well as enable convenient integration of the dendron into diverse complex systems. The protonation of the final PPI dendron at pH 4–5 is predicted to induce lysosomal degradation through the proton-sponge effect, and therefore enable cytosolic release. These features make the prepared dendron a very convenient building-block for use in the construction of larger systems, such as multifunctional drug delivery vehicles.

Nanomedicine: evolutionary and revolutionary developments in the treatment of certain inflammatory diseases

Nanomedicine, although in a nascent stage of development at present, is already a reality. Several pharmaceutical products using this modern technology are already on the market. Nanotechnology offers many potential benefits to medical research. Nanoparticle-based drug carriers can increase the efficacy and safety of drugs by enhancing capacity, improving solubility, combining multiple drugs, protecting against metabolism, and controlling release. Nanoparticles can also form the basis of multifunctional drug delivery vehicles by combining targeting, imaging, and therapeutic moieties. Multifunctional nanoparticles have tremendous potential to treat human diseases. The use of non-viral carriers (nanoparticles) can also improve the cellular/nuclear uptake of corresponding nucleotides. Preclinical characterization of nanoparticles intended for medical applications is complicated-due to the variety of materials used, their unique surface properties, and multifunctional nature. It is hard to predict what precise course nanomedicine will take in years to come. It is, however, very likely that this relatively young research area will become a driving force behind a vast revolution in medical treatment.

SERS-active gold lace nanoshells with built-in hotspots.

Development of multifunctional drug delivery vehicles with therapeutic and imaging capabilities as well as in situ methods of monitoring of intracellular processes will greatly benefit from a simple method of preparation of plasmonic Au structures with nanometer scale gaps between sharp metallic elements where the so-called SERS hot spots can be formed. Here the synthesis of gold lace capsules with average diameters ca. 100 nm made of a network of metallic branches 3-5 nm wide and separated by 1-3 nm gaps is reported. Biocompatible amphiphilic polyurethanes (PUs) were used as template for these particles. The unusual topology of the produced gold lace shells somewhat reminiscent of Fabergé eggs is likely to reflect the network of hydrophobic and hydrophilic domains of PU globules. The gold lace develops from initial open weblike structures by gradual enveloping the PU template. The diameter of gold lace shell is determined by the size of PUs in water and can be adjusted by the molecular mass of PUs. The close proximity between branches makes them excellent supports for surface-enhanced Raman spectroscopy (SERS), which was demonstrated using 1-naphthalenethiol upon excitation with photons with different wavelengths. The loading and releasing of pyrene as a model of hydrophobic drugs and the use of SERS to monitor it were demonstrated.

Fluorocarbon nanoparticles as multifunctional drug delivery vehicles

The history and current status of fluorocarbon nanoparticles in biomedicine is briefly reviewed. The deficiencies of current fluorocarbon nanoparticle formulations are highlighted. Strategies to remedy such deficiencies and to functionalize fluorocarbon nanoparticles are presented. Potential applications of fluorocarbon nanoparticles as multifunctional drug delivery vehicles are discussed. The strength of fluorocarbon nanoparticles as drug delivery vehicles is that they integrate drug delivery with non-invasive MR imaging so that the biodistribution of the pharmaceutical entity (drug+delivery vehicle) can be monitored in real time. This, in turn, permits the physician to adjust treatment plan for each patient based on his/her actual response to the ongoing treatment.

Design strategies to improve soluble macromolecular delivery constructs

Macromolecular therapeutics provide numerous benefits for the delivery of cytotoxic or poorly soluble drugs in vivo. However, these constructs often encounter barriers for drug delivery on both the systemic and subcellular level. Many soluble polymer carriers have been designed to surmount specific physiological barriers individually, but less work has been dedicated to designing an all-encompassing construct that addresses multiple therapeutic barriers at once. Incorporation of multiple agents already individually known to increase effectiveness into one carrier could further improve current drug delivery technology. Recent developments in subcellular delivery of therapeutic agents in soluble macromolecular carriers are discussed in the context of the future possibility for the design of an all-encompassing soluble multi-functional drug delivery vehicle.