Glycolysis-based drug delivery nanosystems for therapeutic use in tumors and applications.

Tumor cells are able to use glycolysis to produce energy under hypoxic conditions, and even under aerobic conditions, they rely mainly on glycolysis for energy production, the Warburg effect. Conventional tumor therapeutic drugs are unidirectional, lacking in targeting and have limited therapeutic effect. The development of a large number of nanocarriers and targeted glycolysis for the treatment of tumors has been extensively investigated in order to improve the therapeutic efficacy. This paper reviews the research progress of nanocarriers based on targeting key glycolytic enzymes and related transporters, and combines nanocarrier systems with other therapeutic approaches to provide a new strategy for targeted glycolytic treatment of tumors, providing a theoretical reference for achieving efficient targeted treatment of tumors.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

LogP of N-acyl-gemcitabine and lectin-corona emerge as key parameters in nanoparticulate intravesical cancer therapy.

After surgical removal of the tumour tissue, bladder cancer is treated by intravesical instillation of cytotoxic drugs such as gemcitabine. Gemcitabine, however, is highly hydrophilic and possesses a short half-life due to fast enzymatic deamination. Additionally, continuous dilution by urine, a hardly permeable urothelial barrier and rapid excretion by urination make therapy difficult. To modify lipophilicity of the drug, N-acyl-gemcitabine derivatives with quite different solubility and logP were synthesized, purified and characterized. The loading of PLGA nanoparticles with the N-acyl-gemcitabine derivatives followed by release in artificial urine, revealed that the drug content increases but the subsequent release decreases with lipophilicity. Additionally, acylation increased cytotoxicity and opened passive diffusion as an additional pathway into cancer cells. To address physiological constraints, the surface of the monodisperse nanoparticles was grafted with bioadhesive wheat germ agglutinin. Cytoadhesion to artificial bladder cancer tissue and even uptake into the cells as indicated by microscopic imaging are expected to prolong the retention time in the bladder cavity as well as to promote uptake into the cells. By using N-caprylic-gemcitabine as most appropriate gemcitabine-derivative for drug loading and making use of the bioadhesive characteristics of wheat germ agglutinin for grafting the corona of PLGA-nanoparticles, an innovative strategy towards smart drug delivery for instillative therapy of bladder cancer is proposed.

Development of a Magnetic Nanostructure for Co-delivery of Metformin and Silibinin on Growth of Lung Cancer Cells: Possible Action Through Leptin Gene and its Receptor Regulation.

OBJECTIVE: Chemotherapeutic combinational approaches would be more efficient in decreasing toxicity of drug, preventing tumor progression in relation to either drug alone. Hence, the aim of this study is to constract magnetic PLGA/PEG nanoparticles (NPs) co-loaded with Metformin (Met) and Silibinin (Sil) to investigate their cytotoxicity as well as their impact on  mRNA expression levels of leptin and leptin receptor genes in A549 lung cancer cells. MATERIALS AND METHODS: The synthesized NPs were characterized by FTIR, FE-SEM, and VSM and then, MTT assay was utilized to assess and compare the cytotoxicity of various concentrations of the chemotheruptic molecules in pure and nanoformulated forms as well as in alone and combination state after 48 h exposure time. Moreover, the mRNA levels of leptin and its receptor genes expression were studied by quantitative real-time PCR. By co-encapsulation of Met and Sil into PLGA/PEG/ Fe3O4, cytotoxic efficiency of the compounds considerably augmented for all concentrations. RESULTS: Cytotoxicity assay displayed that combination of Met and Sil had a synergistic concentration-dependent effect on A549 lung cancer cells. Moreover, qPCR data revealed that the expression levels of the leptin and leptin receptor was considerably reduced with increasing concentrations of drug-encapsulated magnetic NPs, especially Met/Sil-encapsulated PLGA/PEG/ Fe3O4 NPs. CONCLUSION: Present preliminary study shows that co-incorporating Met, Sil, Fe3O4 into PLGA/PEG NPs might provide a more promising and safe treatment strategy for lung cancer.

Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs.

Poor aqueous solubility and poor bioavailability are major issues with many pharmaceutical industries. By some estimation, 70-90% drug candidates in development stage while up-to 40% of the marketed products are poorly soluble which leads to low bioavailability, reduced therapeutic effects and dosage escalation. That's why solubility is an important factor to consider during design and manufacturing of the pharmaceutical products. To-date, various strategies have been explored to tackle the issue of poor solubility. This review article focuses the updated overview of commonly used macro and nano drug delivery systems and techniques such as micronization, solid dispersion (SD), supercritical fluid (SCF), hydrotropy, co-solvency, micellar solubilization, cryogenic technique, inclusion complex formation-based techniques, nanosuspension, solid lipid nanoparticles, and nanogels/nanomatrices explored for solubility enhancement of poorly soluble drugs. Among various techniques, nanomatrices were found a promising and impeccable strategy for solubility enhancement of poorly soluble drugs. This article also describes the mechanism of action of each technique used in solubilization enhancement.

Enteric coating of nanostructured lipid carriers (NLCs) and enteric coating of hard gelatin capsules filled with NLCs: Feasibility studies.

Nanostructured lipid carriers (NLCs) of asenapine maleate (ASPM) were enteric coated with polymethacrylate polymers (Eudragit®) for oral delivery. The present study aimed to compare the feasibility of direct enteric coating of NLCs and enteric coating of hard gelatin capsules filled with lyophilized ASPM-NLCs. Organic solution of Eudragit® was prepared using acetone containing 3% v/v water, acetone or ethanol. Aqueous dispersion of Eudragit® was obtained by neutralization with base. Capsules were enteric coated by dip-coating method with 3:2 ratio of Eudragit® L100-55:S100 (7.5-12.5% w/v). ASPM-NLCs showed particle size of 84.91±2.14nm, polydispersity index of 0.222±0.026, entrapment efficiency of 86.9±1.8% and zeta potential of -4.83±0.29 mV. TEM images showed good sphericity of the particles with the size of ≈100nm. Non-aqueous enteric coating was not successful as NLCs were precipitated in organic solvent. Aqueous enteric coated ASPM-NLCs (lipid:coat=1:2) showed an increased size (150.8±16.7nm) and zeta potential (-23.5±2.2 mV) revealing the deposition of Eudragit®. However, aqueous enteric coated ASPM-NLCs and uncoated ASPM-NLCs showed higher drug release (18.3±3.1-22.3±3.2%) in HCl solution (pH 1.2) indicating no resistance offered by direct enteric coating of NLCs; whereas enteric coated capsules showed less drug release (4.7±0.8%) in HCl solution indicating sufficient gastric protection.

Solid Lipid Nanoparticles: An Approach to Improve Oral Drug Delivery.

Nanoparticles have shown overall beneficial effects in drug administration. Specifically, solid lipid nanoparticles (SLN) have emerged as an alternative to polymer-based systems. However, the oral administration of SLN, the first choice for conventional medications, has not been addressed due to the taboo surrounding the complicated transit that this delivery route entails. This review focuses on the encapsulation of drugs into SLN as a strategy for improving oral administration. Examples of applications of SLN to enhance the absorption and bioavailability of poorly-soluble drugs and protect acid-labile active molecules are discussed. This work also emphasizes the importance of developing SLN-based systems to treat health issues such as neurological diseases and cancer, and combat antibiotic resistance, three significant and increasingly common current public health problems. The review sections clarify how SLN can improve bioavailability, target therapeutic agents, and reduce side effects.

Delivering more for less: nanosized, minimal-carrier and pharmacoactive drug delivery systems.

Traditional nanoparticle carriers such as liposomes, micelles, and polymeric vehicles improve drug delivery by protecting, stabilizing, and increasing the circulatory half-life of the encapsulated drugs. However, traditional drug delivery systems frequently suffer from poor drug loading and require an excess of carrier materials. This carrier material excess poses an additional systemic burden through accumulation, if not degradable the need for metabolism, and potential toxicity. To address these shortcomings, minimal-carrier nanoparticle systems and pharmacoactive carrier materials have been developed. Both solutions provide drug delivery systems in which the majority of the nanoparticle is pharmacologically active. While minimal-carrier and pharmacoactive drug delivery systems can improve drug loading, they can also suffer from poor stability. Here, we review minimal-carrier and pharmacoactive delivery systems, discuss ongoing challenges and outline opportunities to translate minimal-carrier and pharmacoactive drug delivery systems into the clinic.

Comparative Evaluation for Controlled Release of Amoxicillin from RSM-CCD-Optimized Nanocomposites Based on Sodium Alginate and Chitosan-Containing Inclusion Complexes.

Amoxicillin (AMX) is a semisynthetic antibiotic, an analogue of ampicillin, with a wide spectrum of bacterial activity against many microorganisms but possesses some limits. To increase the drug effectiveness, supramolecule nanocomposites composed of ß-cyclodextrin (ß-CD) and chitosan/sodium alginate/GO were chosen in the present study as a sustained release formulation. Nanocomposites of chitosan (CH), sodium alginate (ALG), and graphene oxide (GO) were synthesized at 50 °C. The inclusion complexes (ICs) were processed via the physical mixture (PM), kneading (KM), microwave (MW) method, or coprecipitation (CP) and directly loaded into the nanocomposite. To confirm the formation of true ICs, the ICs were analyzed by DSC, SEM, 1H NMR, 2D NMR ROESY, and XRD. A drug release study was performed to find out which method is best for the controlled release of drugs in different environments of pH 2, 7, and 7.4 at 37 °C. From the observed drug release data, it was found that PM and KM showed a burst release of drugs and the microwave method was the most suitable method to prepare exact ICs of AMX and ß-CD for sustained release of drugs. Kinetics of drug release was analyzed by various kinetic models, and it was observed that the Korsmeyer-Peppas and Peppas-Sahlin models were best fit for drug release in all cases. A Phase solubility study was carried out to find the stoichiometry of IC formation and the complexation constant. The drug release was controlled and pH-dependent, confirming that nanocomposites are pH-sensitive. From drug release analysis, it was acknowledged that ß-CD is capable of causing sustained drug release.

Ophthalmic Nanoemulsions: From Composition to Technological Processes and Quality Control.

Nanoemulsions are considered as the most promising solution to improve the delivery of ophthalmic drugs. The design of ophthalmic nanoemulsions requires an extensive understanding of pharmaceutical as well as technological aspects related to the selection of excipients and formulation processes. This Review aims at providing the readers with a comprehensive summary of possible compositions of nanoemulsions, methods for their formulation (both laboratory and industrial), and differences between technological approaches, along with an extensive outline of the research methods enabling the confirmation of in vitro properties, pharmaceutical performance, and biological activity of the obtained product. The composition of the formulation has a major influence on the properties of the final product obtained with low-energy emulsification methods. Increasing interest in high-energy emulsification methods is a consequence of their scalability important from the industrial perspective. Considering the high-energy emulsification methods, both the composition and conditions of the process (e.g., device power level, pressure, temperature, homogenization time, or number of cycles) are important for the properties and stability of nanoemulsions. It is advisible to determine the effect of each parameter on the quality of the product to establish the optimal process parameters' range which, in turn, results in a more reproducible and efficient production.

Gallic acid for cancer therapy: Molecular mechanisms and boosting efficacy by nanoscopical delivery.

Cancer is the second leading cause of death worldwide. Majority of recent research efforts in the field aim to address why cancer resistance to therapy develops and how to overcome or prevent it. In line with this, novel anti-cancer compounds are desperately needed for chemoresistant cancer cells. Phytochemicals, in view of their pharmacological activities and capacity to target various molecular pathways, are of great interest in the development of therapeutics against cancer. Plant-derived-natural products have poor bioavailability which restricts their anti-tumor activity. Gallic acid (GA) is a phenolic acid exclusively found in natural sources such as gallnut, sumac, tea leaves, and oak bark. In this review, we report on the most recent research related to anti-tumor activities of GA in various cancers with a focus on its underlying molecular mechanisms and cellular pathwaysthat that lead to apoptosis and migration of cancer cells. GA down-regulates the expression of molecular pathways involved in cancer progression such as PI3K/Akt. The co-administration of GA with chemotherapeutic agents shows improvements in suppressing cancer malignancy. Various nano-vehicles such as organic- and inorganic nano-materials have been developed for targeted delivery of GA at the tumor site. Here, we suggest that nano-vehicles improve GA bioavailability and its ability for tumor suppression.

Design of Biopharmaceutical Formulations Accelerated by Machine Learning.

In addition to activity, successful biological drugs must exhibit a series of suitable developability properties, which depend on both protein sequence and buffer composition. In the context of this high-dimensional optimization problem, advanced algorithms from the domain of machine learning are highly beneficial in complementing analytical screening and rational design. Here, we propose a Bayesian optimization algorithm to accelerate the design of biopharmaceutical formulations. We demonstrate the power of this approach by identifying the formulation that optimizes the thermal stability of three tandem single-chain Fv variants within 25 experiments, a number which is less than one-third of the experiments that would be required by a classical DoE method and several orders of magnitude smaller compared to detailed experimental analysis of full combinatorial space. We further show the advantage of this method over conventional approaches to efficiently transfer historical information as prior knowledge for the development of new biologics or when new buffer agents are available. Moreover, we highlight the benefit of our technique in engineering multiple biophysical properties by simultaneously optimizing both thermal and interface stabilities. This optimization minimizes the amount of surfactant in the formulation, which is important to decrease the risks associated with corresponding degradation processes. Overall, this method can provide high speed of converging to optimal conditions, the ability to transfer prior knowledge, and the identification of new nonlinear combinations of excipients. We envision that these features can lead to a considerable acceleration in formulation design and to parallelization of operations during drug development.

Nanoparticle-Based Drug Delivery System: The Magic Bullet for the Treatment of Chronic Pulmonary Diseases.

Chronic pulmonary diseases encompass different persistent and lethal diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), asthma, and lung cancers that affect millions of people globally. Traditional pharmacotherapeutic treatment approaches (i.e., bronchodilators, corticosteroids, chemotherapeutics, peptide-based agents, etc.) are not satisfactory to cure or impede diseases. With the advent of nanotechnology, drug delivery to an intended site is still difficult, but the nanoparticle's physicochemical properties can accomplish targeted therapeutic delivery. Based on their surface, size, density, and physical-chemical properties, nanoparticles have demonstrated enhanced pharmacokinetics of actives, achieving the spotlight in the drug delivery research field. In this review, the authors have highlighted different nanoparticle-based therapeutic delivery approaches to treat chronic pulmonary diseases along with the preparation techniques. The authors have remarked the nanosuspension delivery via nebulization and dry powder carrier is further effective in the lung delivery system since the particles released from these systems are innumerable to composite nanoparticles. The authors have also outlined the inhaled particle's toxicity, patented nanoparticle-based pulmonary formulations, and commercial pulmonary drug delivery devices (PDD) in other sections. Recently advanced formulations employing nanoparticles as therapeutic carriers for the efficient treatment of chronic pulmonary diseases are also canvassed.

Delivery of a Cancer-Testis Antigen-Derived Peptide Using Conformationally Restricted Dipeptide-Based Self-Assembled Nanotubes.

Use of tumor-associated antigens for cancer immunotherapy is limited due to their poor in vivo stability and low cellular uptake. Delivery of antigenic peptides using synthetic polymer-based nanostructures has been actively pursued but with limited success. Peptide-based nanostructures hold much promise as delivery vehicles due to their easy design and synthesis and inherent biocompatibility. Here, we report self-assembly of a dipeptide containing a non-natural amino acid, α,ß-dehydrophenylalanine (ΔF), into nanotubes, which efficiently entrapped a MAGE-3-derived peptide (M3). M3 entrapped in F-ΔF nanotubes was more stable to a nonspecific protease treatment and both F-ΔF and F-ΔF-M3 showed no cellular toxicity for four cancerous and noncancerous cell lines used. F-ΔF-M3 showed significantly higher cellular uptake in RAW 267.4 macrophage cells compared to M3 alone and also induced in vitro maturation of dendritic cells (DCs). Immunization of mice with F-ΔF-M3 selected a higher number of IFN-γ secreting CD8+ T cells and CD4+ T compared to M3 alone. On day 21, a tumor growth inhibition ratio (TGI, %) of 41% was observed in a murine melanoma model. These results indicate that F-ΔF nanotubes are highly biocompatible, efficiently delivered M3 to generate cytotoxic T lymphocytes responses, and able to protect M3 from degradation under in vivo conditions. The F-ΔF dipeptide-based nanotubes may be considered as a good platform for further development as delivery agents.

Synchronizing In Silico, In Vitro, and In Vivo Studies for the Successful Nose to Brain Delivery of an Anticancer Molecule.

Sesamol is a sesame seed constituent with reported activity against many types of cancer. In this work, two types of nanocarriers, solid lipid nanoparticles (SLNs) and polymeric nanoparticles (PNs), were exploited to improve sesamol efficiency against the glioma cancer cell line. The ability of the proposed systems for efficient brain targeting intranasally was also inspected. By the aid of two docking programs, the virtual loading pattern inside these nanocarriers was matched to the real experimental results. Interactions involved in sesamol-carrier binding were also assessed, followed by a discussion of how different scoring functions account for these interactions. The study is an extension of the computer-assisted drug formulation design series, which represents a promising initiative for an upcoming industrial innovation. The results proved the power of combined in silico tools in predicting members with the highest sesamol payload suitable for delivering a sufficient dose to the brain. Among nine carriers, glyceryl monostearate (GMS) and polycaprolactone (PCL) scored the highest sesamol payload practically and computationally. The EE % was 66.09 ± 0.92 and 61.73 ± 0.47 corresponding to a ΔG (binding energy) of -8.85 ± 0.16 and -5.04 ± 0.11, respectively. Dynamic light scattering evidenced the formation of 215.1 ± 7.2 nm and 414.25 ± 1.6 nm nanoparticles, respectively. Both formulations demonstrated an efficient cytotoxic effect and brain-targeting ability compared to the sesamol solution. This was evidenced by low IC50 (38.50 ± 10.37 µM and 27.81 ± 2.76 µM) and high drug targeting efficiency (7.64 ± 1.89-fold and 13.72 ± 4.1-fold) and direct transport percentages (86.12 ± 3.89 and 92.198 ± 2.09) for GMS-SLNs and PCL-PNs, respectively. The results also showed how different formulations, having different compositions and characteristics, could affect the cytotoxic and targeting ability.

Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides.

Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs) were used to enhance oligonucleotide uptake. "match" oligonucleotides complementary to the telomerase RNA template subunit (hTR) and "scramble" (control) oligonucleotides were conjugated to diethylenetriamine pentaacetate (DTPA) for 111In-labeling. AuNPs (15.5 nm) were decorated with a monofunctional layer of oligonucleotides (ON-AuNP) or a multifunctional layer of oligonucleotides, PEG(polethylene glycol)800-SH (to reduce AuNP aggregation) and the cell-penetrating peptide Tat (ON-AuNP-Tat). Match-AuNP enhanced the cellular uptake of radiolabeled oligonucleotides while retaining the ability to inhibit telomerase activity. The addition of Tat to AuNPs increased nuclear localization. 111In-Match-AuNP-Tat induced DNA double-strand breaks and caused a dose-dependent reduction in clonogenic survival of telomerase-positive cells but not telomerase-negative cells. hTR inhibition has been reported to sensitize cancer cells to ionizing radiation, and 111In-Match-AuNP-Tat therefore holds promise as a vector for delivery of radionuclides into cancer cells while simultaneously sensitizing them to the effects of the emitted radiation.

Covalently coupling doxorubicin to polymeric nanoparticles as potential inhaler therapy: in vitro studies.

Lung cancer is the most commonly diagnosed type of cancer worldwide, non-small cell lung cancer accounts for most lung cancers. Doxorubicin is a widely used chemotherapy agent in lung cancer. However, the drug has several undesirable side effects. Here, doxorubicin coupled PEGylated mucoadhesive nanoparticles were designed as a doxorubicin delivery system for pH-triggered release in lung cancer therapy through inhaler administration. Firstly, alginate/chitosan nanoparticles were developed at optimum conditions. Then, PEG diacid bound to structures for doxorubicin binding and providing steric hindrance for phagocytosis. Doxorubicin was linked via an acid-labile amide bond to PEGylated nanoparticles and 444.3 ± 9.2 µg doxorubicin was loaded per mg nanoparticle. Doxorubicin coupled PEG diacid linked alginate/chitosan nanoparticles were checked with FTIR. Hydrodynamic diameter and zeta potential of nanoparticles were measured as 205.7 ± 15.0 nm and -25.17 ± 2.67 mV. The morphology of nanoparticles was evaluated as nearly spherical. Drug release studies were performed both in physiological and acidic media. The drug release from nanoparticles reached 23.6% (pH 5.5) and 18% (pH 7.4) within 48 h. The cytotoxicity experiments were done using A549-luc-C8 cells, also statistical analyzes were carried out. The MTT results indicated the designed drug delivery system possessed anti-tumor efficacy for non-small cell lung cancer therapy.

Boron phenyl alanine targeted ionic liquid decorated chitosan nanoparticles for mitoxantrone delivery to glioma cell line.

Nanotechnology has revolutionized drug delivery in cancer treatment. In this study, novel efficient pH-responsive boron phenylalanine (BPA) targeted nanoparticles (NPs) based on ionic liquid modified chitosan have been introduced for selective mitoxantrone (MTO) delivery to the U87MG glioma cells. Urocanic acid (UA) and imidazolium (Im) based ionic liquids were used for structural modification simultaneously. The NPs were prepared by ionic gelation and fully characterized; the pH-responding and swelling index of NPs were studied carefully. The drug release was studied at a pH of 5.5 in comparison to the neutral state. Also, the cytotoxicity of loaded NPs was evaluated on U87MG glial cells, and cellular uptake was studied. The NPs were smaller than 250 nm, with a spherical pattern and acceptable uniformity with a zeta potential around +20 mV. The loading efficacy was about 85%, and most of the loaded MTO released at a pH of 5.5 after 48 h with a swelling-controlled mechanism. The NPs showed a relatively lower IC50 than the free MTO, and the BPA-targeted NPs have lower IC50 and better cellular uptake than non-targeted NPs in U87MG cells. More studies on this promising formula are on the way, and the results will be published soon.

Electromagnetic Field-Programmed Magnetic Vortex Nanodelivery System for Efficacious Cancer Therapy.

Effective delivery of anticancer drugs into the nucleus for pharmacological action is impeded by a series of intratumoral transport barriers. Despite the significant potential of magnetic nanovehicles in electromagnetic field (EF)-activated drug delivery, modularizing a tandem magnetoresponsive activity in a one-nanoparticle system to meet different requirements at both tissue and cellular levels remain highly challenging. Herein, a strategy is described by employing sequential EF frequencies in inducing a succession of magnetoresponses in the magnetic nanovehicles that aims to realize cascaded tissue penetration and nuclear accumulation. This nanovehicle features ferrimagnetic vortex-domain iron oxide nanorings coated with a thermo-responsive polyethylenimine copolymer (PI/FVIOs). It is shown that the programmed cascading of low frequency (Lf)-EF-induced magnetophoresis and medium frequency (Mf)-EF-stimulated magneto-thermia can steer the Doxorubicin (DOX)-PI/FVIOs to the deep tissue and subsequently trigger intracellular burst release of DOX for successful nuclear entry. By programming the order of different EF frequencies, it is demonstrated that first-stage Lf-EF and subsequent Mf-EF operation enables DOX-PI/FVIOs to effectively deliver 86.2% drug into the nucleus in vivo. This nanodelivery system empowers potent antitumoral activity in various models of intractable tumors, including DOX-resistant MCF-7 breast cancer cells, triple-negative MDA-MB-231 breast cancer cells, and BxPC-3 pancreatic cancer cells with poor permeability.

Dual-modified PCL-PEG nanoparticles for improved targeting and therapeutic efficacy of docetaxel against colorectal cancer.

Polycaprolactone-poly (ethylene glycol) block copolymer (PCL-PEG) based nanoparticles were prepared for the intravenous administration of docetaxel (DTX). PCL-PEG-Tyr and PCL-PEG-Ang were synthesized by using tyrosine (Tyr) and angiopep-2 (Ang) as coupling ligands, and dual-modified PCL-PEG-based nanoparticles (PCL-PEG-Tyr/Ang) were prepared. The physicochemical properties, in vitro drug release, in vitro cytotoxicity, in vitro cellular uptake efficiency, in vivo biodistribution and in vivo antitumor efficacy of PCL-PEG-based nanoparticles were investigated. The PCL-PEG-based nanoparticles were spherical with a mean diameter of 100 nm and high encapsulation efficiencies (> 85%). The results of in vitro drug release showed that the PCL-PEG-based nanoparticles loaded with DTX had sustained-release characteristics. For in vitro cytotoxicity tests, the dual-modified PCL-PEG-based nanoparticles (PCL-PEG-Tyr/Ang) demonstrated the minimum IC50 value (2.94 µg/mL) compared with other PCL-PEG-based nanoparticles. In addition, the cellular uptake of coumarin-6 (C6) in HT29 cells was observed and determined in the PCL-PEG-Tyr/Ang nanoparticles group, which was significantly higher than that in the other PCL-PEG-based groups and C6 solution group. The results of in vivo imaging showed that dual-modified PCL-PEG nanoparticles had better tumor targeting than the other PCL-PEG-based nanoparticles. In the HT29 tumor-xenografted nude mice model, DTX-loaded PCL-PEG-Tyr/Ang nanoparticles also had a significantly higher inhibitory efficacy on tumor growth than Taxotere®-treated group. These results indicated that the dual-modified PCL-PEG-based nanoparticles (PCL-PEG-Tyr/Ang) could be a promising anticancer drug delivery system.