DNA Nanobarrel-Based Drug Delivery for Paclitaxel and Doxorubicin

Co-delivery of anticancer drugs and target agents by endogenous materials is an inevitable approach towards targeted and synergistic therapy. Employing DNA base pair complementarities, DNA nanotechnology exploits a unique nanostructuring method and has demonstrated its capacity for nanoscale positioning and templated assembly. Moreover, the water solubility, biocompatibility, and modifiability render DNA structure suitable candidate for drug delivery applications. We here report single-stranded DNA tail conjugated antitumor drug paclitaxel (PTX), and the co-delivery of PTX, doxorubicin and targeting agent mucin 1 (MUC-1) aptamer on a DNA nanobarrel carrier. We investigated the effect of tail lengths on drug release efficiencies and dual drug codelivery-enabled cytotoxicity. Owing to the rapidly developing field of structural DNA nanotechnology, functional DNA-based drug delivery is promising to achieve clinical therapeutic applications.     

Aptamer-Aptamer Chimera for Targeted Delivery and ATP-Responsive Release of Doxorubicin into Cancer Cells

Aptamers offer a great opportunity to develop innovative drug delivery systems that can deliver cargos specifically into targeted cells. In this study, a chimera consisting of two aptamers was developed to deliver doxorubicin into cancer cells and release the drug in cytoplasm in response to adenosine-5′-triphosphate (ATP) binding. The chimera was composed of the AS1411 anti-nucleolin aptamer for cancer cell targeting and the ATP aptamer for loading and triggering the release of doxorubicin in cells. The chimera was first produced by hybridizing the ATP aptamer with its complementary DNA sequence, which is linked with the AS1411 aptamer via a poly-thymine linker. Doxorubicin was then loaded inside the hybridized DNA region of the chimera. Our results show that the AS1411–ATP aptamer chimera was able to release loaded doxorubicin in cells in response to ATP. In addition, selective uptake of the chimera into cancer cells was demonstrated using flow cytometry. Furthermore, confocal laser scanning microscopy showed the successful delivery of the doxorubicin loaded in chimeras to the nuclei of targeted cells. Moreover, the doxorubicin-loaded chimeras effectively inhibited the growth of cancer cell lines and reduced the cytotoxic effect on the normal cells. Overall, the results of this study show that the AS1411–ATP aptamer chimera could be used as an innovative approach for the selective delivery of doxorubicin to cancer cells, which may improve the therapeutic potency and decrease the off-target cytotoxicity of doxorubicin.     

阿霉素磁性靶向药物的研究进展

综述了磁性微球的主要特性,详细的介绍了阿霉素磁性靶向药物分别在国内和国外的研究进展情况,并对靶向药物的发展方向进行了展望。     

Molecular Assembly of an Aptamer–Drug Conjugate for Targeted Drug Delivery to Tumor Cells

Special delivery! An aptamer‐directed anticancer drug was molecularly engineered to be delivered to target cells for efficient therapeutic application. The covalent conjugation of drug and aptamer creates alternative opportunities for targeted therapy, as multiple yet specific aptamers can be “generated” relatively easily by cell‐SELEX for any target cells; this demonstrates the full potential of cell‐SELEX as a molecular discovery tool for biomedical studies and drug development.

     

Efficacious Doxorubicin Delivery Using Glutathione-Responsive Hollow Non-phospholipid Vesicles Bearing Lipoyl Cholesterols

In this study, we developed redox-sensitive vesicles using synthesised lipoyl cholesterol derivatives, a non-ionic surfactant and an optimum level of free cholesterol. Interestingly, concentration-dependent self-assembly was observed by scanning electron microscopy, wherein vesicles manifested as hollow spherical (at 0.15 mm ) and triangular (0.50 mm ). The redoxresponsive characteristics of the vesicles was probed in the presence of dithiothreitol; they underwent a clear increase in size as observed by dynamic light scattering measurements. These vesicles could easily encapsulate an anticancer drug, doxorubicin, and were observed to be stable in the presence of serum. They showed substantial release of the drug in response to biologically relevant stimulus, that is, glutathione. A toxicity assessment on HeLa and HepG2 cancer cells demonstrated activities of the drug-loaded vesicles comparable to that of free drug, whereas significantly enhanced toxicity and apoptotic induction were observed against drug-resistant HeLa cells, which was determined by studying the cellular internalisation of doxorubicin.     

Intracellular Delivery of Doxorubicin by Iron Oxide-Based Nano-Constructs Increases Clonogenic Inactivation of Ionizing Radiation in HeLa Cells

In this study, we determined the potential of polyethylene glycol-encapsulated iron oxide nanoparticles (IONP_CO) for the intracellular delivery of the chemotherapeutic doxorubicin (IONP_DOX) to enhance the cytotoxic effects of ionizing radiation. The biological effects of IONP and X-ray irradiation (50 kV and 6 MV) were determined in HeLa cells using the colony formation assay (CFA) and detection of γH2AX foci. Data are presented as mean ± SEM. IONP were efficiently internalized by HeLa cells. IONP_CO radiomodulating effect was dependent on nanoparticle concentration and photon energy. IONP_CO did not radiosensitize HeLa cells with 6 MV X-rays, yet moderately enhanced cellular radiosensitivity to 50 kV X-rays (DMF_SF0.1 = 1.13 ± 0.05 (p = 0.01)). IONP_DOX did enhance the cytotoxicity of 6 MV X-rays (DMF_SF0.1 = 1.3 ± 0.1; p = 0.0005). IONP treatment significantly increased γH2AX foci induction without irradiation. Treatment of HeLa cells with IONP_CO resulted in a radiosensitizing effect for low-energy X-rays, while exposure to IONP_DOX induced radiosensitization compared to IONP_CO in cells irradiated with 6 MV X-rays. The effect did not correlate with the induction of γH2AX foci. Given these results, IONP are promising candidates for the controlled delivery of DOX to enhance the cytotoxic effects of ionizing radiation.     

Apoferritin Modified Magnetic Particles as Doxorubicin Carriers for Anticancer Drug Delivery

Magnetic particle mediated transport in combination with nanomaterial based drug carrier has a great potential for targeted cancer therapy. In this study, doxorubicin encapsulation into the apoferritin and its conjugation with magnetic particles was investigated by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). The quantification of encapsulated doxorubicin was performed by fluorescence spectroscopy and compared to CE-LIF. Moreover, the significant enhancement of the doxorubicin signal was observed by addition of methanol into the sample solution.     

Biocompatible Polymer Coated Paramagnetic Nanoparticles for Doxorubicin Delivery: Synthesis and Anticancer Effects Against Human Breast Cancer Cells

To increase the efficacy of doxorubicin in induction of apoptosis, pH-responsive nanocarriers with an average particle size of 20 nm by using chitosan-polymethacrylic acid (CTS-PMAA) shells and Fe₃O₄ cores via in situ polymerization approach were synthesized. Doxorubicin hydrochloride (DOX) was loaded effectively to nanocarrier through electrostatic interactions and strong hydrogen banding. The cumulative release of DOX-loaded nanoparticles was pH dependent with a maximum release rate at pH 5.8. In vitro cytotoxicity assay revealed the biocompatibility of blank nanocarrier and superior anticancer performance of DOX-loaded nanoparticles verified by DAPI staining and MTT assay tests.     

Modification of Magnetite Cellulose Nanoparticles via Click Reaction for use in Controlled Drug Delivery

Superparamagnetic Fe₃O₄ nanoparticles (MNPs) were functionalized by modified cellulose. The modified cellulose was synthesized through bromoacetylation of cellulose (BACell) followed by the substitution of sodium azide to form BACell-N₃. The remaining methylene bromide groups on BACell-N₃ was further reacted with the MNPs to form Fe₃O₄/Cell-N₃. Then propargyl alcohol (PA) was immobilized on the azide-terminated Fe₃O₄ nanoparticles through copper (I)-catalyzed azide-alkyne cycloaddition (click reaction) to form Fe₃O₄/Cell/TAA nanoparticles. Doxorubicin (DOX) was loaded on prepared nanoparticles and release profiles of the DOX as a model drug from the Fe₃O₄/Cell/TAA nanoparticles and its loading capacity were determined by UV–Vis absorption at λ_max 483?nm.     

Syntheses of Polypeptides and Their Biomedical Application for Anti-Tumor Drug Delivery

Polypeptides have attracted considerable attention in recent decades due to their inherent biodegradability and biocompatibility. This mini-review focuses on various ways to synthesize polypeptides, as well as on their biomedical applications as anti-tumor drug carriers over the past five years. Various approaches to preparing polypeptides are summarized, including solid phase peptide synthesis, recombinant DNA techniques, and the polymerization of activated amino acid monomers. More details on the polymerization of specifically activated amino acid monomers, such as amino acid N-carboxyanhydrides (NCAs), amino acid N-thiocarboxyanhydrides (NTAs), and N-phenoxycarbonyl amino acids (NPCs), are introduced. Some stimuli-responsive polypeptide-based drug delivery systems that can undergo different transitions, including stability, surface, and size transition, to realize a better anti-tumor effect, are elaborated upon. Finally, the challenges and opportunities in this field are briefly discussed.     

Reduction-Triggered Doxorubicin Delivery by Self-Assembled Nanospheres of Lipoylated Caffeine

This study reports a new amphiphilic bioconjugate (CAFF-LA) derived from the lipoylation of a hydroxyethyl derivative of caffeine. In water, CAFF-LA self-assembles into nanospheres with an average size of 155 nm, as evidenced from dynamic light scattering and electron microscopy studies. The nanospheres are stable in serum and could be disintegrated upon exposure to the reducing environment of dithiothreitol (DTT; 10 mM) and glutathione (GSH; 10 mM). These nanospheres easily encapsulate the chemotherapy medication, doxorubicin (DOX), and demonstrate an efficacious transport into doxorubicin-resistant cervical cancer (HeLa) cells, wherein a marked induction in apoptosis and significantly lower IC₅₀ have been observed when compared to that of free drug. The in vitro assessment of cell viability and hemocompatibility present these nanospheres as potentially safe and efficient intracellular reduction stimulus-responsive drug-delivery vehicles.     

Transdermal Drug Delivery Systems and Their Use in Obesity Treatment

Transdermal drug delivery (TDD) has recently emerged as an effective alternative to oral and injection administration because of its less invasiveness, low rejection rate, and excellent ease of administration. TDD has made an important contribution to medical practice such as diabetes, hemorrhoids, arthritis, migraine, and schizophrenia treatment, but has yet to fully achieve its potential in the treatment of obesity. Obesity has reached epidemic proportions globally and posed a significant threat to human health. Various approaches, including oral and injection administration have widely been used in clinical setting for obesity treatment. However, these traditional options remain ineffective and inconvenient, and carry risks of adverse effects. Therefore, alternative and advanced drug delivery strategies with higher efficacy and less toxicity such as TDD are urgently required for obesity treatment. This review summarizes current TDD technology, and the main anti-obesity drug delivery system. This review also provides insights into various anti-obesity drugs under study with a focus on the recent developments of TDD system for enhanced anti-obesity drug delivery. Although most of presented studies stay in animal stage, the application of TDD in anti-obesity drugs would have a significant impact on bringing safe and effective therapies to obese patients in the future.     

Nanomedicine Strategies for Management of Drug Resistance in Lung Cancer

Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge, as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and the encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer, presents novel nanomedicine therapeutics aimed at improving the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for the clinical application of nanomedicine in the management of LC resistance.     

Exploiting the Lactose–GM3 Interaction for Drug Delivery

Protein–protein and protein–carbohydrate interactions as a means to target the cell surface for therapeutic applications have been extensively investigated. However, carbohydrate–carbohydrate interactions (CCIs) have largely been overlooked. Here, we investigate the concept of CCI‐mediated drug delivery. Lactose‐functionalized β‐cyclodextrin (L‐β‐CD) hosting doxorubicin (Dox) was evaluated for site‐specific delivery to cancer cells via interaction with GM₃, a cell‐surface carbohydrate. The host–guest complex was evaluated in B16 melanoma cells, which express exceptionally high levels of GM₃, and acute monocytic leukemia (THP‐1) and mouse fibroblast (NIH‐3T3) cells, which lack GM₃ on the cell surface. Doxorubicin (Dox) was delivered more efficiently into B16 cells compared with NIH‐3T3 and THP‐1 cells. In B16 cells pretreated with sialidase or sodium periodate, thus preventing CCI formation, drug uptake was significantly decreased. Taken together, the results of these studies strongly support CCI‐mediated uptake via the GM₃–lactose interaction as the mechanism of controlled drug delivery.     

Intelligent Drug Delivery by Peptide-Based Dual-Function Micelles

To endow the polymeric prodrug with smart properties through a safe and simple method, matrix metalloproteinase (MMPs) responsive peptide GPLGVRGDG was introduced into the block copolymer to prepare TPGS₃₃₅₀-GPLGVRGDG-DOX&DOX micelles, where TPGS₃₃₅₀ is D-α-tocopheryl polyethylene glycol 3350 succinate. During the doxorubicin delivery, the cleavage of the peptide chain triggers de-PEGylation, and the remaining VRGDG sequence was retained on the surface of the micelles, which can act as a ligand to facilitate cell uptake. Moreover, the cytotoxicity of TPGS₃₃₅₀-GPLGVRGDG-DOX&DOX micelles against 4T1 cells was significantly improved, compared with TPGS₃₃₅₀-GPLGVRG-DOX&DOX micelles and TPGS₃₃₅₀-DOX&DOX micelles. During in vivo studies, TPGS₃₃₅₀-GPLGVRGDG-DOX&DOX micelles exhibited good anticancer efficacy with long circulation in the body and more efficient accumulation at the tumor site. Therefore, TPGS₃₃₅₀-GPLGVRGDG-DOX&DOX micelles have improved antitumor activity and reduced toxic side effects. This work opens new potential for exploring the strategy of drug delivery in clinical applications.     

Description of Release Process of Doxorubicin from Modified Carbon Nanotubes

The article discusses the release process of doxorubicin hydrochloride (DOX) from multi-wall carbon nanotubes (MWCNTs). The studies described a probable mechanism of release and actions between the surface of functionalized MWCNTs and anticancer drugs. The surface of carbon nanotubes (CNTs) has been modified via treatment in nitric acid to optimize the adsorption and release process. The modification efficiency and physicochemical properties of the MWCNTs+DOX system were analyzed by using SEM, TEM, EDS, FTIR, Raman Spectroscopy and UV-Vis methods. Based on computer simulations at pH 7.4 and the experiment at pH 5.4, the kinetics and the mechanism of DOX release from MWNT were discussed. It has been experimentally observed that the acidic pH (5.4) is appropriate for the efficient release of the drug from CNTs. It was noted that under acidic pH conditions, which is typical for the tumour microenvironment almost 90% of the drug was released in a relatively short time. The kinetics models based on different mathematical functions were used to describe the release mechanism of drugs from MWCNTs. Our studies indicated that the best fit of experimental kinetic curves of release has been observed for the Power-law model and the fitted parameters suggest that the drug release mechanism of DOX from MWCNTs is controlled by Fickian diffusion. Molecular dynamics simulations, on the other hand, have shown that in a neutral pH solution, which is close to the blood pH, the release process does not occur keeping the aggregation level constant. The presented studies have shown that MWCNTs are promising carriers of anticancer drugs that, depending on the surface modification, can exhibit different adsorption mechanisms and release.     

药库型微型胶囊囊材研究进展

微包囊、微球作为一种新的药物释放体系,具有极大的发展潜力.药物载体是药物释放体系的重要组成部分,也是影响药效的主要因素.磁性微球、纳米胶囊的出现对囊材与载体材料的研究提出了新的要求.对药库型微型胶囊囊材与载体材料的研究现状与发展趋势进行了综述.     

Addressing Doxorubicin Resistance in Bone Sarcomas Using Novel Drug-Resistant Models

Bone sarcomas have not shown a significant improvement in survival for decades, due, in part, to the development of resistance to current systemic treatments, such as doxorubicin. To better understand those mechanisms mediating drug-resistance we generated three osteosarcoma and one chondrosarcoma cell lines with a stable doxorubicin-resistant phenotype, both in vitro and in vivo. These resistant strains include a pioneer model generated from a patient-derived chondrosarcoma line. The resistant phenotype was characterized by a weaker induction of apoptosis and DNA damage after doxorubicin treatment and a lower migratory capability. In addition, all resistant lines expressed higher levels of ABC pumps; meanwhile, no clear trends were found in the expression of anti-apoptotic and stem cell-related factors. Remarkably, upon the induction of resistance, the proliferation potential was reduced in osteosarcoma lines but enhanced in the chondrosarcoma model. The exposure of resistant lines to other anti-tumor drugs revealed an increased response to cisplatin and/or methotrexate in some models. Finally, the ability to retain the resistant phenotype in vivo was confirmed in an osteosarcoma model. Altogether, this work evidenced the co-existence of common and case-dependent phenotypic traits and mechanisms associated with the development of resistance to doxorubicin in bone sarcomas.     

Efficient pH Dependent Drug Delivery to Target Cancer Cells by Gold Nanoparticles Capped with Carboxymethyl Chitosan

Doxorubicin (DOX) was immobilized on gold nanoparticles (AuNPs) capped with carboxymethyl chitosan (CMC) for effective delivery to cancer cells. The carboxylic group of carboxymethyl chitosan interacts with the amino group of the doxorubicin (DOX) forming stable, non-covalent interactions on the surface of AuNPs. The carboxylic group ionizes at acidic pH, thereby releasing the drug effectively at acidic pH suitable to target cancer cells. The DOX loaded gold nanoparticles were effectively absorbed by cervical cancer cells compared to free DOX and their uptake was further increased at acidic conditions induced by nigericin, an ionophore that causes intracellular acidification. These results suggest that DOX loaded AuNPs with pH-triggered drug releasing properties is a novel nanotheraputic approach to overcome drug resistance in cancer.     

可降解高分子纳米纤维药物控释系统的研究进展

可降解高分子药物控释系统通过对药物剂量的有效控制,能够降低药物的毒副作用,提高药物的稳定性和利用率。近年来,静电纺丝纳米纤维因其具有比表面积大等特点,作为新型药物控制释放载体受到研究者的广泛关注。本文综述了可降解高分子纳米纤维药物控释系统的研究进展,对可降解高分子纳米纤维的制备及其在药物控释方面的研究进行介绍,并讨论了影响可降解高分子纳米纤维药物释放的因素。