Designing Mesoporous Prussian Blue@zinc Phosphate Nanoparticles with Hierarchical Pores for Varisized Guest Delivery and Photothermally-Augmented Chemo-Starvation Therapy.

Background: With the rapid development of nanotechnology, constructing a multifunctional nanoplatform that can deliver various therapeutic agents in different departments and respond to endogenous/exogenous stimuli for multimodal synergistic cancer therapy remains a major challenge to address the inherent limitations of chemotherapy. Methods: Herein, we synthesized hollow mesoporous Prussian Blue@zinc phosphate nanoparticles to load glucose oxidase (GOx) and DOX (designed as HMPB-GOx@ZnP-DOX NPs) in the non-identical pore structures of their HMPB core and ZnP shell, respectively, for photothermally augmented chemo-starvation therapy. Results: The ZnP shell coated on the HMPB core, in addition to providing space to load DOX for chemotherapy, could also serve as a gatekeeper to protect GOx from premature leakage and inactivation before reaching the tumor site because of its degradation characteristics under mild acidic conditions. Moreover, the loaded GOx can initiate starvation therapy by catalyzing glucose oxidation while causing an upgradation of acidity and H2O2 levels, which can also be used as forceful endogenous stimuli to trigger smart delivery systems for therapeutic applications. The decrease in pH can improve the pH-sensitivity of drug release, and O2 can be supplied by decomposing H2O2 through the catalase-like activity of HMPBs, which is beneficial for relieving the adverse conditions of anti-tumor activity. In addition, the inner HMPB also acts as a photothermal agent for photothermal therapy and the generated hyperthermia upon laser irradiation can serve as an external stimulus to further promote drug release and enzymatic activities of GOx, thereby enabling a synergetic photothermally enhanced chemo-starvation therapy effect. Importantly, these results indicate that HMPB-GOx@ZnP-DOX NPs can effectively inhibit tumor growth by 80.31% and exhibit no obvious systemic toxicity in mice. Conclusion: HMPB-GOx@ZnP-DOX NPs can be employed as potential theranostic agents that incorporate multiple therapeutic modes to efficiently inhibit tumors.

Better together: nanoscale co-delivery systems of therapeutic agents for high-performance cancer therapy.

Combination therapies can enhance the sensitivity of cancer to drugs, lower drug doses, and reduce side effects in cancer treatment. However, differences in the physicochemical properties and pharmacokinetics of different therapeutic agents limit their application. To avoid the above dilemma and achieve accurate control of the synergetic ratio, a nanoscale co-delivery system (NCDS) has emerged as a prospective tool for combined therapy in cancer treatment, which is increasingly being used to co-load different therapeutic agents. In this study, we have summarized the mechanisms of therapeutic agents in combination for cancer therapy, nanoscale carriers for co-delivery, drug-loading strategies, and controlled/targeted co-delivery systems, aiming to give a general picture of these powerful approaches for future NCDS research studies.

Pickering emulsion co-delivery system: Stimuli-responsive biomineralized particles act as particulate emulsifiers and bioactive carriers.

Pickering emulsions provide a promising platform for the efficient delivery of bioactive. However, co-delivery of fragile bioactives with different physicochemical properties for comprehensive effects still faces practical challenges due to the limited protection for bioactives and the lack of stimuli-responsive property for on-demand release. Herein, a stimuli-responsive co-delivery system is developed based on biomineralized particles stabilized Pickering emulsions. In this tailor co-delivery system, hydrophilic bioactive (pepsin) with the fragile structure is encapsulated and immobilized by biomineralization, the obtained biomineralized particles (PPS@CaCO3) are further utilized as emulsifiers to form O/W Pickering emulsions, in which the hydrophobic oxidizable bioactive (curcumin) is stably trapped into the dispersed phase. The results show that two bioactives are successfully co-encapsulated in Pickering emulsions, and benefiting from the protection capacities of biomineralization and Pickering emulsions, the activity of pepsin and curcumin shows a 7.33-fold and 144.83-fold enhancement compared to the free state, respectively. Moreover, In vitro study demonstrates that Pickering emulsions enable to co-release of two bioactives with high activity retention by the acid-induced hydrolyzation of biomineralized particles. This work provides a powerful stimuli-responsive platform for the co-delivery of multiple bioactive compounds, enabling high activity of bioactives for the comprehensive health effects.

Dendritic polymer prodrug-based unimolecular micelles for pH-responsive co-delivery of doxorubicin and camptothecin with synergistic controlled drug release effect.

Combination chemotherapy has been recognized as a more powerful strategy for tumor treatment rather than the single chemotherapy. However, the interactive mechanism of the two hydrophobic chemotherapeutic drugs has not been explored by now. Aiming for a better synergistic effect, such interactive mechanism was investigated in the present work, by designing CPT@DOX-DPUTEA-PEG nanomedicine with encapsulated camptothecin (CPT) and conjugated doxorubicin (DOX). The synergistic controlled drug release effect was found for the two drugs loaded on the different sites of the dendritic polyurethane core. Synergism was achieved on the HepG2 cells with a combination index (CI) of 0.58 in the in vitro cellular experiments. The results demonstrated the promising application of the unimolecular micelles-based nanomedicine with independently loading of two hydrophobic chemotherapeutic drugs.

Preparation, Biological Activities, and Potential Applications of Hen Egg-Derived Peptides: A Review.

Food-derived peptides have been extensively studied for their benefits in humans. Hen eggs, characterized by high protein and digestibility, are an excellent source of food-derived bioactive peptides. This review summarizes the preparation methods, purification, and identification of hen egg-derived peptides (HEPs). The preparation methods mainly include enzymatic hydrolysis, microbial fermentation, and chemical synthesis. Genetic engineering is an emerging trend of HEP preparation. Then, we summarize the biological activities of HEPs, such as antioxidant activities, enzyme inhibitory activity, and antibacterial activity, of which the enzyme inhibitory activity is comprehensively summarized for the first time. The structure-activity relationship and underlying mechanism of the HEPs are further elucidated. Finally, the applications, future challenges, and opportunities of HEPs were mainly discussed in the food and non-food sectors. We focus on the potential applications of HEPs in intestinal health and assembly delivery and provide a reference for the further utilization and commercial development of HEPs.

Mesoporous silica nanospheres-mediated insecticide and antibiotics co-delivery system for synergizing insecticidal toxicity and reducing environmental risk of insecticide.

Mesoporous silica nanoparticles (MSNs) are efficient carriers of drugs, and are promising in developing novel pesticide formulations. The cotton aphids Aphis gossypii Glover is a world devastating insect pest. It has evolved high level resistance to various insecticides thus resulted in the application of higher doses of insecticides, which raised environmental risk. In this study, the MSNs based pesticide/antibiotic delivery system was constructed for co-delivery of ampicillin (Amp) and imidacloprid (IMI). The IMI@Amp@MSNs complexes have improved toxicity against cotton aphids, and reduced acute toxicity to zebrafish. From the 16S rDNA sequencing results, Amp@MSNs, prepared by loading ampicillin to the mesoporous of MSNs, greatly disturbed the gut community of cotton aphids. Then, the relative expression of at least 25 cytochrome P450 genes of A. gossypii was significantly suppressed, including CYP6CY19 and CYP6CY22, which were found to be associated with imidacloprid resistance by RNAi. The bioassay results indicated that the synergy ratio of ampicillin to imidacloprid was 1.6, while Amp@MSNs improved the toxicity of imidacloprid by 2.4-fold. In addition, IMI@Amp@MSNs significantly improved the penetration of imidacloprid, and contributed to the amount of imidacloprid delivered to A. gossypii increased 1.4-fold. Thus, through inhibiting the relative expression of cytochrome P450 genes and improving penetration of imidacloprid, the toxicity of IMI@Amp@MSNs was 6.0-fold higher than that of imidacloprid. The greenhouse experiments further demonstrated the enhanced insecticidal activity of IMI@Amp@MSNs to A. gossypii. Meanwhile, the LC50 of IMI@Amp@MSNs to zebrafish was 3.9-fold higher than that of IMI, and the EC50 for malformation was 2.8-fold higher than IMI, respectively, which indicated that the IMI@Amp@MSNs complexes significantly reduced the environmental risk of imidacloprid. These findings encouraged the development of pesticide/antibiotic co-delivery nanoparticles, which would benefit pesticide reduction and environmental safety.

Gint4.T-siHDGF chimera-capped mesoporous silica nanoparticles encapsulating temozolomide for synergistic glioblastoma therapy.

Due to glioblastoma (GBM) being the most intractable brain tumor, the continuous improvement of effective treatment methods is indispensable. The combination of siRNA-based gene therapy and chemotherapy for GBM treatment has now manifested great promise. Herein, Gint4.T-siHDGF chimera-capped mesoporous silica nanoparticles (MSN) encapsulating chemotherapy drug temozolomide (TMZ), termed as TMSN@siHDGF-Gint4.T, is developed to co-deliver gene-drug siHDGF and TMZ for synergistic GBM therapy. TMSN@siHDGF-Gint4.T possesses spherical nucleic acid-like architecture that can improve the enzyme resistance of siHDGF and increase the blood-brain barrier (BBB) permeability of the nanovehicle. The aptamer Gint4.T of chimera endows the nanovehicle with GBM cell-specific binding ability. When administered systemically, TMSN@siHDGF-Gint4.T can traverse BBB and enter GBM cells. In the acidic lysosome environment, the cleavage of benzoic-imine bond on MSN surface leads to an initial rapid release of chimera, followed by a slow release of TMZ encapsulated in MSN. The sequential release of siHDGF and TMZ first allows siHDGF to exert its gene-silencing effect, and the downregulation of HDGF expression further enhances the cytotoxicity of TMZ. In vivo experimental results have demonstrated that TMSN@siHDGF-Gint4.T significantly inhibits tumor growth and extends the survival time of GBM-bearing mice. Thus, the as-developed TMSN@siHDGF-Gint4.T affords a potential approach for the combination treatment of GBM.

An efficient co-delivery system based on multilayer structural nanoparticles for programmed sequential release of resveratrol and vitamin D3 to combat dextran sodium sulfate-induced colitis in mice.

Multilayer structural nanoparticles (MSNPs) fabricated by layer-by-layer self-assembly were used for the co-encapsulation of resveratrol (Res) and vitamin D3 (Vd). Res and Vd co-encapsulated MSNPs (Res-Vd-MSNPs) were evaluated by appearance, morphology, particle size, ζ potential and encapsulation efficiency (EE). The results showed that Res-Vd-MSNPs were spherical in shape with a particle size of 625.4 nm and a surface charge of +26.1 mV. The EE of Res and Vd was as high as 93.6 % and 90.8 %, respectively. Res-Vd-MSNPs exhibited better stability and lower degradation rate in simulated gastric fluid, allowing the programmed sequential release of Vd and Res in simulated intestinal fluid and simulated colonic fluid, which was also confirmed by in vivo fluorescence imaging of mice. In addition, Res-Vd-MSNPs effectively alleviated the clinical symptoms of dextran sulfate sodium salt (DSS)-induced colitis in mice, including weight loss, diarrhea and fecal bleeding, and it especially exerted a preventive effect on DSS-induced colon tissue damage and colon shortening. Furthermore, Res-Vd-MSNPs suppressed the expression of anti-inflammatory cytokines such as TNF-α, IL-1ß and IL-6 and ameliorated DSS-induced oxidative damage, decreased colonic myeloperoxidase (MPO) and nitric oxide (NO) activities and elevated glutathione (GSH) level in DSS-treated mice. This study illustrated that MSNPs were potential carriers for developing the co-delivery system for the synergistic prevention and treatment of ulcerative colitis.

Engineered exosomes as drug and RNA co-delivery system: new hope for enhanced therapeutics?

Chemotherapy often faces some obstacles such as low targeting effects and drug resistance, which introduce the low therapeutic efficiency and strong side effects. Recent advances in nanotechnology allows the use of novel nanosystems for targeted drug delivery, although the chemically synthesized nanomaterials always show unexpected low biocompability. The emergence of exosome research has offered a better understanding of disease treatment and created novel opportunities for developing effective drug delivery systems with high biocompability. Moreover, RNA interference has emerged as a promising strategy for disease treatments by selectively knocking down or over-expressing specific genes, which allows new possibilities to directly control cell signaling events or drug resistance. Recently, more and more interests have been paid to develop optimal delivery nanosystems with high efficiency and high biocompability for drug and functional RNA co-delivery to achieve enhanced chemotherapy. In light of the challenges for developing drug and RNA co-delivery system, exosomes have been found to show very attractive prospects. This review aims to explore current technologies and challenges in the use of exosomes as drug and RNA co-delivery system with a focus on the emerging trends and issues associated with their further applications, which may contribute to the accelerated developments of exosome-based theraputics.

A nano-targeted co-delivery system based on gene regulation and molecular blocking strategy for synergistic enhancement of platinum chemotherapy sensitivity in ovarian cancer.

Ovarian cancer (OC) has a low five-year survival rate, mainly because of its drug resistance to chemotherapy. It is the key to reverse drug resistance to combine multiple sensitization pathways to play a synergistic role. A nano scaled targeted co-delivery system (P123-PEI-G12, PPG) modified by bifunctional peptide tLyP-1-NLS (G12) was fabricated by using Pluronic P123 conjugated with low molecular weight polyethyleneimine (PEI). This delivery system can co-delivery Olaparib (Ola) and p53 plasmids to synergistically enhance the sensitivity of OC to platinum-based chemotherapy. P53@P123-PEI-G2/Ola (Co-PPGs) can achieve efficient tumor accumulation and cellular internalization through G12-mediated targeting. Co-PPGs then break down in the tumor cells, releasing the drug. Co-PPGs significantly enhanced the sensitivity of cisplatin (DDP) in platinum-resistant ovarian cancer (PROC) and synergistically inhibited the proliferation of PROC in vitro and in vivo. The sensitizing and synergistic effects of Co-PPGs were related to the activation of p53, inhibition of poly-ADP-ribose polymerase (PARP) and p-glycoprotein (P-gp) expression. This work provides a promising strategy for the effective treatment of PROC.

Tumor immunosuppression relief via acidity modulation combined PD-L1 siRNA for enhanced immunotherapy.

The efficacy of immune checkpoint therapy is limited by the immunosuppressive tumor microenvironment (TME), and lactate, the most universal component of TME, has been rediscovered that plays important roles in the regulation of metabolic pathways, angiogenesis, and immunosuppression. Here, a therapeutic strategy of acidity modulation combined with programmed death ligand-1 (PD-L1) siRNA (siPD-L1) is proposed to synergistically enhance tumor immunotherapy. The lactate oxidase (LOx) is encapsulated into the hollow Prussian blue (HPB) nanoparticles (NPs) prepared by hydrochloric acid etching followed by the modification with polyethyleneimine (PEI) and polyethylene glycol (PEG) via sulfur bonds (HPB-S-PP@LOx), siPD-L1 is loaded via electrostatic adsorption to obtain HPB-S-PP@LOx/siPD-L1. The obtained co-delivery NPs can accumulate in tumor tissue with stable systemic circulation, and simultaneous release of LOx and siPD-L1 in intracellular high glutathione (GSH) environment after uptake by tumor cells without being destroyed by lysosome. Moreover, LOx can catalyze the decomposition of lactate in the hypoxic tumor tissue with the aid of oxygen release by the HPB-S-PP nano-vector. The results show that the acidic TME regulation via lactate consumption can improve the immunosuppressive TME, including revitalizing the exhausted CD8+ T cells and decreasing the proportion of immunosuppressive Tregs, and synergistically elevating the therapeutic effect of PD1/PD-L1 blockade therapy via siPD-L1. This work provides a novel insight for tumor immunotherapy and explores a promising therapy for triple-negative breast cancer.

Recent Advances in Nanoparticle-Mediated Co-Delivery System: A Promising Strategy in Medical and Agricultural Field.

Drug and gene delivery systems mediated by nanoparticles have been widely studied for life science in the past decade. The application of nano-delivery systems can dramatically improve the stability and delivery efficiency of carried ingredients, overcoming the defects of administration routes in cancer therapy, and possibly maintaining the sustainability of agricultural systems. However, delivery of a drug or gene alone sometimes cannot achieve a satisfactory effect. The nanoparticle-mediated co-delivery system can load multiple drugs and genes simultaneously, and improve the effectiveness of each component, thus amplifying efficacy and exhibiting synergistic effects in cancer therapy and pest management. The co-delivery system has been widely reported in the medical field, and studies on its application in the agricultural field have recently begun to emerge. In this progress report, we summarize recent progress in the preparation and application of drug and gene co-delivery systems and discuss the remaining challenges and future perspectives in the design and fabrication.

Co-Delivery System of Curcumin and Colchicine Using Functionalized Mesoporous Silica Nanoparticles Promotes Anticancer and Apoptosis Effects.

Purpose: Many natural agents have a high anticancer potential, and their combination may be advantageous for improved anticancer effects. Such agents, however, often are not water soluble and do not efficiently target cancer cells, and the kinetics of their action is poorly controlled. One way to overcome these barriers is to combine natural agents with nanoparticles. Our aim in the current study was to fabricate an anticancer nanoformulation for co-delivery of two natural agents, curcumin (CR) and colchicine (CL), with a core-shell structure. Using cancer cell lines, we compared the anticancer efficacy between the combination and a nanoformulation with CL alone. Methods: For the single-drug nanoformulation, we used phosphonate groups to functionalize mesoporous silica nanoparticles (MSNs) and loaded the MSNs with CL. Additional loading of this nanoformulation with CR achieved the co-delivery format. To create the structure with a core shell, we selected a chitosan−cellulose mixture conjugated with targeting ligands of folic acid for the coating. For evaluating anticancer and apoptosis effects, we assessed changes in important genes and proteins in apoptosis (p53, caspase-3, Bax, Bcl-2) in several cell lines (MCF-7, breast adenocarcinoma; HCT-116, colon carcinoma; HOS, human osteosarcoma; and A-549, non−small cell lung cancer). Results: Nanoformulations were successfully synthesized and contained 10.9 wt.% for the CL single-delivery version and 18.1 wt.% for the CL+CR co-delivery nanoformulation. Anticancer effects depended on treatment, cell line, and concentration. Co-delivery nanoformulations exerted anticancer effects that were significantly superior to those of single delivery or free CL or CR. Anticancer effects by cell line were in the order of HCT-116 > A549 > HOS > MCF-7. The lowest IC50 value was obtained for the nanoformulation consisting of CL and CR coated with a polymeric shell conjugated with FA (equivalent to 4.1 ± 0.05 µg/mL). With dual delivery compared with the free agents, we detected strongly increased p53, caspase-3, and Bax expression, but inhibition of Bcl-2, suggesting promotion of apoptosis. Conclusions: Our findings, although preliminary, indicate that the proposed dual delivery nanoformulation consisting of nanocore: MSNs loaded with CL and CR and coated with a shell of chitosan−cellulose conjugated folic acid exerted strong anticancer and apoptotic effects with potent antitumor activity against HCT-116 colon cells. The effect bested CL alone. Evaluating and confirming the efficacy of co-delivery nanoformulations will require in vivo studies.

Precision medicine-guided co-delivery of ASPN siRNA and oxaliplatin by nanoparticles to overcome chemoresistance of colorectal cancer.

The development of chemoresistance is a major hurdle for the treatment of colorectal cancer (CRC), which contributes remarkably to the poor clinical prognosis. Nanodrug delivery systems show great potential in overcoming chemoresistance, but limited by the lack of identification of chemoresistance targets from cancer patients. In the present study, we enrolled chemotherapy-resistant or sensitive CRC patients and used the next-generation RNA sequencing to reveal that Asporin (ASPN) is highly expressed in tumor tissues from oxaliplatin (OXA)-resistant patients and closely correlated with a poor prognosis of CRC. Downregulation of ASPN reversed OXA resistance and promoted cell apoptosis both in vitro and in vivo. To overcome ASPN-mediated OXA resistance, we constructed a nanoparticle-based co-delivery system (denoted as PPO-siASPN) for simultaneous delivery of OXA and siRNA targeting ASPN (siASPN). PPO-siASPN not only facilitated the intracellular delivery of OXA through the enhanced cellular uptake, but effectively suppressed ASPN expression for synergistic antitumor activity in vitro and in vivo. In the more clinically relevant patient-derived xenograft (PDX) mouse model, systemic administration of PPO-siASPN achieved a remarkable therapeutic effect. This study uncovered the critical role of ASPN in causing OXA resistance in CRC patients and suggests a promising nanoformulation that may be more effective than current standard-of-care medications.

Nano-Based Co-Delivery System for Treatment of Rheumatoid Arthritis.

A systemic autoimmune condition known as rheumatoid arthritis (RA) has a significant impact on patients' quality of life. Given the complexity of RA's biology, no single treatment can totally block the disease's progression. The combined use of co-delivery regimens integrating various diverse mechanisms has been widely acknowledged as a way to make up for the drawbacks of single therapy. These days, co-delivery systems have been frequently utilized for co-treatment, getting over drug limitations, imaging of inflammatory areas, and inducing reactions. Various small molecules, nucleic acid drugs, and enzyme-like agents intended for co-delivery are frequently capable of producing the ability to require positive outcomes. In addition, the excellent response effect of phototherapeutic agents has led to their frequent use for delivery together with chemotherapeutics. In this review, we discuss different types of nano-based co-delivery systems and their advantages, limitations, and future directions. In addition, we review the prospects and predicted challenges for the combining of phototherapeutic agents with conventional drugs, hoping to provide some theoretical support for future in-depth studies of nano-based co-delivery systems and phototherapeutic agents.

Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review.

Chemotherapy drugs have been used for a long time in the treatment of cancer, but serious side effects are caused by the inability of the drug to be solely delivered to the tumor when treating cancer with chemotherapy. Natural products have attracted more and more attention due to the antitumor effect in multiple ways, abundant resources and less side effects. Therefore, the combination of natural active ingredients and chemotherapy drugs may be an effective antitumor strategy, which can inhibit the growth of tumor and multidrug resistance, reduce side effects of chemotherapy drugs. Nano-drug co-delivery system (NDCDS) can play an important role in the combination of natural active ingredients and chemotherapy drugs. This review provides a comprehensive summary of the research status and application prospect of nano-delivery strategies for the combination of natural active ingredients and chemotherapy drugs, aiming to provide a basis for the development of anti-tumor drugs.

A cationic amino acid polymer nanocarrier synthesized in supercritical CO2 for co-delivery of drug and gene to cervical cancer cells.

The present study was undertaken to investigate the ability of a drug curcumin-loaded polymer to inhibit the growth of cervical cancer cells by enhancing the anti-cancer efficiency of curcumin. We synthesized poly(methacryloyl beta-alanine) (PMBA) as a nanocarrier by radical polymerization in supercritical CO2. The results showed that the curcumin encapsulated and folic acid (FA)-treated PMBA (Poly@Cur-FA) for 24 h activated the reactive oxygen species-mediated programmed cell death machinery in HeLa cells. This remarkable effect of Poly@Cur-FA treatment was visualized using different fluorescent probes, which demonstrated that the Poly@Cur-FA treatment disrupted the cell membrane, as also supported by scanning electron microscopy observations. The effect of Poly@Cur-FA dispersion on the cells was observed under a transmission electron microscope. Further, the HeLa cells were treated with the polymer encapsulated curcumin and Bcl2 siRNA (Pol-Cur-siRNA) for 24 h, which effectively suppressed the Bcl2 and simulated the autophagic pathway. This co-delivery system was designed to inhibit curcumin efflux and can enhance the treatment efficacy by targeting multiple signaling pathways, including cell cycle, apoptotic, and autophagic pathways. Collectively, the Pol-Cur-siRNA system appears to offer an efficient combinational therapeutic strategy that might overcome the problems associated with the chemosensitivity against the standard synthetic anti-cancer drugs. To support the experimental data, an artificial neural network model was developed to foresee the drug and gene release behaviors.

Polyethyleneimine (PEI) as a Polymer-Based Co-Delivery System for Breast Cancer Therapy.

Cancer has become one of the leading causes of morbidity and mortality worldwide. This disease is classified broadly by tissue, organ, and system; different cancer types and subtypes require different treatments. Drug bioavailability, selectivity, and high dosage, as well as extended treatment, are significantly associated with the development of resistance - a complex problem in cancer therapy. It is expected that the combination of anticancer drugs and drug delivery systems, using polymers to increase the access of such agents to their site of action, will improve the efficacy of therapy. Polyethyleneimine (PEI) is a polymer used as a co-delivery system for anticancer drugs and gene therapy. PEI is also useful for other purposes, such as transfection and bio-adsorbent agents. In co-delivery, PEI can promote drug internalization. However, PEI with a high molecular weight is linked to higher cytotoxicity, thus requiring further evaluation of clinical safety. This review focuses on the utilization of PEI as a co-delivery system for anticancer therapy, as well as its potential to overcome resistance, particularly in the treatment of specific subtypes (eg, breast cancer). In conclusion, PEI has promising applications and is improvable for the development of anticancer drugs.

Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy.

BACKGROUND: Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG)n, and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect. RESULTS: In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration. CONCLUSION: These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment.

A modular ROS-responsive platform co-delivered by 10-hydroxycamptothecin and dexamethasone for cancer treatment.

Traditional and single treatment strategies are difficult to achieve good results due to tumor resistance and complex mechanisms. Combination therapy through co-delivery systems is one of the methods to improve the effectiveness of cancer treatment. The polyprodrug platform has inherent advantages such as high drug loading and strong stability. Herein, a new reactive oxygen species (ROS)-responsive micelle composed of poly 10-hydroxycamptothecin (pHCPT) and PEG is reported, which loaded dexamethasone (DEX) as synergistic drugs. The micelles collapse in the complex microenvironment of tumor cells to release DEX. The first released DEX can increase the ROS level of tumor cells, thereby facilitating the cleavage of thioketal bonds to release intact HCPT molecules. Meanwhile, DEX can normalize tumor blood vessels, reduce adverse reactions, and further improve the efficacy of HCPT. This co-delivery system shows an ideal tumor suppressive effect in vivo and in vitro. Designing drugs into a modular multi-drug platform and selecting appropriate synergistic drugs according to the treatment plan provides a convenient strategy for future clinical treatment.