Light-Triggered Mechanical Disruption of Extracellular Barriers by Swarms of Enzyme-Powered Nanomotors for Enhanced Delivery.

Targeted drug delivery depends on the ability of nanocarriers to reach the target site, which requires the penetration of different biological barriers. Penetration is usually low and slow because of passive diffusion and steric hindrance. Nanomotors (NMs) have been suggested as the next generation of nanocarriers in drug delivery due to their autonomous motion and associated mixing hydrodynamics, especially when acting collectively as a swarm. Here, we explore the concept of enzyme-powered NMs designed as such that they can exert disruptive mechanical forces upon laser irradiation. The urease-powered motion and swarm behavior improve translational movement compared to passive diffusion of state-of-the-art nanocarriers, while optically triggered vapor nanobubbles can destroy biological barriers and reduce steric hindrance. We show that these motors, named Swarm 1, collectively displace through a microchannel blocked with type 1 collagen protein fibers (barrier model), accumulate onto the fibers, and disrupt them completely upon laser irradiation. We evaluate the disruption of the microenvironment induced by these NMs (Swarm 1) by quantifying the efficiency by which a second type of fluorescent NMs (Swarm 2) can move through the cleared microchannel and be taken up by HeLa cells at the other side of the channel. Experiments showed that the delivery efficiency of Swarm 2 NMs in a clean path was increased 12-fold in the presence of urea as fuel compared to when no fuel was added. When the path was blocked with the collagen fibers, delivery efficiency dropped considerably and only depicted a 10-fold enhancement after pretreatment of the collagen-filled channel with Swarm 1 NMs and laser irradiation. The synergistic effect of active motion (chemically propelled) and mechanical disruption (light-triggered nanobubbles) of a biological barrier represents a clear advantage for the improvement of therapies which currently fail due to inadequate passage of drug delivery carriers through biological barriers.

The Renoprotective Effect of Linagliptin in Type 2 Diabetic Patients with Severely Increased Albuminuria.

INTRODUCTION: Previous studies have suggested that linagliptin may represent renoprotective effects besides its anti-hyperglycemic properties in patients with type 2 diabetes. However, there is a lack of decisive evidence to support this assumption. This study aimed to address the effect of linagliptin in type 2 diabetic patients with severely increased albuminuria. METHODS: In this randomized double-blind, placebo-controlled clinical trial, type 2 diabetic patients with severely increased albuminuria (albuminuria ≥ 300 mg/24 h) were enrolled. Patients were randomized to linagliptin (5 mg/d) and placebo based on a computer-generated list of random numbers. Biochemical (fasting blood sugar (FBS) (mg/dL), hemoglobin A1c (HbA1c) (%), proteinuria (mg/24h), blood urea nitrogen (BUN) (mg/dL), serum creatinine (mg/dL)) and clinical variables (weight (kg), systolic, and diastolic blood pressure (mmHg)) were measured at baseline and 3 and 6 months post intervention. RESULTS: At baseline, no statistically significant difference was detected in demographic characteristics between the two groups (P > .05). A significant decrease was observed in proteinuria, FBS, weight, SBP, and DBP in the intervention group after 6 months (Ptime < .05), however; none of the clinical and biochemical variables showed a significant difference between groups after 6 months (Pgroup > .05). CONCLUSION: Linagliptin may serve as a renoprotective therapeutic option in diabetic patients with severely increased albuminuria due to its role in proteinuria reduction. Results of this study can be used for future large-scale, long-term studies investigating the renoprotective effects of linagliptin in patients with diabetic nephropathy. DOI: 10.52547/ijkd.6110.

Silica-Quantum Dot Nanomaterials as a Versatile Sensing Platform.

Traditional analytical methods are bounded due to required high consumption of reagents, time, expensive equipment and complicated sample preparation. Thus, there is a demand for easy, fast and sensitive procedure to determine various analytes. In this regards, quantum dots (QDs) as fluorescent nanomaterials have attracted considerable attention due to their unique optical properties. Numerous studies have been reported regarding the application of QDs in sensor development for the detection of different analytes. Moreover, mesoporous silica nanoparticles which show ideal properties including biocompatibility, uniform pore size, stability in wide range of pH and an extremely high surface area could offer great opportunity in combination with QDs for the construction of sensing platforms. The fluorescent, chemiluminescent and electrochemical sensors based on silica-QDs materials could be used for the quantitative recognition of an extensive range of analytes like organic compounds, metal cations, toxic industrial compounds, drugs, and biogenic composites. In this review, we have summarized sensors based on combined QD-silica nanomaterials and their applications in the recognition of different analytes which are published over approximately the past five years.

Ladder-like targeted and gated doxorubicin delivery using bivalent aptamer in vitro and in vivo.

Regarding side effects of commonly used chemotherapeutic drugs on normal tissues, researchers introduced smart delivery and on-demand release systems. Herein, we applied a bivalent aptamer composed of ATP and AS1411 aptamers for separate targeting and gating of mesoporous silica nanoparticles in a ladder like structure with one bifunctional molecule. First part of the apatmer, AS1411, direct the delivery system to the desired site while the second part, ATP aptamer, opens the pores and release the drug just after penetrance to the cytoplasm ensuring delivery of DOX into the tumor cells. This approach faced the previous challenge of coincident targeting and gating with one aptamer. Our results demonstrated that the proposed nano-system remarkably accumulated in cancer tissue and released the drug in a sustained pattern in cancer cells. It was notably effective for inducing apoptosis in cancer cells and tumor growth inhibition without any significant side effect on normal cells and organs. Moreover, Si-cs-DOX-AAapt improved the mice survival time compared with free doxorubicin and there was no significant change in weight of mice administered with the targeted formulation. This report may open new insight for providing smart delivery systems for successful cancer treatment by introducing separate gating and targeting property by a bivalent aptamer to increase the control over drug release.

Targeted MMP-2 responsive chimeric polymersomes for therapy against colorectal cancer.

In the current study, polyethylene glycol (PEG) was linked to polylactide (PLA) through the synthetic peptide PVGLIG which can be selectively cleaved by the tumor-associated matrix metalloproteinase 2 (MMP-2) enzyme. The synthesized chimeric triblock polymer of PEG-b-PVGLIG-PLA was implemented to form nanoscale self-assemble chimeric polymersomes. The hydrophobic SN38 was loaded into polymersomes with 70.3% ± 3.0% encapsulation efficiency demonstrating monodispersed spherical morphologies with 172 ±â€¯30 nm dimension. The prepared chimeric polymersomal formulation provided controlled release of SN38 at physiological condition while illustrating seven-folds higher release rate when exposed to MMP-2 enzyme. At the next stage, AS1411 aptamer was conjugated onto the surface of MMP-2 responsive polymersomal formulation in order to provide guided drug delivery against nucleolin positive cells. In vitro cellular toxicity assay against C26 cell line (nucleolin positive) demonstrated significantly higher toxicity of targeted formulation in comparison with non-targeted one in low SN38 concentrations (0.15-1.25 µg/mL). In vivo study in mice bearing subcutaneous C26 tumor showed higher therapeutic index for MMP-2 responsive chimeric polymersomal formulation of SN38 in comparison with non-responsive one. On the other hand, AS1411 aptamer-targeted MMP-2 responsive chimeric polymersomal formulation exhibited highest therapeutic index compared to other groups. It could be concluded that the targeted chimeric polymersomes bearing both cleavable peptide sequence between their blocks and targeting ligand on their surface, provide favorable characteristics as an ideal delivery system against cancer.

Curcumin-entrapped MUC-1 aptamer targeted dendrimer-gold hybrid nanostructure as a theranostic system for colon adenocarcinoma.

Gold NPs have great potential in biomedical applications. PAMAM dendrimers are spherical, hyper branched macromolecules which can encapsulate therapeutic molecules while stabilizing metal nanoparticle such as gold NPs. The aim of the current study was to investigate the theranostic capability of curcumin-loaded dendrimer-gold hybrid structure. Dendrimer-gold hybrid structure was synthesized by complexing AuCl4- ions with PEGylated amine-terminated generation 5 poly (amidoamine) dendrimer. The resultant hybrid system was loaded with curcumin. The curcumin-loaded PEGylated Au dendrimer was further conjugated to MUC-1 aptamer in order to target the colorectal adenocarcinoma in vitro and in vivo. Obtained results demonstrated that the targeted theranostic agent was accumulated in HT29 and C26 cells in vitro and showed higher cellular cytotoxicity in comparison with non-targeted system. On the other hand, in vivo experiment demonstrated the potential of targeted theranostic system in CT-scan tumor imaging as well as cancer therapy. Findings from this study suggested that MUC-1 targeted curcumin-loaded PEGylated Au dendrimers have good X-ray attenuation and is desirable probe for CT imaging while demonstrating high therapeutic index against colorectal cancer adenocarcinoma.

A new chemotherapy agent-free theranostic system composed of graphene oxide nano-complex and aptamers for treatment of cancer cells.

The common cancer treatment strategies like chemotherapy and radiotherapy are nonspecific and can trigger severe side effects by damaging normal cells. So, targeted cancer therapies, such as apoptosis induction, have attracted great attention in recent years. In this project, two nano-complexes, MUC1 aptamer-NAS-24 aptamer-Graphene oxide (GO) and MUC1 aptamer-Cytochrome C aptamer-GO, were designed to induce cell programmed death in MDA-MB-231 and MCF-7 cells (breast cancer cell lines) and to verify the level of apoptosis in both cell lines. MUC1 aptamer was a molecular recognition probe that led the internalization of two nano-complexes into MDA-MB-231 and MCF-7 cells (MUC1 positive cells) but not into HepG2 cell (liver cancer cell line, MUC1 negative cells). The apoptosis induction relied on binding of NAS-24 aptamer to its target, vimentin, in MDA-MB-231 and MCF-7 (target cells) with different levels of vimentin content. The function of first nano-complex was confirmed by binding of FAM-labeled cytochrome C aptamer to its target (cytochrome C) which was released from mitochondria, based on the function of the first nano-complex. Fluorometric analysis and gel retardation assay proved the formation of nano-complexes. The results of flow cytometry and fluorescence microscopy indicated efficient apoptosis induction just in target cells (MDA-MB-231 and MCF-7 cells) but not in non-target cells (HepG2 cell). The results of MTT assay also confirmed cell death process. Overall, our results proved excellent targeted apoptosis in breast cancer cells by designed nano-complexes which can be applied as an efficient cancer therapy method.

Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo.

In the current study camptothecin-loaded pegylated PAMAM dendrimer were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against colorectal cancer cells which over expresses nucleolin receptors. The morphological properties and size dispersity of the prepared nanoparticles were evaluated using transmission electron microscope (TEM) and DLS. The drug-loading content and encapsulation efficiency were obtained 8.1% and 93.67% respectively. The in vitro release of camptothecin from the formulation was provided the sustained release of encapsulated camptothecin during 4days. Comparative in vitro cytotoxicity experiments demonstrated that the targeted camptothecin loaded-pegylated dendrimers had higher antiproliferation activity, towards nucleolin-positive HT29 and C26 colorectal cancer cells than nucleolin-negative CHO cell line. Fluorscence microscopy and flow cytometry also confirmed the enhanced cellular uptake of AS1411 targeted pegylated-dendrimer. In vivo study in C26 tumor-bearing BALB/C mice revealed that the AS1411-functionalized camptothecin loaded pegylated dendrimers improved antitumor activity and survival rate of the encapsulated camptothecin. Conjugation of AS1411 aptamer to the camptothecin loaded-pegylated dendrimer surface provides site-specific delivery of camptothecin, inhibit C26 tumor growth in vivo and significantly decrease systemic toxicity. These results suggested that the new nucleolin-targeted pegylated PAMAM dendrimer as a delivery system for camptothecin have the potential for the treatment of nucleolin-overexpressed colorectal cancer.

Cancer immunotherapy via nucleic acid aptamers.

Over the past decade, immune therapy has become a standard treatment for a variety of cancers. Monoclonal antibodies, immune adjuvants and vaccines against oncogenic viruses are now well-established cancer therapies. Immune modulation is a principal element of supportive care for many high-dose chemotherapy regimens. Aptamers are short nucleic acids that bind to defined targets with high affinity and specificity. The first aptamers have been selected around two decades ago by an in vitro process named SELEX (systematic evolution of ligands by exponential enrichment). Since then, numerous aptamers with specificities for a variety of targets from small molecules to proteins or even whole cells have been selected. Targeting immunomodulatory ligands in the progressive tumor lesions of the patients would be prophylactic or therapeutic and may reduce drug-associated toxicities. A new class of inhibitory and agonistic ligands composed of short oligonucleotide (ODN) aptamers was developed recently that exhibited bioactivities comparable or superior to that of antibodies. This paper addressed progress in cancer immunotherapy with nucleic acid aptamers and highlighted recent developments either in immune system targeting or in immunotherapy methods involved aptamers. We discussed aptamer limitations when used as therapeutic agents for cancer treatment and suggested ways to overcome those limitations.