Nanoscale Drug Delivery Vehicles Research Articles

Porous silicon nanotube bundles as nanocarriers for small interfering RNA delivery

AbstractWe describe in this work an evaluation of bundles of hollow mesoporous silicon nanotubes to facilitate transfection of HeLa cells using small interfering RNA designed to knock down expression of Enhanced Green Fluorescent Protein (eGFP). These experiments entail direct visualization of the nanotube bundles associated with the cells using both scanning electron microscopy (SEM) and confocal fluorescence imaging. These nanotube bundles are generated by surface modification of nanotube arrays with aminopropyl‐triethoxysilane (APTES), followed by their ultrasonication in water, to create the amine‐terminated structures capable of electrostatic conjugation of siRNA at an efficiency of 23%–50% (depending on initial siRNA concentration). Delivery and transfection to HeLa cells are verified by quantification of fluorescence imaging; an average percent knockdown of ∼50% eGFP is achieved. As nanoscale drug delivery vehicles are expected to be resorbed in clinical use, we also assess SiNT bundle degradation during the above in vitro timescale using scanning and transmission electron (TEM) microscopies. We conclude with a brief discussion of challenges and opportunities in future experiments involving this platform.

Different leukocyte subsets are targeted by systemic and locoregional administration despite conserved nanomaterial characteristics optimal for lymph node delivery.

Lymph nodes (LNs) house a large proportion of the body's leukocytes. Accordingly, engineered nanomaterials are increasingly developed to direct therapeutics to LNs to enhance their efficacy. Yet while lymphatic delivery of nanomaterials to LNs upon locoregional injection has been extensively evaluated, nanomaterial delivery to LN-localized leukocytes after intravenous administration has not been systematically explored nor benchmarked. In this work, a panel of inert, fluorescent nanoscale tracers and drug delivery vehicles were utilized to interrogate intravenous versus locoregionally administered nanomaterial access to LNs and leukocyte subsets therein. Hydrodynamic size and material effects on LN accumulation extents were similar between intravenous versus intradermal injection routes. Nanomaterial distribution to various LN leukocyte subsets differed substantially with injection route, however, in a manner not proportional to total LN accumulation. While intravenously administered nanomaterials accumulated in LNs lowly compared to systemic tissues, in sharp contrast to locoregional delivery, they exhibited size-dependent but material-independent access to immune cells within the LN parenchyma, which are not easily accessed with locoregional delivery.

Current advances in non‐viral gene delivery systems: Liposomes versus extracellular vesicles

AbstractIn the past decade, nucleic acid‐based drugs have emerged as an extremely promising approach for silencing specific disease‐related genes and targeting undruggable ones. However, most nucleic acid drug therapies have not advanced to clinical practice due to their poor stability against serum enzyme degradation and cytotoxicity. Nanoscale drug delivery vehicles show potential to improve efficacy of nucleic acid drugs via targeted delivery to disease‐causing genes, yet, safe and efficient nanocarriers remain elusive. Lipid‐based nanoparticles such as liposomes (LSs) and extracellular vesicles (EVs) are among the most extensively exploited nanoscale vehicles for therapeutic cargo delivery. LS‐based nucleic acid therapies have been used for several years, with many already adopted to the clinic. More recently, EVs hold considerable promise as nucleic acid delivery vehicles due to their high biocompatibility, low immunogenicity, and the inherent abilities to interact with target cells and cross biological barriers. Moreover, a novel LS/EV hybrid gene delivery system has been engineered to preserve the benefits of both systems and generate an advanced drug delivery system. The current review focuses specifically on LS‐ and EV‐based gene therapies and provides the key advantages and shortcomings of these systems with particular emphasis on their potential use as therapeutic vectors.

Sevelamer arsenite nanoparticle as a Pi-responsive drug carrier and embolic agent for chemoembolization

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50–300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO’s anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

Mechanistic Understanding From Molecular Dynamics Simulation in Pharmaceutical Research 1: Drug Delivery.

In this review, we outline the growing role that molecular dynamics simulation is able to play as a design tool in drug delivery. We cover both the pharmaceutical and computational backgrounds, in a pedagogical fashion, as this review is designed to be equally accessible to pharmaceutical researchers interested in what this new computational tool is capable of and experts in molecular modeling who wish to pursue pharmaceutical applications as a context for their research. The field has become too broad for us to concisely describe all work that has been carried out; many comprehensive reviews on subtopics of this area are cited. We discuss the insight molecular dynamics modeling has provided in dissolution and solubility, however, the majority of the discussion is focused on nanomedicine: the development of nanoscale drug delivery vehicles. Here we focus on three areas where molecular dynamics modeling has had a particularly strong impact: (1) behavior in the bloodstream and protective polymer corona, (2) Drug loading and controlled release, and (3) Nanoparticle interaction with both model and biological membranes. We conclude with some thoughts on the role that molecular dynamics simulation can grow to play in the development of new drug delivery systems.

Tubulin Double Helix: Lateral and Longitudinal Curvature Changes of Tubulin Protofilament.

By virtue of their native structures, tubulin dimers are protein building blocks that are naturally preprogrammed to assemble into microtubules (MTs), which are cytoskeletal polymers. Here, polycation-directed (i.e., electrostatically tunable) assembly of tubulins is demonstrated by conformational changes to the tubulin protofilament in longitudinal and lateral directions, creating tubulin double helices and various tubular architectures. Synchrotron small-angle X-ray scattering and transmission electron microscopy reveal a remarkable range of nanoscale assembly structures: single- and double-layered double-helix tubulin tubules. The phase transitions from MTs to the new assemblies are dependent on the size and concentration of polycations. Two characteristic scales that determine the number of observed phases are the size of polycation compared to the size of tubulin (≈4nm) and to MT diameter (≈25nm). This work suggests the feasibility of using polycations that have scissor- and glue-like properties to achieve "programmable breakdown" of protein nanotubes, tearing MTs into double-stranded tubulins and building up previously undiscovered nanostructures. Importantly, a new role of tubulins is defined as 2D shape-controllable building blocks for supramolecular architectures. These findings provide insight into the design of protein-based functional materials, for example, as metallization templates for nanoscale electronic devices, molecular screws, and drug delivery vehicles.

Doxorubicin-loading core-shell pectin nanocell: A novel nanovehicle for anticancer agent delivery with multidrug resistance reversal.

Tumor is a prevalent great threat to public health worldwide and multidrug resistance (MDR) of tumor is a leading cause of chemotherapy failure. Nanomedicine has shown prospects in overcoming the problem. Doxorubicin (DOX), a broad-spectrum anticancer drug, showed limited efficacy due to MDR. Herein, a doxorubicin containing pectin nanocell (DOX-PEC-NC) of core-shell structure, a pectin nanoparticle encapsulated with liposome-like membrane was developed. The DOX-PEC-NC, spheroid in shape and sized around 150 nm, exerted better sustained release behavior than doxorubicin loading pectin nanoparticle (DOX-PEC-NP) or liposome (DOX-LIP). In vitro anticancer study showed marked accumulation of doxorubicin in different tumor cells as well as reversal of MDR in HepG2/ADR cells and MCF-7/ADR cells caused by treatment of DOX-PEC-NC. In H22 tumor-bearing mice, DOX-PEC-NC showed higher anticancer efficacy and lower toxicity than doxorubicin. DOX-PEC-NC can improve anticancer activity and reduce side effect of doxorubicin due to increased intracellular accumulation and reversal of MDR in tumor cells, which may be a promising nanoscale drug delivery vehicle for chemotherapeutic agents.

Clinical and therapeutic efficacy of biodegradable nanostructures in experimental infections

One of the main promising directions in the development of pharmacology is the development of selective drugs and effective approaches to their production using nanoscale drug delivery vehicles. Providing the necessary therapeutic concentration of drugs in target cells is not an easy task. To solve it, a specific drug carrier is required. The most promising is the use of biodegradable delivery systems, due to the lack of the need to use expensive equipment, and it is also possible to synthesize them in production volumes. The need to develop systems for the controlled delivery of drugs, especially antibacterial drugs, is due to their clear advantage over antibiotics in standardized dosage forms. Increasingly, in poultry industry, high mortality rates of chickens began to be observed in the acute form of enterotoxemia due to Clostridium perfringens and its associations with another microflora. The aim of this paper is to study the therapeutic efficacy of a free and included in biodegradable system antibacterial drug (cefotaxime) for bacterial infections in birds. There were formed 3 experimental and 1 control group of broiler chickens of the cross Cobb-500 daily age of 15 animals each. At the age of 10 days, the birds of group 1-3 were orally infected with virulent diurnal cultures of microorganisms: Clostridium perfringens. During the experiment, daily monitoring of the general condition and behavior of the birds, consumption of feed and water was carried out, the clinical status of the sick birds, the time of onset of positive dynamics and the time of recovery were evaluated. After completing the course of therapy, monitoring of the state of the birds continued for 7 days. After completion of the experiment, bacteriological examination showed that the use of cefotaxime at a dose of 10 mg/kg for 7 days does not eradicate Clostridium perfringens, while the use of cefotaxime based on chitosan and cefotaxime based on exosomes at a dose of 10 mg/kg provides 100% therapeutic efficiency.

Polyelectrolyte Complexation: Entropy, Medicine, and the Beginning of Life

Polymeric materials, which include plastics, fabrics and the vast majority of biological substances, are abundant in modern society. On the molecular scale, these materials are built from the interconnection of similar chemical subunits to form chainlike macromolecules. The medical, electrochemical, synthetic and materials science communities have increasingly turned their attention to polyelectrolytes, a subset of polymers with electric charge, in part because of their ability to spontaneously and reversibly phase-separate (complex) in aqueous solution. This entropic and electrostatic separation can yield well-defined nanoparticles, dynamic gels and other useful materials. These materials are called polyelectrolyte complexes (PECs) and have formed the basis of complex-core micelle technologies that show promise as nanoscale drug-delivery vehicles for cancer treatment, and which have long been suspected to play a role in the chemical origin of life. This article describes the thermodynamics underlying polyelectrolyte complexation, and then illustrates the application of PECs in medicine and their possible role in the beginning of life, interconnecting these far-flung domains through their reliance on the spontaneous organisation of nanoscale space by chemical activity, the singular physical process of electrolyte complexation.

Study of the physicochemical properties of exosome dispersions obtained by ultrafiltration

The article presents the results of studying the physicochemical properties of exosome preparations obtained by ultrafiltration, which indicate a high degree of the composition and properties dependence of the obtained product on the material of the filters used. Quantitative determination of proteins and nucleic acids in exosome samples using UPN-50 filters allows us to conclude that the content of the main impurity compounds in the preparation is significantly reduced compared to dispersions obtained using filters with pore sizes of 220 and 450 nm. Analysis of flow cytometry data made it possible to demonstrate that when using the UPN-50 filter, an increase in the contribution to the dispersion of all types of fractions of non-exosomal size was observed, the appearance of which can result from fraction destruction associated with pore size or filter material properties. drying of the dispersion was observed in the studied exosome samples. Fraction sizes ranged from 40 to 450 nm (an average of about 200 nm). Exosomes from the entire variety of membrane vesicles are fractions that have the most suitable characteristics that allow them to be used as a nanoscale drug delivery vehicle while ensuring the necessary quality control of the drug at the sample preparation stage.

Fructose-Enhanced Antimicrobial Activity of Silver Nanoparticle-Embedded Polymersome Nanocarriers.

In recent years, an increasing body of research has indicated that the antimicrobial activity of certain antibiotic drugs can be enhanced by the addition of specific metabolites. This study aimed to incorporate these findings into polymersomes (novel polymer-based nanoscale drug delivery vehicles) which can be loaded with various therapeutic molecules and nanoparticles. Polymersome technology has shown promising results in treating antibiotic-resistant infections by co-encapsulating the antibiotic methicillin with silver nanoparticles. Here, silver nanoparticle-embedded polymersomes (AgPs) were synthesized in a similar fashion with gentamicin replacing methicillin as the antibiotic agent and supplemented with fructose to promote efficacy. Two clinically-isolated strains of methicillin-resistant Staphylococcus aureus (MRSA) (ATCC #43300 and ATCC #25923) were cultured and treated with the new AgP formulations, with the former strain being susceptible to gentamicin and the latter strain being resistant to gentamicin. The treatment of the non-resistant strain yielded promising results with the polymersomes without fructose supplementation inducing a maximal growth rate reduction of up to 40% and an increase in lag time of up to 141% relative to the untreated control. Impressively, the fructose-loaded polymersomes completely eliminated the bacterial growth over the observed time period at the higher doses and outperformed the no-fructose treatment at all concentrations. However, despite significantly reducing bacterial growth, the treatment of the gentamicin-resistant strain did not seem to be enhanced by the addition of fructose. Lastly, the present study demonstrated that the presence of fructose in the polymersomes seemed to slightly ameliorate the cytotoxic effect of the treatment on human dermal fibroblasts (a model mammalian cell). In addition to developing and testing a new polymersome formulation with fructose resulting in increased efficacy, the results of this study also demonstrated the variability inherent to developing novel antimicrobial treatments for different bacterial strains.

Self-assembly/disassembly hysteresis of nanoparticles composed of marginally soluble, short elastin-like polypeptides

BackgroundElastin-like polypeptides (ELPs) are a fascinating biomaterial that has undergone copious development for a variety of therapeutic applications including as a nanoscale drug delivery vehicle. A comprehensive understanding of ELP self-assembly is lacking and this knowledge gap impedes the advancement of ELP-based biomaterials into the clinical realm. The systematic examination of leucine-containing ELPs endeavors to expand existing knowledge about fundamental assembly–disassembly behaviours.ResultsIt was observed that these marginally soluble, short ELPs tend to behave consistently with previous observations related to assembly-related ELP phase transitions but deviated in their disassembly. It was found that chain length, concentration and overall sequence hydrophobicity may influence the irreversible formation of sub-micron particles as well as the formation of multi-micron scale, colloidally unstable aggregates. Amino acid composition affected surface charge and packing density of the particles. Particle stability upon dilution was found to vary depending upon chain length and hydrophobicity, with particles composed of longer and/or more hydrophobic ELPs being more resistant to disassembly upon isothermal dilution.ConclusionsTaken together, these results suggest marginally soluble ELPs may self-assemble but not disassemble as expected and that parameters including particle size, zeta potential and dilution resistance would benefit from widespread systematic evaluations. This information has the potential to reveal novel preparation methods capable of expanding the utility of all existing ELP-based biomaterials.

Enzyme-responsive peptide dendrimer-gemcitabine conjugate as a controlled-release drug delivery vehicle with enhanced antitumor efficacy.

Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycyl phenylalanyl leucyl glycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h. This nanoparticle demonstrated enhanced antitumor efficacy in a 4T1 murine breast cancer model without obvious systemic toxicity, resulting in significantly suppressed relative tumor volumes (86.17±38.27%) and a 2-fold higher value of tumor growth inhibition (∼90%) than GEM·HCl treatment. These results suggest that the PEGylated peptide dendrimer-gemcitabine conjugate can be an effective antitumor agent for breast cancer therapy. Statement of Significance We found that the functionalized dendrimer based nanoscale drug delivery vehicles exhibited enhanced therapeutic indexes and reduced toxicity as compared to the free drug gemcitabine. Compared with current nanoparticles, such as dendritic anticancer drug delivery systems, the new design was capable of self-assembling into nanoscale particles with sizes of about 80-110nm, which is suitable as antitumor drug delivery vehicle due to the potential longer intravascular half-life and higher accumulation in tumor tissue via EPR effect. Owing to the optimized architecture, the system was given the enzyme-responsive drug release feature, and showed excellent antitumor activity on the 4T1 breast tumor model due to the evidences from tumor growth curves, immunohistochemical analysis and confocal laser scanning microscopy. Meanwhile, no significant side effect was observed by histological analysis. This study demonstrated that PEGylated peptide dendritic architecture may be used as efficient and safe nanoscale drug delivery vehicle for cancer therapy.

Stimuli-Sensitive Biodegradable and Amphiphilic Block Copolymer-Gemcitabine Conjugates Self-Assemble into a Nanoscale Vehicle for Cancer Therapy.

The availability and the stability of current anticancer agents, particularly water-insoluble drugs, are still far from satisfactory. A widely used anticancer drug, gemcitabine (GEM), is so poorly stable in circulation that some polymeric drug-delivery systems have been under development for some time to improve its therapeutic index. Herein, we designed, prepared, and characterized a biodegradable amphiphilic block N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-GEM conjugate-based nanoscale and stimuli-sensitive drug-delivery vehicle. An enzyme-sensitive oligopeptide sequence glycylphenylalanylleucylglycine (GFLG) was introduced to the main chain with hydrophilic and hydrophobic blocks via the reversible addition-fragmentation chain transfer (RAFT) polymerization. Likewise, GEM was conjugated to the copolymer via the enzyme-sensitive peptide GFLG, producing a high molecular weight (MW) product (90 kDa) that can be degraded into smaller MW segments (<50 kDa), and ensuring potential rapid site-specific release and stability in vivo. The amphiphilic copolymer-GEM conjugate can self-assemble into compact nanoparticles. NIR fluorescent images demonstrated that the conjugate-based nanoparticles could accumulate and be retained within tumors, resulting in significant increased antitumor efficacy compared to free GEM. The conjugate was not toxic to organs of the mice as measured by body weight reductions and histological analysis. In summary, this biodegradable amphiphilic block HPMA copolymer-gemcitabine conjugate has the potential to be a stimuli-sensitive and nanoscale drug-delivery vehicle.

Development of Self-Assembled Biomimetic Boc-Protected Peptide-Polymer Based Nanovehicles for Targeted Delivery to Tumor Cells

Although effective, chemotherapeutic drugs often cause undesired side-effects. Thus, encapsulating chemotherapeutic drugs into nanoscale drug delivery vehicles (DDVs) has the potential to reduce side effects and promote targeted delivery. By mimicking ABA like block-co-polymer systems, we have developed a new amphiphilic biomimetic co-polymer Boc-Ile-PEG-Ile-Boc which was found to readily self-assemble into nanomicelles within hydrophilic shell structures. To facilitate targeting tumor cells, the nanoassemblies were bound to folate, leading to the formation of core shell like structures (IBP-F). Gold nanoparticles (AuNPs), were then embedded followed by functionalization with a second layer of folate. The final DDV system abbreviated (IBP-F-Au-F) formed a multi-layered nanostructure that was capable of efficiently encapsulating the anti-tumor drug tamoxifen. For comparison, we also examined the efficacy of the IBP-F assemblies as DDVs in the absence of AuNPs and a second folate layer. Release profiles showed an initial burst release, followed by sustained release. The DDVs were found to be biocompatible. Upon encapsulating the DDVs with tamoxifen, cell proliferation was inhibited over a period of 72 hours for both DDVs, while non-cancerous dermal fibroblasts continued to proliferate, thus indicating specific targeting ability of the DDVs. Confocal microscopy studies conducted in the presence of human breast cancer cells, MDA-MDB 231 revealed that the drug loaded assemblies were successfully internalized within the cells. SPR analysis demonstrate that IBP-F-Au-F had a higher affinity for breast cancer cells over non-cancerous keratinocyte cells. Thus, we have developed a new family of DDVs that selectively targets tumor cells.

Fabrication of aptamer decorated dextran coated nano-graphene oxide for targeted drug delivery

In the current study, dextran (DEX) was covalently conjugated to the surface of nano-GO sheets, making stable biocompatible dextran coated GO (GO-DEX). The prepared GO-DEX was nontoxic to 4T1 mammary carcinoma cell line at concentrations up to 300μg/mL.AS1411 aptamer, a ssDNA aptamer which can improve the intracellular uptake by nucleolin recognition, also has been introduced to hydroxyl groups of DEX in GO-DEX to produce GO-DEX-Apt. Moreover, curcumin (CUR), a natural polyphenol, found in the rhizomes of Curcuma longa (turmeric) which shows antineoplastic effects, was loaded onto the GO-DEX and GO-DEX-Apt via Ͽ-Ͽ stacking interactions with a high loading capacity (⿼29wt%). The GO-DEX-Apt-CUR could efficiently enter into 4T1 and MCF-7 nucleolin over-expressed cancer cells confirmed by fluorescence microscope and flowcytometry, and it also showed significantly higher cytotoxicity. These types of targeted nanoscale drug delivery vehicles on the basis of DEX coated GO may find potential application in cancer chemotherapy.

A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways.

Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivatable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with photo-initiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivatable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release whilst reducing systemic drug exposure and associated toxicities.

A stimuli-responsive Janus peptide dendron-drug conjugate as a safe and nanoscale drug delivery vehicle for breast cancer therapy.

Smart nanoscale drug delivery systems have been investigated as potential candidates for drug delivery vehicles. Here, we used a breast cancer model to determine if the enzyme-responsive Janus dendron (mPEGylated dendron-PVGLIG-DOX) conjugate-based nanoscale system would be an effective and safe drug delivery vehicle for chemotherapy. To this end, we prepared and characterized the matrix metalloprotease-2 (MMP-2)/MMP-9-sensitive linker of the proline-valine-glycine-leucine-isoleucine-glycine (Pro-Val-Gly-Leu-Ile-Gly, PVGLIG) oligopeptide via a convenient and fast liquid-phase synthesis. Second, using a rational design strategy, the Janus dendron (Boc-G2L-G3L-OMe) was successfully modified with mPEG and PVGLIG-DOX via a two-step highly efficient copper-catalyzed alkyne-azide click cycloaddition (CuAAC) reaction. Morphology studies such as dynamic light scattering, scanning electron microscopy, and atomic force microscopy were performed to confirm that the Janus mPEGylated dendron-PVGLIG-DOX conjugate self-assembled into compact nanoparticles with a slightly negatively charged surface. The nanoscale system, which included nanoparticles with 4.0 wt% (weight percent) of doxorubicin (DOX), was analyzed using ultraviolet-visible absorption spectra, fluorescence emission spectra, and matrix assisted laser desorption/ionization time-of-flight. Nanoscale systems incubated with exogenous MMP-2 killed breast cancer cells were more effective than those lacking MMP-2. Compared to free DOX, the nanoscale system substantially reduced the side effects accompanied by a similar antitumor efficacy. Moreover, it had minimal systemic toxicities, especially DOX-induced toxicities to the normal organs of both tumor bearing and healthy mice, as determined by changes in the body weight and histological analysis. These data demonstrate that the Janus dendron drug conjugate-based nanoscale system may be an effective chemotherapy delivery vehicle for breast cancer.

Targeting cancer cells in the tumor microenvironment: opportunities and challenges in combinatorial nanomedicine.

Cancer therapies of the future will rely on synergy between drugs delivered in combination to achieve both maximum efficacy and decreased toxicity. Nanoscale drug delivery vehicles composed of highly tunable nanomaterials ('nanocarriers') represent the most promising approach to achieve simultaneous, cell-selective delivery of synergistic ratios of combinations of drugs within solid tumors. Nanocarriers are currently being used to co-encapsulate and deliver synergistic ratios of multiple anticancer drugs to target cells within solid tumors. Investigators exploit the unique environment associated with solid tumors, termed the tumor microenvironment (TME), to make 'smart' nanocarriers. These sophisticated nanocarriers exploit the pathological conditions in the TME, thereby creating highly targeted nanocarriers that release their drug payload in a spatially and temporally controlled manner. The translational and commercial potential of nanocarrier-based combinatorial nanomedicines in cancer therapy is now a reality as several companies have initiated human clinical trials.

Extreme resilience in cochleate nanoparticles.

Cochleates, prospective nanoscale drug delivery vehicles, are rolls of negatively charged phospholipid membrane layers. The membrane layers are held together by calcium ions; however, neither the magnitude of membrane interaction forces nor the overall mechanical properties of cochleates have been known. Here, we manipulated individual nanoparticles with atomic force microscopy to characterize their nanomechanical behavior. Their stiffness (4.2-12.5 N/m) and membrane-rupture forces (45.3-278 nN) are orders of magnitude greater than those of the tough viral nanoshells. Even though the fundamental building material of cochleates is a fluid membrane, the combination of supramolecular geometry, the cross-linking action of calcium, and the tight packing of the ions apparently lead to extreme mechanical resilience. The supramolecular design of cochleates may provide efficient protection for encapsulated materials and give clues to understanding biomolecular structures of similar design, such as the myelinated axon.