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Gaseous signaling molecules (GSMs) including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) have presented excellent therapeutic efficacy such as anti‐inflammatory, anti‐microbial and anti‐cancer effects and multiple biomedical applications in recent years. As the three most vital signaling molecules in human physiology, these three GSMs show so intertwined and orchestrated interactions that the synergy of multiple gases may demonstrate a more complex therapeutic potential than single gas delivery. Consequently, researchers have been devoted to developing codelivery systems of GSMs by synthesizing a single molecule as a dual donor to maximize the gaseous therapeutic efficacy. In this minireview, we summarize the recent developments of molecules or materials enabling codelivery of GSMs for biomedical applications. It appears that compared with the abundant cases of codelivery of NO and H2S, research on codelivery of CO and the other two GSMs separately remains to be explored. [ABSTRACT FROM AUTHOR]

Activated platelets (PLT) could adhere to tumor cells to promote tumor progression and metastasis. Therefore, inhibiting platelet activation and blocking the interaction between tumor cells and platelets are an effective approach to inhibit distal tumor metastasis. In this study, chondroitin sulfate (CS)–glycyrrhetinic acid (GA) dual ligand-modified liposomes (CS–GA–LIP) were prepared for codelivery of aspirin (ASP) and curcumin (CUR). In order to simulate the tumor microenvironment, we established the "HuH-7 + PLT" in vitro coculture cell model and the "H22 + NIH/3T3" coinjected mice model. Physicochemical analysis showed that the particle size of CUR&ASP/CS–GA–LIP was 133.27 nm with high stability. In vitro studies found that CUR&ASP/CS–GA–LIP could target both hepatocellular carcinoma cells and platelets, enhance drug retention in tumor cells, and effectively inhibit tumor proliferation and migration. In addition, in vivo antitumor results demonstrated that CUR&ASP/CS–GA–LIP could aggregate in tumor tissues, inhibit platelet activation and neoangiogenesis, and down-regulate the expression of matrix metalloproteinase 2 (MMP-2), exhibiting strong antiproliferative and antipulmonary metastatic abilities. Consequently, the combination therapy based on CS–GA–LIP might be a valuable antihepatocellular carcinoma strategy. [ABSTRACT FROM AUTHOR]

The synergistic effect of drug and gene delivery is expected to significantly improve cancer therapy. However, it is still challenging to design suitable nanocarriers that are able to load simultaneously anticancer drugs and nucleic acids due to their different physico-chemical properties. In the present work, an amphiphilic block copolymer comprising a biocompatible poly(ethylene glycol) (PEG) block and a multi-alkyne-functional biodegradable polycarbonate (PC) block was modified with a number of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) side chains applying the highly efficient azide–alkyne "click" chemistry reaction. The resulting cationic amphiphilic copolymer with block and graft architecture (MPEG-b-(PC-g-PDMAEMA)) self-associated in aqueous media into nanosized micelles which were loaded with the antioxidant, anti-inflammatory, and anticancer drug quercetin. The drug-loaded nanoparticles were further used to form micelleplexes in aqueous media through electrostatic interactions with DNA. The obtained nanoaggregates—empty and drug-loaded micelles as well as the micelleplexes intended for simultaneous DNA and drug codelivery—were physico-chemically characterized. Additionally, initial in vitro evaluations were performed, indicating the potential application of the novel polymer nanocarriers as drug delivery systems. [ABSTRACT FROM AUTHOR]

The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC.

Antimalarial drugs are being encapsulated in nanotechnology-based carriers because there are not enough new treatment options and people are becoming more resistant to the ones that are already available. This approach uses two or more biochemical targets of malarial parasites. The codelivery of artemether and lumefantrine (AL) combines the synergistic effect of artemether for an early onset of action followed by the prolonged effect of lumefantrine. The bioavailability of artemether and lumefantrine is low due to their low solubility. Thus, an alternative lipidic formulation, namely nanocochleate, was developed for the selected drugs by adding calcium ions into preformed nanoliposomes (AL-loaded liposomes). Using phospholipon 90H and cholesterol, a thin-film hydration method produced drug-loaded liposomes. The synthesized AL-loaded liposomes were further incorporated into nanocochleates. The formulations were evaluated for in vitro and in vivo parameters. Nanocochleates had a particle size of 200.7 nm, a zeta potential of −9.4 mV, and an entrapment efficiency of 73.12% ± 1.82% and 61.46% ± 0.78%, respectively, for artemether and lumefantrine. Whereas liposomes had a particle size of 210 nm and an entrapment efficiency of 67.34% ± 1.52% and 53.24% ± 0.78%, respectively, for artemether and lumefantrine. An X-ray diffraction study confirmed the amorphous state of artemether and lumefantrine in liposomes and nanocochleate. Nanocochleate showed a controlled release profile for loaded drugs. When compared with free drugs, nanocochleate showed low tissue distribution and a 20-fold increase in bioavailability in rats. Thus, nanocochleate offers an interesting alternative to an existing dosage form for the treatment of malaria. [ABSTRACT FROM AUTHOR]

Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction. Herein, we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indomethacin (IND) and antioxidant superoxide dismutase (SOD) by assembling the biopharmaceutical SOD onto the “vector” of rod-like pure IND crystals, followed by coating with anti-ICAM-1 antibody (Ab) for targeting endothelial cells. The codelivery system has a 237 nm diameter in length and extremely high drug loading of 39% IND and 2.3% SOD. Pharmacokinetics and biodistribution studies demonstrate the extended blood circulation and the strong pulmonary accumulation of the system after intravenous injection in the lipopolysaccharide (LPS)-induced inflammatory murine model. Particularly, the system allows a robust capacity to target pulmonary endothelium mostly due to the rod-shape and Ab coating effect. In vitro, the preparation shows the synergistic anti-inflammatory and antioxidant effects in LPS-activated endothelial cells. In vivo, the preparation exhibits superior pharmacodynamic efficacy revealed by significantly downregulating the inflammatory/oxidative stress markers, such as TNF-α, IL-6, COX-2, and reactive oxygen species (ROS), in the lungs. In conclusion, the codelivery system based on rod-like pure crystals could well target the pulmonary endothelium and effectively alleviate lung inflammation. The study offers a promising approach to combat pulmonary endothelium-associated diseases.

Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies. Heat shock protein 90 (Hsp90) as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance. Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance. In this study, a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX, and a COA-modified 4-arm PEG polymer (4PSC) was synthesized. COA, an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression, was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity. Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity. By blocking the Hsp90 signaling pathway, 4PSC significantly enhanced the antitumor effect of PTX, inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro. Remarkable results were further confirmed in vivo with two preclinical tumor models. These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.

Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction. Herein, we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indomethacin (IND) and antioxidant superoxide dismutase (SOD) by assembling the biopharmaceutical SOD onto the "vector" of rod-like pure IND crystals, followed by coating with anti-ICAM-1 antibody (Ab) for targeting endothelial cells. The codelivery system has a 237 nm diameter in length and extremely high drug loading of 39% IND and 2.3% SOD. Pharmacokinetics and biodistribution studies demonstrate the extended blood circulation and the strong pulmonary accumulation of the system after intravenous injection in the lipopolysaccharide (LPS)-induced inflammatory murine model. Particularly, the system allows a robust capacity to target pulmonary endothelium mostly due to the rod-shape and Ab coating effect. In vitro , the preparation shows the synergistic anti-inflammatory and antioxidant effects in LPS-activated endothelial cells. In vivo , the preparation exhibits superior pharmacodynamic efficacy revealed by significantly downregulating the inflammatory/oxidative stress markers, such as TNF- α , IL-6, COX-2, and reactive oxygen species (ROS), in the lungs. In conclusion, the codelivery system based on rod-like pure crystals could well target the pulmonary endothelium and effectively alleviate lung inflammation. The study offers a promising approach to combat pulmonary endothelium-associated diseases. The codelivery system Ab-INRplex attaches to the ICAM-1 overexpressed on inflamed endothelial cells, and synergistically relieves the inflammation by inhibiting COX-2 and reactive oxygen species production. [Display omitted] [ABSTRACT FROM AUTHOR]

This review discusses the application of nanoliposomes containing siRNA/drug to overcome multidrug resistance for all types of cancer treatments. As drug resistance-associated factors are overexpressed in many cancer cell types, pumping chemotherapy drugs out of the cytoplasm leads to an inadequate therapeutic response. The siRNA/drug-loaded nanoliposomes are a promising approach to treating multidrug-resistant cancer, as they can effectively transmit a small-molecule drug into the target cytoplasm, ensuring that the drug binds efficiently. Moreover, nanoliposome-based therapeutics with advances in nanotechnology can effectively deliver siRNA to cancer cells. Overall, nanoliposomes have the potential to effectively deliver siRNA and small-molecule drugs in a targeted manner and are thus a promising tool for the treatment of cancer and other diseases. [ABSTRACT FROM AUTHOR]

Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies. Heat shock protein 90 (Hsp90) as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance. Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance. In this study, a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX, and a COA-modified 4-arm PEG polymer (4PSC) was synthesized. COA, an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression, was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity. Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity. By blocking the Hsp90 signaling pathway, 4PSC significantly enhanced the antitumor effect of PTX, inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro. Remarkable results were further confirmed in vivo with two preclinical tumor models. These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies. The schematic illustration of the chemotherapy failure (left) and chemotherapy therapeutic strategy of 4 PSC/PTX nanomicelles (right). [Display omitted] [ABSTRACT FROM AUTHOR]

The homology-independent targeted integration (HITI) strategy enables effective CRISPR/Cas9-mediated knockin of therapeutic genes in nondividing cells in vivo, promising general therapeutic solutions for treating genetic diseases like X-linked juvenile retinoschisis. Herein, supramolecular nanoparticle (SMNP) vectors are used for codelivery of two DNA plasmids-CRISPR-Cas9 genome-editing system and a therapeutic gene, Retinoschisin 1 (RS1)-enabling clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) knockin of the RS1 gene with HITI. Through small-scale combinatorial screenings, two SMNP vectors, with Cas9 and single guide RNA (sgRNA)-plasmid in one and Donor-RS1 and green fluorescent protein (GFP)-plasmid in the other, with optimal delivery performances are identified. These SMNP vectors are then employed for CRISPR/Cas9 knockin of RS1/GFP genes into the mouse Rosa26 safe-harbor site in vitro and in vivo. The in vivo study involves intravitreally injecting the two SMNP vectors into the mouse eyes, followed by repeated ocular imaging by fundus camera and optical coherence tomography, and pathological and molecular analyses of the harvested retina tissues. Mice ocular organs retain their anatomical integrity, a single-copy 3.0-kb RS1/GFP gene is precisely integrated into the Rosa26 site in the retinas, and the integrated RS1/GFP gene is expressed in the retinas, demonstrating CRISPR/Cas9 knockin of RS1/GFP gene.

Abstract In this paper, we step forward in optimizing the efficiency of niosomal systems for carrying curcumin and miR-34a as single-/co-delivery to treat breast cancer. Curcumin, via regulation of p53 protein, affects the molecular signaling pathways and leads to cell death. Likewise, miRNAs, via alternation of the expression of genes, can suppress the development of tumor activities. To conquer and optimize the delivery limitation of curcumin and miRNA, niosomal systems with certain compositions (seven formulations) of Tween-80:Tween-60:cholesterol:DOTAP:PEG are introduced, which enhances the carrier size, surface charge, entrapment efficiency, transfection, and drug release. The results showed that Tween-60 has a significant influence on the entrapment efficiency of the composition. By including the PEG and DOTAP, high enhancements in the overall characteristics of the delivery system were observed. To assess the biological activity of samples, with/without the niosomal delivery system, cytotoxicity, apoptosis, in-vitro, and in-vivo cellular uptake were studied. The recorded data revealed better results from niosomal carriers than their free forms. The best result in single delivery was achieved by miRNA in F6, which had the highest apoptosis, uptake, and smallest tumor volumes under a controlled release. In conclusion, we successfully designed a nanoscale niosomal system to carry drugs and genes to the tumor site to treat cancer cells and provided remarkable data for the scientific society.

Photodynamic therapy (PDT) is a promising anticancer noninvasive technique that relies on the generation of reactive oxygen species (ROS). Unfortunately, PDT still has many limitations, including the resistance developed by cancer cells to the cytotoxic effect of ROS. Autophagy, which is a stress response mechanism, has been reported as a cellular pathway that reduces cell death following PDT. Recent studies have demonstrated that PDT in combination with other therapies can eliminate anticancer resistance. However, combination therapy is usually challenged by the differences in the pharmacokinetics of the drugs. Nanomaterials are excellent delivery systems for the efficient codelivery of two or more therapeutic agents. In this work, we report on the use of polysilsesquioxane (PSilQ) nanoparticles for the codelivery of chlorin-e6 (Ce6) and an autophagy inhibitor for early- or late-stage autophagy. Our results, obtained from a reactive oxygen species (ROS) generation assay and apoptosis and autophagy flux analyses, demonstrate that the reduced autophagy flux mediated by the combination approach afforded an increase in the phototherapeutic efficacy of Ce6-PSilQ nanoparticles. We envision that the promising results in the use of multimodal Ce6-PSilQ material as a codelivery system against cancer pave the way for its future application with other clinically relevant combinations. [ABSTRACT FROM AUTHOR]

Aim: To codeliver an anticancer drug (doxorubicin) and siRNA in the form of nanoparticles into CD44-overexpressing colon cancer cells (HT-29) using an anionic, amphiphilic biopolymer comprising modified hyaluronic acid (6-O-[3-hexadecyloxy-2-hydroxypropyl]-hyaluronic acid). Materials & methods: Characterization of nanoparticles was performed using dynamic light scattering, scanning electron microscopy, transmission electron microscopy, molecular docking, in vitro drug release and gel mobility assays. Detailed in vitro experiments, including a gene silencing study and western blot, were also performed. Results: A 69% knockdown of the target gene was observed, and western blot showed 5.7-fold downregulation of the target protein. The repulsive forces between siRNA and 6-O-(3-hexadecyloxy-2-hydroxypropyl)-hyaluronic acid were overcome by hydrogen bonding and hydrophobic interactions. Conclusion: The authors successfully codelivered a drug and siRNA by anionic vector. Mutations in genes are the main reason for the development of cancer. siRNA can selectively downregulate the key genes responsible for a particular cancer; however, this depends on successful delivery of siRNA into cancer cells. Usually, a negatively charged cell membrane repels negatively charged siRNA, which hinders siRNA entry into cancer cells. Usually, positively charged (cationic) polymers are used to mask siRNA for crossing the cancer cell membrane. However, cationic polymers are usually toxic to the body and show several adverse effects. By contrast, negatively charged polymers are safe alternatives for delivering siRNA into cancer cells. However, the main challenge of using anionic polymer lies behind the repulsive interaction between siRNA and negatively charged vectors, as both are negative. Herein we report successful codelivery of siRNA and an anticancer drug into cancer cells using a negatively charged polymer. Enemies into friends: anionic, amphiphilic hyaluronic acid codelivers drug and siRNA, overcoming electrostatic repulsion, in human colon cancer cell line (HT-29) by active targeting. This is the first report on codelivery of a drug and gene by an anionic, nonviral vector. [ABSTRACT FROM AUTHOR]

Aims: The development of rapamycin (RAP) and resveratrol (RSV) coloaded liposomes (RAP-RSV-LIP) for breast cancer therapy. Materials & methods: Liposomes were prepared using a high-pressure homogenization technique and evaluated according to their physicochemical characteristics, cellular uptake and cytotoxicity against tumoral and normal cells. Results & conclusion: The RAP-RSV-LIP showed negative surface charge, size around 100 nm, low polydispersity and high encapsulation efficiency for RAP and RSV (58.87 and 63.22%, respectively). RAP-RSV-LIP showed great stability over 60 days and a prolonged drug-release profile. In vitro studies indicated that RAP-RSV-LIP were internalized in an estrogen receptor-positive human breast cancer cell line (MCF-7, 34.2%) and improved cytotoxicity when compared with free drugs. Therefore RAP-RSV-LIP showed great antitumoral potential against breast cancer cells. [ABSTRACT FROM AUTHOR]

Anticancer drugs in monotherapy are ineffective to treat various kinds of cancer due to the heterogeneous nature of cancer. Moreover, available anticancer drugs possessed various hurdles, such as drug resistance, insensitivity of cancer cells to drugs, adverse effects and patient inconveniences. Hence, plant-based phytochemicals could be a better substitute for conventional chemotherapy for treatment of cancer due to various properties: lesser adverse effects, action via multiple pathways, economical, etc. Various preclinical studies have demonstrated that a combination of phytochemicals with conventional anticancer drugs is more efficacious than phytochemicals individually to treat cancer because plant-derived compounds have lower anticancer efficacy than conventional anticancer drugs. Moreover, phytochemicals suffer from poor aqueous solubility and reduced bioavailability, which must be resolved for efficacious treatment of cancer. Therefore, nanotechnology-based novel carriers are employed for codelivery of phytochemicals and conventional anticancer drugs for better treatment of cancer. These novel carriers include nanoemulsion, nanosuspension, nanostructured lipid carriers, solid lipid nanoparticles, polymeric nanoparticles, polymeric micelles, dendrimers, metallic nanoparticles, carbon nanotubes that provide various benefits of improved solubility, reduced adverse effects, higher efficacy, reduced dose, improved dosing frequency, reduced drug resistance, improved bioavailability and higher patient compliance. This review summarizes various phytochemicals employed in treatment of cancer, combination therapy of phytochemicals with anticancer drugs and various nanotechnology-based carriers to deliver the combination therapy in treatment of cancer. [ABSTRACT FROM AUTHOR]

Aim: Folate-targeted Pluronic™ F-127/poly(lactic acid) (FA-F127-PLA) polymersomes were used as codelivery carriers of doxorubicin hydrochloride (DOX) and paclitaxel (PTX) to achieve a targeted synergistic antitumor effect. Materials & methods: The cytotoxicity of PTX/DOX polymersomes against OVCAR-3 cells was determined by methyl thiazolyl tetrazolium assay. The cellular uptake of PTX/DOX polymersomes was examined by HPLC and micro-bicinchoninic acid techniques. Results: The polymersomes showed a bilayer core–shell structure with negative charge and good dispersion. PTX1/DOX5 polymersomes with a mass ratio of PTX to DOX of 1:5 showed the best synergistic effect and the highest cellular uptake. Conclusion: FA-F127-PLA polymersomes have the great promise for codelivery of multiple chemotherapeutics to achieve a targeted antitumor synergistic effect. Hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic paclitaxel (PTX) are two well-known anticancer drugs. Coadministration of DOX and PTX as a free drug cocktail has been widely used in clinical treatment to further improve their anticancer effect. However, this free drug cocktail often causes a lot of side effects such as cardiotoxicity and nephrotoxicity. In order to reduce the side effects of the drug cocktail and enhance their targeted delivery, folic acid-targeted Pluronic™ F-127 / poly(lactic acid) (FA-F127-PLA) polymersomes were used to load the drug cocktail. Both the cytotoxicity and cellular uptake data showed that PTX/DOX coloaded FA-F127-PLA polymersomes had better synergistic anticancer ability than a DOX and PTX free-drug cocktail. Better synergistic anticancer effect of doxorubicin hydrochloride and paclitaxel drug cocktail was achieved by codelivering them via folate-targeted Pluronic™ F-127 / poly(lactic acid) polymersomes. [ABSTRACT FROM AUTHOR]

Combination therapy combining two drugs in one modified drug delivery system is used to achieve synergistic analgesic effect, and bring effective control of pain management, especially postoperative pain management. In the present study, a combination of drug delivery technologies was utilized. Transcriptional transactivator (TAT) peptide modified, transdermal nanocarriers were designed to codeliver ropivacaine (RVC) and meloxicam (MLX) and anticipated to achieve longer analgesic effect and lower side effect. TAT modified nanostructured lipid carriers (TAT-NLCs) were used to co-deliver RVC and MLX. RVC and MLX co-loaded TAT-NLCs (TAT-NLCs-RVC/MLX) were evaluated through in vitro skin permeation and in vivo treatment studies. NLCs-RVC/MLX showed uniform and spherical morphology, with a size of 133.4 ± 4.6nm and a zeta potential of 20.6 ± 1.8 mV. The results illustrated the anesthetic pain relief ability of the present constructed system was significantly improved by the TAT modification through the enhanced skin permeation efficiency and the co-delivery of MLX along with RVC that improved pain management by reducing inflammation at the injured area. This study provides an efficient and facile method for preparing TAT-NLCs-RVC/MLX as a promising system to achieve synergistic analgesic effect. [ABSTRACT FROM AUTHOR]

Chrysophanol and hesperidin are natural nutraceuticals that exhibit synergistic bioactivities, but their hydrophobicity limits their applications, and it is unclear whether coencapsulation can improve their solubility and release behaviors. The objective of this work was to coencapsulate chrysophanol and hesperidin by octenylsuccinated β -glucan aggregates (OS β G-Agg) and to reveal how coencapsulation improves their release and bioaccessibility. Mechanisms underlying the hypothesis of beneficial effects in coloading, corelease and bioaccessibility were revealed. The solubilization of OS β G-Agg was due to hydrogen-bonding among β -glucan moieties of OS β G and hydroxyl groups of chrysophanol and hesperidin and hydrophobic interactions among octenyl chains of OS β G and hydrophobic moieties of chrysophanol and hesperidin. Structural analyses confirmed the hypothesis that chrysophanol molecules were nearly embedded deeper into the interior of hydrophobic domains, and most of hesperidin molecules were incorporated into the exterior of the hydrophobic domains of OS β G-Agg due to the strength of these interactions, but they interacted in OS β G-Agg with a dense and compact structure rather than existing in isolation. The combined effects delayed their release and enhanced their bioaccessibility because of dynamic equilibrium between the favorable interactions and unfavorable structural erosion and relaxation of OS β G-Agg. Overall, OS β G-Agg is effective at codelivering hydrophobic phenolics for functional foods and pharmaceuticals. [Display omitted] • Coloading improved the release and bioaccessibility of chrysophanol and hesperidin. • Hydrodynamic, hydrophilic and hydrophobic structures of OS β G-aggregates were revealed. • Chrysophanol and hesperidin loaded in different domains of OS β G-aggregates. • Coloading caused transition from a loose structure to a compact aggregating structure. • Coencapsulation of chrysophanol and hesperidin was due to Multiple interactions. [ABSTRACT FROM AUTHOR]

The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC. [Display omitted] [ABSTRACT FROM AUTHOR]

Combined drug administration is a potential strategy to increase efficacy through therapeutic synergy. Small molecule drugs and protein drugs are the two most popular kinds of drugs in medicine. However, efficiently encapsulating these two drugs still have key challenges due to their distinct properties (molecular weight, hydrophilicity, chemical groups, etc.), weak ability to penetrate through various biobarriers (cell membrane, endosome escape, tissue barriers dependent on the method of administration, etc.) and the easy deactivation of protein drugs during the construction of carrier and delivery process. Here, we utilize the hexahistidine-metal assembly (HmA), which can encapsulate a wide spectrum of drugs with high loading efficiency, to coencapsulate Dexp (a small molecule drug) and BVZ (protein drug) by a one-pot coassembly strategy. Our data demonstrated that Dexp and BVZ were coloaded into Dexp&BVZ@HmA with high efficiency, while the bioactivity of BVZ was well-maintained. Most importantly, when evaluating the therapeutic outcomes of drugs@HmA in a corneal neovascularization (CNV) model in vitro and in vivo, the combination group presented overwhelming efficacy compared to the monotherapy group. This strategy offers a platform to codeliver protein and small drugs and has the potential for treating anterior segment diseases as well as other diseases that need combination therapy.

A novel Cur/TPP‐β‐CD/CS/Vc microparticles (MPs) filled CMCS/OSA composite hydrogel was prepared by dispersed the chitosan/vitamin C (CS/Vc) complex and curcumin/TPP‐β‐cyclodextrin (Cur/TPP‐β‐CD) complex in the hydrogel precursor of oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMCS). Structural properties of the MPs/CMCS/OSA composite hydrogel were characterized by Fourier transform infrared, scanning electron microscope, TG, rheological, and texture analyzer. It was found that the polymeric MPs with a diameter of about 2.5 μm were homogenously embedded in the composite hydrogel by hydrogen bonding and electronic force, resulting in obvious enhanced mechanical strength and stability of the MPs hybrid hydrogel. In vitro release studies show that the release of Cur and Vc can be more efficiently controlled by the different encapsulation pathways. Moreover, the preferential release of the Cur than that of Vc has been confirmed by the two‐dimensional ultraviolet correlation spectroscopy. Therefore, the MPs/CMCS/OSA composite hydrogel can be used for independently controlled release of dual bioactive compounds during codelivery. [ABSTRACT FROM AUTHOR]

In this paper, we step forward in optimizing the efficiency of niosomal systems for carrying curcumin and miR-34a as single-/co-delivery to treat breast cancer. Curcumin, via regulation of p53 protein, affects the molecular signaling pathways and leads to cell death. Likewise, miRNAs, via alternation of the expression of genes, can suppress the development of tumor activities. To conquer and optimize the delivery limitation of curcumin and miRNA, niosomal systems with certain compositions (seven formulations) of Tween-80:Tween-60:cholesterol:DOTAP:PEG are introduced, which enhances the carrier size, surface charge, entrapment efficiency, transfection, and drug release. The results showed that Tween-60 has a significant influence on the entrapment efficiency of the composition. By including the PEG and DOTAP, high enhancements in the overall characteristics of the delivery system were observed. To assess the biological activity of samples, with/without the niosomal delivery system, cytotoxicity, apoptosis, in-vitro, and in-vivo cellular uptake were studied. The recorded data revealed better results from niosomal carriers than their free forms. The best result in single delivery was achieved by miRNA in F6, which had the highest apoptosis, uptake, and smallest tumor volumes under a controlled release. In conclusion, we successfully designed a nanoscale niosomal system to carry drugs and genes to the tumor site to treat cancer cells and provided remarkable data for the scientific society. [ABSTRACT FROM AUTHOR]

Malignant breast tumors constitute the most frequent cancer diagnosis among women. Notwithstanding the progress in treatments, this condition persists as a major public health issue. Paclitaxel (PTX) is a first-line classical chemotherapeutic drug used as a single active pharmaceutical ingredient (API) or in combination therapy for breast cancer (BC) treatment. Adverse effects, poor water solubility, and inevitable susceptibility to drug resistance seriously limit its therapeutic efficacy in the clinic. Piplartine (PPT), an alkaloid extracted from Piper longum L., has been shown to inhibit cancer cell proliferation in several cell lines due to its pro-oxidant activity. However, PPT has low water solubility and bioavailability in vivo , and new strategies should be developed to optimize its use as a chemotherapeutic agent. In this context, the present study aimed to synthesize a series of acetalated dextran nanoparticles (Ac-Dex NPs) encapsulating PPT and PTX to overcome the limitations of PPT and PTX, maximizing their therapeutic efficacy and achieving prolonged and targeted codelivery of these anticancer compounds into BC cells. Biodegradable, pH-responsive, and biocompatible Ac-Dex NPs with diameters of 100-200 nm and spherical morphologies were formulated using a single emulsion method. Selected Ac-Dex NPs containing only PPT or PTX as well as those coloaded with PPT and PTX achieved excellent drug-loading capabilities (PPT, ca. 11-33%; PTX, ca. 2-14%) and high encapsulation efficiencies (PPT, ∼57-98%; PTX, ∼80-97%). Under physiological conditions (pH 7.4), these NPs exhibited excellent colloidal stability and were capable of protecting drug release, while under acidic conditions (pH 5.5) they showed structural collapse, releasing the therapeutics in an extended manner. Cytotoxicity results demonstrated that the encapsulation in Ac-Dex NPs had a positive effect on the activities of both PPT and PTX against the MCF-7 human breast cancer cell line after 48 h of treatment, as well as toward MDA-MB-231 triple-negative BC cells. PPT/PTX@Ac-Dex NPs were significantly more cytotoxic (IC 50/PPT = 0.25-1.77 μM and IC 50/PTX = 0.07-0.75 μM) and selective (SI = 2.9-6.7) against MCF-7 cells than all the control therapeutic agents: free PPT (IC 50 = 4.57 μM; SI = 1.2), free PTX (IC 50 = 0.97 μM; SI = 1.0), the single-drug-loaded Ac-Dex NPs, and the physical mixture of both free drugs. All combinations of PPT and PTX resulted in pronounced synergistic antiproliferative effects in MCF-7 cells, with an optimal molar ratio of PPT to PTX of 2.3:1. PPT/PTX-2@Ac-Dex NPs notably promoted apoptosis, cell cycle arrest at the G2/M, accumulation of intracellular reactive oxygen species (ROS), and combined effects from both PPT and PTX on the microtubule network of MCF-7 cells. Overall, the combination of PTX and PPT in pH-responsive Ac-Dex NPs may offer great potential to improve the therapeutic efficacy, overcome the limitations, and provide effective simultaneous delivery of these therapeutics for BC treatment.

Photodynamic therapy (PDT) is a promising anticancer noninvasive technique that relies on the generation of reactive oxygen species (ROS). Unfortunately, PDT still has many limitations, including the resistance developed by cancer cells to the cytotoxic effect of ROS. Autophagy, which is a stress response mechanism, has been reported as a cellular pathway that reduces cell death following PDT. Recent studies have demonstrated that PDT in combination with other therapies can eliminate anticancer resistance. However, combination therapy is usually challenged by the differences in the pharmacokinetics of the drugs. Nanomaterials are excellent delivery systems for the efficient codelivery of two or more therapeutic agents. In this work, we report on the use of polysilsesquioxane (PSilQ) nanoparticles for the codelivery of chlorin-e6 (Ce6) and an autophagy inhibitor for early- or late-stage autophagy. Our results, obtained from a reactive oxygen species (ROS) generation assay and apoptosis and autophagy flux analyses, demonstrate that the reduced autophagy flux mediated by the combination approach afforded an increase in the phototherapeutic efficacy of Ce6-PSilQ nanoparticles. We envision that the promising results in the use of multimodal Ce6-PSilQ material as a codelivery system against cancer pave the way for its future application with other clinically relevant combinations.

Anticancer drugs in monotherapy are ineffective to treat various kinds of cancer due to the heterogeneous nature of cancer. Moreover, available anticancer drugs possessed various hurdles, such as drug resistance, insensitivity of cancer cells to drugs, adverse effects and patient inconveniences. Hence, plant-based phytochemicals could be a better substitute for conventional chemotherapy for treatment of cancer due to various properties: lesser adverse effects, action via multiple pathways, economical, etc. Various preclinical studies have demonstrated that a combination of phytochemicals with conventional anticancer drugs is more efficacious than phytochemicals individually to treat cancer because plant-derived compounds have lower anticancer efficacy than conventional anticancer drugs. Moreover, phytochemicals suffer from poor aqueous solubility and reduced bioavailability, which must be resolved for efficacious treatment of cancer. Therefore, nanotechnology-based novel carriers are employed for codelivery of phytochemicals and conventional anticancer drugs for better treatment of cancer. These novel carriers include nanoemulsion, nanosuspension, nanostructured lipid carriers, solid lipid nanoparticles, polymeric nanoparticles, polymeric micelles, dendrimers, metallic nanoparticles, carbon nanotubes that provide various benefits of improved solubility, reduced adverse effects, higher efficacy, reduced dose, improved dosing frequency, reduced drug resistance, improved bioavailability and higher patient compliance. This review summarizes various phytochemicals employed in treatment of cancer, combination therapy of phytochemicals with anticancer drugs and various nanotechnology-based carriers to deliver the combination therapy in treatment of cancer.

In the tumor microenvironment (TME), the cross-talk between tumor cells and hepatic stellate cells (HSCs) could facilitate tumor drug resistance and metastasis, leading to poor prognosis in the patients with hepatocellular carcinoma (HCC). Herein, blocking the cross-talk would be an effective antitumor strategy. In this study, nanoscale dual-ligand-modified multifunctional liposomes (CMDLs) were prepared for the codelivery of curcumin and metformin. To mimic a real TME, the "HSC + HCC" cell cocultured model and "m-HSC–HCC" coimplanted model were established to evaluate the antitumor effect in vitro and in vivo, respectively. These models have been proven to be more efficient for antitumor analysis than tumor cells alone. Compared to free drugs, CMDLs well strengthened drug internalization and drug retention in vitro. Notably, the combined drug formulations, especially CMDLs, exhibited a greater proapoptotic effect than single treatment groups. Furthermore, the in vivo antitumor studies showed that CMDLs exhibited low extracellular matrix deposition, less tumor angiogenesis, and superior anti-HCC efficacy than the other groups in both subcutaneous H22 cells and "m-HSC + H22" coimplanted mice models. The antitumor mechanisms revealed that the combination therapy based on the nanoscale CMDLs could not only inhibit the activation of HSCs by blocking the TGF-β/Smad2 pathway but also block tumor metastasis by reversing epithelial mesenchymal transformation of HCC, which provides a promising approach for anti-HCC therapy. [ABSTRACT FROM AUTHOR]

To treat various cancers, including lung cancer, chemotherapy requires the systematic administering of chemotherapy. The chemotherapeutic effectiveness of anticancer drugs has been enhanced by polymer nanoparticles (NPs), according to new findings. As an outcome, we have developed biodegradable triblock poly(ethylene glycol)-poly(e-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) polymeric NPs for the co-delivery of sorafenib (SORA) and crizotinib (CRIZ) and investigated their effect on lung cancer by in vitro and in vivo. There is little polydispersity in the SORA-CRIZ@NPs, an average size of 30.45 ± 2.89 nm range. A steady release of SORA and CRIZ was observed, with no burst impact. The apoptosis rate of SORA-CRIZ@NPs was greater than that of free drugs in 4T1 and A549 cells. Further, in vitro cytotoxicity of the polymeric NPs loaded with potential anticancer drugs was more quickly absorbed by cancer cells. On the other hand, compared to free drugs (SORAþCRIZ), SORAþCRIZ@NPs showed a substantial reduction of tumor development, longer survival rate, and a lowered side effect when delivered intravenously to nude mice xenograft model with 4T1 cancer cells. TUNEL positivity was also increased in tumor cells treated with SORA-CRIZ@NPs, demonstrating the therapeutic effectiveness. SORA-CRIZ@NPs might be used to treat lung cancer soon, based on the results from our new findings. [ABSTRACT FROM AUTHOR]

The present study reports the generation of 2-hydroxyethyl starch microparticles for co-delivery and controlled release of multiple agents. The obtained microparticles are characterized by using Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis, energy-dispersive X-ray spectroscopy, and scanning electron microscopy. By using ofloxacin and ketoprofen as drug models, the release sustainability of the microparticles is examined at pH 1.2, 5.4, and 6.8 at 37 -C, with Fickian diffusion being found to be the major mechanism controlling the kinetics of drug release. Upon being loaded with the drug models, the microparticles show high efficiency in acting against Escherichia coli and Bacillus cereus. The results suggest that our reported microparticles warrant further development for applications in which co-administration of multiple bioactive agents is required. [ABSTRACT FROM AUTHOR]

Zeliang Wei,1,2 Haibo Wang,3 Guang Xin,1 Zhi Zeng,1 Shiyi Li,1 Yue Ming,1 Xiaoyu Zhang,1 Zhihua Xing,1 Li Li,2 Youping Li,1 Boli Zhang,1,4 Junhua Zhang,4 Hai Niu,1,5 Wen Huang1 1Laboratory of Ethnopharmacology, West China Medical School, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Textile Institute, College of Light Industry, Textile and Food Engineering, Sichuan University, Chengdu, People’s Republic of China; 4Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 5College of Mathematics, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Wen Huang; Hai Niu Email huangwen@scu.edu.cn; niuhai@scu.edu.cnBackground: The metastasis, one of the biggest barriers in cancer therapy, is the leading cause of tumor deterioration and recurrence. The anti.-metastasis has been considered as a feasible strategy for clinical cancer management. It is well known that diosgenin could inhibit tumor metastasis and doxorubicin (DOX) could induce tumor apoptosis. However, their efficient delivery remains challenging.Purpose: To address these issues, a novel pH-sensitive polymer-prodrug based on diosgenin nanoparticles (NPs) platform was developed to enhance the efficiency of DOX delivery (DOX/NPs) for synergistic therapy of cutaneous melanoma, the most lethal form of skin cancer with high malignancy, early metastasis and high mortality.Methods and Results: The inhibitory effect of DOX/NPs on tumor proliferation and migration was superior to that of NPs or free DOX. What is more, DOX/NPs could combine mitochondria-associated metastasis and apoptosis with unique internalization pathway of carrier to fight tumors. In addition, biodistribution experiments proved that DOX/NPs could efficiently accumulate in tumor sites through enhancing permeation and retention (EPR) effect compared with free DOX. Importantly, the data from in vivo experiment revealed that DOX/NPs without heart toxicity significantly inhibited tumor metastasis by exerting synergistic therapeutic effect, and reduced tumor volume and weight by inducing apoptosis.Conclusion: The nanocarrier DOX/NPs with satisfying pharmaceutical characteristics based on the establishment of two different functional agents is a promising strategy for synergistically enhancing effects of cancer therapy.Keywords: anti-metastasis, antitumor, self-assembly, codelivery, doxorubicin

Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease occurring at the arterial subendothelial space. Macrophages play a critical role in the initiation and development of AS. Herein, targeted codelivery of anti-miR 155 and anti-inflammatory baicalein is exploited to polarize macrophages toward M2 phenotype, inhibit inflammation and treat AS. The codelivery system consists of a carrier-free strategy (drug-delivering-drug, DDD), fabricated by loading anti-miR155 on baicalein nanocrystals, named as baicalein nanorods (BNRs), followed by sialic acid coating to target macrophages. The codelivery system, with a diameter of 150 nm, enables efficient intracellular delivery of anti-miR155 and polarizes M1 to M2, while markedly lowers the level of inflammatory factors in vitro and in vivo. In particular, intracellular fate assay reveals that the codelivery system allows for sustained drug release over time after internalization. Moreover, due to prolonged blood circulation and improved accumulation at the AS plaque, the codelivery system significantly alleviates AS in animal model by increasing the artery lumen diameter, reducing blood pressure, promoting M2 polarization, inhibiting secretion of inflammatory factors and decreasing blood lipids. Taken together, the codelivery could potentially be used to treat vascular inflammation.

Abstract Background Multidrug resistance (MDR) is a pressing obstacle in clinical chemotherapy for breast cancer. Based on the fact that the drug efflux is an important factor in MDR, we designed a codelivery system to guide the drug efflux inhibitor verapamil (VRP) and the chemotherapeutic agent novantrone (NVT) synergistically into breast cancer cells to reverse MDR. Results This co-delivery system consists of following components: the active targeting peptide RGD, an inorganic calcium phosphate (CaP) shell and an organic inner core. VRP and NVT were loaded into CaP shell and phosphatidylserine polyethylene glycol (PS-PEG) core of nanoparticles (NPs) separately to obtain NVT- and VRP-loaded NPs (NV@CaP-RGD). These codelivered NPs allowed VRP to prevent the efflux of NVT from breast cancer cells by competitively combining with drug efflux pumps. Additionally, NV@CaP-RGD was effectively internalized into breast cancer cells by precise delivery through the effects of the active targeting peptides RGD and EPR. The pH-triggered profile of CaP was also able to assist the NPs to successfully escape from lysosomes, leading to a greatly increased effective intracellular drug concentration. Conclusion The concurrent administration of VRP and NVT by organic/inorganic NPs is a promising therapeutic approach to reverse MDR in breast cancer.

Colon cancer (CC) is one of the most prevalent cancers in the world, and chemotherapy is widely applied to combat it. However, chemotherapy drugs have severe side effects and emergence of multi drug resistance (MDR) is common. This bottleneck can be overcome by niosome nanocarriers that minimize drug dose/toxicity meanwhile allow co-loading of incompatible drugs for combination therapy. In this research, silibinin (Sil) as a hydrophobic drug was loaded into the lipophilic part, and methotrexate (MTX) into the hydrophilic part of niosome by the thin film hydration (TFH) method to form Nio@MS NPs for CT26 colon cancer therapy in vitro . Our results indicated synthesis of ideal niosome nanoparticles (NPs) with spherical morphology, size of ∼100 nm, and a zeta potential of -10 mV. The IC 50 value for Nio@MS was determined ∼2.6 µg ml -1 , which was significantly lower than MTX-Sil (∼6.86 µg ml -1 ), Sil (18.46 µg ml -1 ), and MTX (9.8 µg ml -1 ). Further, Nio@MS significantly reduced cell adhesion density, promoted apoptosis and increased gene expression level of caspase 3 and BAX while promoted significant downregulation of BCL2. In conclusion, the design and application of niosome to co-administer Sil and MTX can increase the drugs cytotoxicity, reduce their dose and improve anti-cancer potential by combating MDR., (© 2024 IOP Publishing Ltd.)

Adjuvants and immunomodulators that effectively drive a Th17-skewed immune response are not part of the standard vaccine toolkit. Vaccine adjuvants and delivery technologies that can induce Th17 or Th1/17 immunity and protection against bacterial pathogens, such as tuberculosis (TB), are urgently needed. Th17-polarized immune response can be induced using agonists that bind and activate C-type lectin receptors (CLRs) such as macrophage inducible C-type lectin (Mincle). A simple but effective strategy was developed for codelivering Mincle agonists with the recombinant Mycobacterium tuberculosis fusion antigen, M72, using tunable silica nanoparticles (SNP). Anionic bare SNP, hydrophobic phenyl-functionalized SNP (P-SNP), and cationic amine-functionalized SNP (A-SNP) of different sizes were coated with three synthetic Mincle agonists, UM-1024, UM-1052, and UM-1098, and evaluated for adjuvant activity in vitro and in vivo. The antigen and adjuvant were coadsorbed onto SNP via electrostatic and hydrophobic interactions, facilitating multivalent display and delivery to antigen presenting cells. The cationic A-SNP showed the highest coloading efficiency for the antigen and adjuvant. In addition, the UM-1098-adsorbed A-SNP formulation demonstrated slow-release kinetics in vitro, excellent stability over 12 months of storage, and strong IL-6 induction from human peripheral blood mononuclear cells. Co-adsorption of UM-1098 and M72 on A-SNP significantly improved antigen-specific humoral and Th17-polarized immune responses in vivo in BALB/c mice relative to the controls. Taken together, A-SNP is a promising platform for codelivery and proper presentation of adjuvants and antigens and provides the basis for their further development as a vaccine delivery platform for immunization against TB or other diseases for which Th17 immunity contributes to protection.

In this paper, the self-assembled folate-biotin-quaternized starch nanoparticles (FBqS NPs) were used as carrier system of doxorubicin (DOX) and siRNAIGF1R for the codelivery of both into human lung adenocarcinoma cell lines (A549 cells) in vitro. The cytotoxicity, targeted ligand competition, cell proliferation inhibition, cellular uptake, endocytosis mechanism and target protein suppression of drug-loaded FBqS NPs were evaluated in detail. Compared with several other drug formulations under same condition, siRNAIGF1R/DOX/FBqS NPs exhibited the greatest cytotoxicity to A549 cells and the cytotoxicity was competitively inhibited by free folate in dose-dependent manner. The A549 cells treated by siRNAIGF1R/DOX/FBqS NPs showed the lowest cell proliferation capacity. The energy-dependent clathrin- and caveolae-mediated endocytosis might be the primary cellular uptake mechanism of drug-loaded FBqS NPs. The expression of IGF1R protein in A549 cells treated by siRNAIGF1R/FBqS NPs declined dramatically. So the FBqS NPs were expected as the co-carrier system of chemotherapeutants and siRNAs for future clinical application.

Although topical application of minoxidil is a widely used, FDA-approved therapy for androgenetic alopecia (AGA) treatment, it suffers from low bioavailability, the requirement for frequent long-term use, and side effects. With a similar structure as minoxidil, kopexil and kopyrrol are less toxic and have been commercialized, but show an inferior hair regeneration effect compared to minoxidil. Herein, we developed a hyaluronic acid (HA)-based dissolvable microneedles (MNs) delivery platform integrated with kopexil and kopyrrol coencapsulated nanoliposomes (KK-NLPs) to effectively and safely treat AGA. Facilitated by nanoliposomes and MNs, the encapsulated KK-NLPs performed efficient skin penetration and enhanced cellular internalization into human dermal papilla cells. Furthermore, within the target cells, the codelivered kopexil and kopyrrol show synergistic effects by orchestrating an upregulation in the expression of Ki67, β-catenin, vascular endothelial growth factor (VEGF), and CD31. These molecular responses collectively foster cell proliferation, migration, and antioxidative effects, thereby facilitating the expedited progression of hair follicles (HFs) into the anagen phase and promoting peripheral angiogenesis. Notably, the KK-NLPs-integrated MNs treatment group exhibits noteworthy enhanced hair regeneration in vivo , with identical or superior therapeutic effects at a much lower dosage than that of minoxidil. These results suggest the great potential of this kopexil and kopyrrol codelivery nanoliposomes-integrated MNs platform for AGA treatment in a safe and efficient way.

The nonviral delivery systems that combine genes with photosensitizers for multimodal tumor gene/photodynamic therapy (PDT) have attracted much attention. In this study, a series of ROS-sensitive cationic bola-lipids were applied for the gene/photosensitizer codelivery. Zn-DPA was introduced as a cationic headgroup to enhance DNA binding, while the hydrophobic linking chains may facilitate the formation of lipid nanoparticles (LNP) and the encapsulation of photosensitizer Ce6. The length of the hydrophobic chain played an important role in the gene transfection process, and 14-TDZn containing the longest chains showed better DNA condensation, gene transfection, and cellular uptake. 14-TDZn LNPs could well load photosensitizer Ce6 to form 14-TDC without a loss of gene delivery efficiency. 14-TDC was used for codelivery of p53 and Ce6 to achieve enhanced therapeutic effects on the tumor cell proliferation inhibition and apoptosis. Results showed that the codelivery system was more effective in the inhibition of tumor cell proliferation than individual p53 or Ce6 monotherapy. Mechanism studies showed that the production of ROS after Ce6 irradiation could increase the accumulation of p53 protein in tumor cells, thereby promoting caspase-3 activation and inducing apoptosis, indicating some synergistic effect. These results demonstrated that 14-TDC may serve as a promising nanocarrier for gene/PDT combination therapy.

Multidrug resistance (MDR) has long been a major obstacle in the treatment of malignant tumors. Combination therapy provides a viable and promising strategy to overcome MDR. This article discusses the advantages of nano-based combination therapy and proposes a 3R delivery principle (right place, right time, and right dose) as a reference for development of cancer nanomedicine containing drug combinations. The article also reviews the strategies of nano-based codelivery, with emphasis on the techniques designed to overcome chemoresistance, enhance drug targeting delivery, and reduce immunosuppression.

Abstract The homology‐independent targeted integration (HITI) strategy enables effective CRISPR/Cas9‐mediated knockin of therapeutic genes in nondividing cells in vivo, promising general therapeutic solutions for treating genetic diseases like X‐linked juvenile retinoschisis. Herein, supramolecular nanoparticle (SMNP) vectors are used for codelivery of two DNA plasmids—CRISPR‐Cas9 genome‐editing system and a therapeutic gene, Retinoschisin 1 (RS1)—enabling clustered regularly interspaced short palindromic repeats (CRISPR)‐associated protein 9 (CRISPR/Cas9) knockin of the RS1 gene with HITI. Through small‐scale combinatorial screenings, two SMNP vectors, with Cas9 and single guide RNA (sgRNA)‐plasmid in one and Donor‐RS1 and green fluorescent protein (GFP)‐plasmid in the other, with optimal delivery performances are identified. These SMNP vectors are then employed for CRISPR/Cas9 knockin of RS1/GFP genes into the mouse Rosa26 safe‐harbor site in vitro and in vivo. The in vivo study involves intravitreally injecting the two SMNP vectors into the mouse eyes, followed by repeated ocular imaging by fundus camera and optical coherence tomography, and pathological and molecular analyses of the harvested retina tissues. Mice ocular organs retain their anatomical integrity, a single‐copy 3.0‐kb RS1/GFP gene is precisely integrated into the Rosa26 site in the retinas, and the integrated RS1/GFP gene is expressed in the retinas, demonstrating CRISPR/Cas9 knockin of RS1/GFP gene.

Coassembled nanoparticles composed of functionalized mesoporous silica and pillar[5]arene‐appended Au nanoparticles obtained through the formation of a host–guest complex are designed and synthesized as a mitochondrial‐selective dual‐drug delivery system. A pyridinium‐based ligand and fluorescein isothiocyanate are immobilized onto mesoporous silica to act as the mitochondria‐targeting ligand and fluorescence tracker, respectively, of a material dubbed NP‐3. Carboxylated pillar[5]arene‐capped Au nanoparticles (CP‐AuNPs) are fabricated by the templated reduction of Au3+. Interestingly, coassembled nanoparticles (NP‐1) composed of doxorubicin (DOX) loaded NP‐3 and CP‐AuNPs are then prepared via the formation of a host–guest complex between the pyridinium‐based ligand of NP‐3 and the pillar[5]arene of CP‐AuNPs. To demonstrate the effectiveness of NP‐2 and NP‐1 as mitochondrial targeting drug delivery systems, DOX and F16 are employed as model drugs. These drugs loaded onto NP‐2 and CP‐AuNPs, respectively, are selectively delivered to mitochondria, indicating the usefulness of NP‐2 and CP‐AuNPs as mitochondrial‐specific drug‐delivery carriers in cancer cells. More interestingly, the use of NP‐1 is also associated with the selective accumulation of DOX and F16 in mitochondria. The selective mitochondrial‐targeting of NP‐1 is possible by NP‐2 and F16 exposed to the cytoplasm, allowing the codelivery of the two drugs to the mitochondria. [ABSTRACT FROM AUTHOR]

Chemotherapy remains one of the most effective treatments for many cancers in a clinic. At present, various targets have been used to modify the PEGylated liposomes for doxorubicin (Dox) delivery, but the antitumor effect of Dox is not satisfactory. Therefore, combination chemotherapeutics has been considered as a promising method to improve tumor treatment. These years, RAF/MEK/ERK-mediated cell signaling pathway has been discovered to inhibit the growth of tumors. Thus, Sorafenib tosylate (Sor) was used in this study, which directly inhibited tumor cell proliferation through blocking RAF/MEK/ERK-mediated cell signaling pathway and indirectly inhibited tumor cell growth through blocking angiogenesis by VEGFR and PDGF. In this article, we develop a "combination delivery system" to deliver the hydrophobic drug (Sor) in phospholipid bilayer and hydrophilic drug (Dox) in inner cores for enhancing the antitumor effect. Moreover, in vitro experiments verified whether the physicochemical properties of carriers were stable and transferrin-modified liposomes displayed the highest uptake. The results of in vivo experiments showed that the codelivery system inhibited the tumor growth more effectively than monotherapy. Overall, this combination delivery system for delivering the hydrophobic and hydrophilic drugs simultaneously may offer a novel strategy for breast cancer treatment and provide a reference for the possibility of clinical usage. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease occurring at the arterial subendothelial space. Macrophages play a critical role in the initiation and development of AS. Herein, targeted codelivery of anti-miR 155 and anti-inflammatory baicalein is exploited to polarize macrophages toward M2 phenotype, inhibit inflammation and treat AS. The codelivery system consists of a carrier-free strategy (drug-delivering-drug, DDD), fabricated by loading anti-miR155 on baicalein nanocrystals, named as baicalein nanorods (BNRs), followed by sialic acid coating to target macrophages. The codelivery system, with a diameter of 150 nm, enables efficient intracellular delivery of anti-miR155 and polarizes M1 to M2, while markedly lowers the level of inflammatory factors in vitro and in vivo. In particular, intracellular fate assay reveals that the codelivery system allows for sustained drug release over time after internalization. Moreover, due to prolonged blood circulation and improved accumulation at the AS plaque, the codelivery system significantly alleviates AS in animal model by increasing the artery lumen diameter, reducing blood pressure, promoting M2 polarization, inhibiting secretion of inflammatory factors and decreasing blood lipids. Taken together, the codelivery could potentially be used to treat vascular inflammation. Image 1 Targeted codelivery of anti-miR 155 and anti-inflammatory drug, baicalein, by using a carrier-free strategy effectively promotes polarization of macrophages from M1 toward M2 in vitro and in vivo. The codelivery system has prolonged blood-circulation time and can accumulate in the plaque after intravenous injection. The platform is potent to combat vascular inflammation. [ABSTRACT FROM AUTHOR]

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Background: Multidrug resistance (MDR) is a pressing obstacle in clinical chemotherapy for breast cancer. Based on the fact that the drug efflux is an important factor in MDR, we designed a codelivery system to guide the drug efflux inhibitor verapamil (VRP) and the chemotherapeutic agent novantrone (NVT) synergistically into breast cancer cells to reverse MDR. Results: This co-delivery system consists of following components: the active targeting peptide RGD, an inorganic calcium phosphate (CaP) shell and an organic inner core. VRP and NVT were loaded into CaP shell and phosphatidylserine polyethylene glycol (PS-PEG) core of nanoparticles (NPs) separately to obtain NVT- and VRP-loaded NPs (NV@CaP-RGD). These codelivered NPs allowed VRP to prevent the efflux of NVT from breast cancer cells by competitively combining with drug efflux pumps. Additionally, NV@CaP-RGD was effectively internalized into breast cancer cells by precise delivery through the effects of the active targeting peptides RGD and EPR. The pH-triggered profile of CaP was also able to assist the NPs to successfully escape from lysosomes, leading to a greatly increased effective intracellular drug concentration. Conclusion: The concurrent administration of VRP and NVT by organic/inorganic NPs is a promising therapeutic approach to reverse MDR in breast cancer. [ABSTRACT FROM AUTHOR]

In this paper, the self-assembled folate-biotin-quaternized starch nanoparticles (FBqS NPs) were used as carrier system of doxorubicin (DOX) and siRNAIGF1R for the codelivery of both into human lung adenocarcinoma cell lines (A549 cells) in vitro. The cytotoxicity, targeted ligand competition, cell proliferation inhibition, cellular uptake, endocytosis mechanism and target protein suppression of drug-loaded FBqS NPs were evaluated in detail. Compared with several other drug formulations under same condition, siRNAIGF1R/DOX/FBqS NPs exhibited the greatest cytotoxicity to A549 cells and the cytotoxicity was competitively inhibited by free folate in dose-dependent manner. The A549 cells treated by siRNAIGF1R/DOX/FBqS NPs showed the lowest cell proliferation capacity. The energy-dependent clathrin- and caveolae-mediated endocytosis might be the primary cellular uptake mechanism of drug-loaded FBqS NPs. The expression of IGF1R protein in A549 cells treated by siRNAIGF1R/FBqS NPs declined dramatically. So the FBqS NPs were expected as the co-carrier system of chemotherapeutants and siRNAs for future clinical application. [ABSTRACT FROM AUTHOR]

Ning Wang, Zhihan Wang,* Shihong Nie,* Linjiang Song, Tao He, Suleixin Yang, Xi Yang, Cheng Yi, Qinjie Wu, Changyang Gong State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China *These authors contributed equally to this work Abstract: The combination of chemotherapy drugs attracts more attention in clinical cancer trials. However, the poor water solubility of chemotherapeutic drugs restricts their anticancer application. In order to improve antitumor efficiency and reduce side effects of free drugs, we prepared paclitaxel (PTX) and honokiol (HK) combination methoxy poly(ethylene glycol)–poly(caprolactone) micelles (P–H/M) by solid dispersion method against breast cancer. The particle size of P–H/M was 28.7±2.5 nm, and transmission electron microscope image confirmed that P–H/M were spherical in shape with small particle size. After being encapsulated in micelles, the release of PTX or HK showed a sustained behavior in vitro. In addition, both the cytotoxicity and the cellular uptake of P–H/M were increased in 4T1 cells, and P–H/M induced more apoptosis than PTX-loaded micelles or HK-loaded micelles, as analyzed by flow cytometry assay and Western blot. Furthermore, the antitumor effect of P–H/M was significantly improved compared with PTX-loaded micelles or HK-loaded micelles in vivo. P–H/M were more effective in inhibiting tumor proliferation, inducing tumor apoptosis, and decreasing the density of microvasculature. Moreover, bioimaging analysis showed that drug-loaded polymeric micelles could accumulate more in tumor tissues compared with the free drug. Our results suggested that P–H/M may have potential applications in breast cancer therapy. Keywords: paclitaxel, honokiol, micelles, codelivery, breast cancer

Active targeting nanoparticles were developed to simultaneously codeliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Curcumin (Cur). In the nanoparticles (TRAIL-Cur-NPs), TRAIL was used as both active targeting ligand and therapeutic agent, and Cur could upregulate death receptors (DR4 and DR5) to increase the apoptosis-inducing effects of TRAIL. Compared with corresponding free drugs, TRAIL-Cur-NPs group showed enhanced cellular uptake, cytotoxicity and apoptosis induction effect on HCT116 colon cancer cells. In addition, in vivo anticancer studies suggested that TRAIL-Cur-NPs had superior therapeutic effect on tumors without obvious toxicity, which was mainly due to the high tumor targeting and synergistic effect of TRAIL and Cur. The synergistic mechanism of improved antitumor efficacy was proved to be upregulation of DR4 and DR5 in tumor cells induced by Cur. Thus, the prepared codelivery nanoparticles may have potential applications in colorectal cancer therapy.

Graphical abstract Highlights • A novel doxorubicin formulation was fabricated to treat multi-drug resistant tumors. • The oleanolic acid modified composite can ameliorate off-target side effects. • The nanocomposite can increase the drug penetration into tumors by reducing fibrosis. • In addition, it targets tumor cells, and provides synergistic cancer therapy. Abstract In this study, a novel chitosan-based (CS) nanocarrier was developed for doxorubicin (DOX) and oleanolic acid (OA) co-delivery. CS was first functionalized with folic acid to allow selective uptake by cancer cells, and then subsequently with OA. The resultant copolymer self-assembled into nanoparticles (NPs) upon addition to water. These FA-CS-g-OA@DOX nanoparticles (NPs) had appropriate size (180 nm) and size distribution (PDI < 0.45) for tumor therapy, as well as a high drug-loading efficiency (15.6% w/w DOX; 5.1% w/w OA) and pH-responsive release properties. In breast cancer MDA-MB-231 cells, more efficient uptake of FA-CS-g-OA@DOX NPs than of free DOX was observed by confocal laser scanning microscopy and flow cytometry. The in vitro cytotoxicity of FA-CS-g-OA@DOX NPs against MDA-MB-231 cells was higher than with free DOX and free OA, while the NPs were less harmful to healthy HUVEC cells. In vivo pharmacokinetic studies showed that FA-CS-g-OA@DOX NPs had a much longer circulation time than free DOX, while biodistribution results revealed that FA-CS-g-OA@DOX could actively target a MDA-MB-231 xenograft tumor in mice. The NPs are found to have apoptosis-enhancing and anti-proliferative capacities in vivo. The presence of OA in the formulation both sensitizes cancer cells to DOX and mitigates DOX-induced damage to healthy tissues. The FA-CS-g-OA@DOX NPs generated in this work hence have great potential for the treatment of multi-drug resistant breast cancers, and further offer a platform to target other cancers. [ABSTRACT FROM AUTHOR]