Ultrasmall Rhodium Nanozyme with RONS Scavenging and Photothermal Activities for Anti-Inflammation and Antitumor Theranostics of Colon Diseases.

Colitis-associated colorectal cancer (CAC), in which chronic inflammation is a well-recognized carcinogen, requires concurrent anti-inflammation and antitumor treatments in the clinic. Herein, we report polyethylene glycol (PEG)-coated (PEGylated) ultrasmall rhodium nanodots (Rh-PEG NDs) can serve as a metallic nanozyme with reactive oxygen and nitrogen species (RONS) scavenging properties as well as photothermal activities for anti-inflammation and antitumor theranostics in colon diseases. Benefiting from multienzyme activities against RONS, Rh-PEG NDs can decrease the levels of pro-inflammatory cytokines (TNF-α, IL-6), resulting in good anti-inflammatory effect on dextran sulfate sodium-induced colitis. By virtue of high photothermal conversion efficiency (48.9%), Rh-PEG NDs demonstrate complete ablation of CT-26 colon tumor without any recurrence. Most importantly, Rh-PEG NDs exhibit good biocompatibility both at the cellular and animal levels. Our findings provide a paradigm to utilize metallic nanozymes for the potential management of colon diseases.

Ultrasound-Assisted miR-122-Loaded Polymeric Nanodroplets for Hepatocellular Carcinoma Gene Therapy.

Ultrasound-induced microbubble sonoporation has been shown to effectively improve drug/gene delivery efficiency by enhancing tissue and cell permeability. However, the microscale size and short duration of ultrasound contrast agents limit their accumulation in target areas. Here, a kind of ultrasound-triggered phase-transitioning and size-changing cationic nanodroplet, perfluoropentane/C9F17-PAsp(DET)/miR-122/poly(glutamic acid)-g-MeO-poly(ethylene glycol) (PGA-g-mPEG) ternary nanodroplets (PFP-TNDs/miR-122), was developed to deliver microRNA-122 (miR-122) for hepatocellular carcinoma (HCC) treatment. PFP served as an ultrasound-sensitive core for ultrasound-triggered phase transition and size change from the nanoscale to the microscale. Positively charged C9F17-PAsp(DET) ensured adequate miRNA loading. PGA-g-mPEG, which served as the shell of the nanodroplet, modified the nanodroplets, enhanced their stability in serum, and protected miR-122 from degradation in vivo. The results exhibited that PFP-TNDs/miR-122 has a nanosize diameter (362 ± 15 nm) and remained stable for 24 h. After treatment with PFP-TNDs/miR-122 combined with ultrasound irradiation, the miR-122 expression level was significantly increased by approximately 600-fold in HepG2 cells, 500-fold in SMMC-7721 cells, and 30-fold in human HCC xenografts. Moreover, PFP-TNDs/miR-122 combined with ultrasound radiation effectively suppressed the growth, migration, and invasion of HCC cells, and inhibited tumor proliferation in mice. This study revealed that the biodegradable PFP-TNDs is a promising therapeutic gene carrier with functions of gene protection and effective gene delivery for clinical applications. Furthermore, PFP-TNDs/miR-122 associated with ultrasound irradiation may pave a new way to improve the prognosis of patients with HCC.

Polydopamine-Encapsulated Perfluorocarbon for Ultrasound Contrast Imaging and Photothermal Therapy.

Biomedical nanoplatforms have been widely investigated for ultrasound (US) imaging and cancer therapy. Herein, perfluorocarbon (PFC) is encapsulated into biocompatible polydopamine (PDA) to form a theranostic nanosystem, followed by the modification of polyethylene glycol (PEG) to stabilize the nanoparticle via a facile one-pot method. Under 808 nm near-infrared laser irradiation, PDA can generate hyperthermia to transform PFC droplets to bubbles with high US imaging sensitivity. The US imaging detection of the PFC-PDA-PEG nanosystem is achievable in a time span of up to 25 min in vitro at a low US frequency and mechanical index, manifesting a US imaging performance for in vivo application. Moreover, tumor cells incubated with the nanosystem are ablated effectively under laser irradiation at 808 nm. The results illustrate the potential of the PDA-based theranostic agent in US imaging-guided photothermal therapy of tumor.

Targeted Ultrasound-Triggered Phase Transition Nanodroplets for Her2-Overexpressing Breast Cancer Diagnosis and Gene Transfection.

For successful gene therapy, it is imperative to accumulate therapeutic gene in tumor tissues followed by efficiently delivering gene into targeted cells. Ultrasound irradiation, as a noninvasive and cost-effective external stimulus, has been proved to be one of the most potential external-stimulating gene delivery strategies recently in further improving gene transfection. In this study, we developed tumor-targeting ultrasound-triggered phase-transition nanodroplets AHNP-PFP-TNDs comprising a perfluorinated poly(amino acid) C11F17-PAsp (DET) as a core for simultaneously loading perfluoropentane (PFP) and nucleic acids, and a polyanionic polymer PGA-g-PEG-AHNP as the shell for not only modifying the surface of nanodroplets but also introducing an anti-Her2/neu peptide (AHNP) aiming to targeted treatment of Her2-overexpressing breast cancer. The results showed the average diameter of AHNP-PFP-TNDs was below 400 nm, nearly spherical in shape. The modification of PGA-g-PEG-AHNP not only increased the serum stability of the nanodroplets but also improved the affinity between nanodroplets and Her2-overexpressing breast cells. Both intratumor and intravenous injection of AHNP-PFP-TNDs into nude mice bearing HGC-27 xenografts showed that the gene transfection efficiency and the ultrasound contrast effect were significantly enhanced after exposed to the ultrasound irradiation with optimized ultrasound parameters. Therefore, this targeting nanodroplets system could be served as a potential theranostic vector for tumor targeting ultrasound diagnosis and gene therapy.

Stabilized magnetic cerasomes for drug delivery.

Doxorubicin hydrochloride (DOX)-loaded magnetic cerasomes (DLMCs) were successfully constructed by loading both hydrophobic Fe3O4 nanoparticles (NPs) and antitumor drug DOX into the aqueous interior of cerasomes via facile one-step construction. A possible explanation is that the hydrophobic Fe3O4 NPs can be trapped inside the aqueous core of cerasomes through the formation of an intermediate Fe3O4/micelle complex. It was found that the loading content of Fe3O4 in DLMCs could reach the maximum at a Fe3O4/lipid molar ratio of 4:1. Moreover, DLMCs demonstrated high superparamagnetism and responded strongly to magnetic fields. In addition, DLMCs had a high encapsulation efficiency of 43.4 ± 4.7% and a high drug loading content of 3.2 ± 1.3%. In comparison to drug-loaded liposomes, DLMCs exhibited higher storage stability and better sustained release behavior. A cellular uptake study showed that the use of an external magnetic field enables a rapid and efficient uptake of DLMCs by cancer cells, resulting in higher capability to kill tumor cells than non-magnetic drug-loaded cerasomes. This study suggests that magnetic cerasome offers a potential and effective drug carrier for anticancer applications.

Oral Delivery of Protein Drugs via Lysine Polymer-Based Nanoparticle Platforms.

Oral delivery of proteins has opened a new perspective for the treatment of different diseases. However, advances of oral protein formulation are usually hindered by protein susceptibility and suboptimal absorption in the gastrointestinal tract (GIT). Polymeric nano drug delivery systems are considered revolutionary candidates to solve these issues, which can be preferably tunable against specific delivery challenges. Herein, a tailored family of lysine-based poly(ester amide)s (Lys-aaPEAs) is designed as a general oral protein delivery platform for efficient protein loading and protection from degradation. Insulin, as a model protein, can achieve effective internalization by epithelial cells and efficient transport across the intestinal epithelium layer into the systemic circulation, followed by controlled release in physiological environments. After the oral administration of insulin carried by Lys-aaPEAs with ornamental hyaluronic acid (HA), mice with type 1 diabetes mellitus showed an acceptable hypoglycemic effect with alleviated complications. A successful oral insulin delivery is associated with patient comfort and convenience and simultaneously avoids the risk of hypoglycemia compared with injections, which is of great feasibility for daily diabetes therapy. More importantly, this versatile Lys-aaPEAs polymeric library can be recognized as a universal vehicle for oral biomacromolecule delivery, providing more possibilities for treating various diseases.

Highly sensitive determination of L-glutamic acid in pig serum with an enzyme-free molecularly imprinted polymer on a carbon-nanotube modified electrode.

Through electrochemical polymerization using L-glutamic acid (L-Glu) as a template and 4,6-diaminoresorcinol as a functional monomer, an enzyme-free molecularly imprinted polymer (MIP) based L-Glu sensor with multi-walled carbon nanotubes (MWCNTs) decorated on a glassy carbon electrode (GCE), namely G-MIP/MWCNTs/GCE, was developed in this work. The reaction conditions were optimized as follows: electrochemical polymerization of 23 cycles, pH of 3.0, molar ratio of template/monomer of 1 : 4, volume ratio of elution reagents of acetonitrile/formic acid of 1 : 1, and elution time of 2 min. The prepared materials and molecularly imprinted polymer were characterized by using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) as well as electrochemical methods. The electrochemical properties of different electrodes were investigated via differential pulse voltammetry (DPV), showing that the electrode of G-MIP/MWCNTs/GCE exhibited excellent catalytic oxidation activity towards L-Glu. A good linear relationship between peak-currents and L-Glu concentrations in a range from 1.00 × 10-8 to 1.00 × 10-5 mol L-1 was observed, with a detection limit of 5.13 × 10-9 mol L-1 (S/N = 3). The imprinted sensor possesses excellent selectivity, high sensitivity, and good stability, which have been successfully applied for the detection of L-Glu in pig serum samples with a recovery rate of 97.4-105.5%, being comparable to commercial high-performance liquid chromatography, demonstrating a simple, rapid, and accurate way for the determination of L-Glu in the fields of animal nutrition and biomedical engineering.

Catalytic rhodium (Rh)-based (mesoporous polydopamine) MPDA nanoparticles with enhanced phototherapeutic efficiency for overcoming tumor hypoxia.

Catalytic nanomedicine with high oxygen-generation efficiency may find applications in alleviating tumor hypoxia and improving the efficiency of photodynamic therapy (PDT). In this study, a catalytic nanosystem (Ce6-Rh@MPDA) was developed using mesoporous polydopamine nanoparticles (MPDA) to encapsulate catalase-like rhodium nanoparticles (Rh NPs) and photosensitizer chlorine6 (Ce6) for photoacoustic/fluorescence dual imaging-guided tumor therapy. The Rh NPs can catalyze the production of O2 from tumor-enriched H2O2in situ, in which the mesoporous structure of MPDA plays an important role via improving the catalytic efficiency of Rh NPs. Moreover, the hyperthermia generated by both MPDA and Rh NPs under laser irradiation accelerates the O2 generation to promote the PDT. The Ce6-Rh@MPDA nanoparticles described herein represent a multifunctional metal-based catalytic nanomedicine which not only alleviates tumor hypoxia but also enables a synergistic antitumor treatment using PTT and PDT.

Intrinsically ESIPT-exhibiting and enhanced emission in polymer nanoparticles as signaling for sensing nitrite.

A straightforward approach to the fabrication of intrinsically excited-state intramolecular proton transfer (ESIPT)-fluorescent polymer nanoparticles (e-PNPs) was developed. The e-PNPs were obtained by self-assembly of the homopolymers derived from 4-aminosalicylic acid in aqueous solution. By incorporating ESIPT modules into polymer nanoparticles, the ESIPT reaction can be endowed with moderate hydrophobic micro-environment by nanoparticle scaffolds, eliciting enhanced ESIPT emission. The newly developed e-PNPs exhibit strong tautomeric fluorescence(e-FL), good photostability, low-toxicity and favourable biocompatibility in aqueous solution. Upon the addition of NO2-, the e-FL can be significantly quenched owing to the reaction of NO2- with the amide groups on e-PNPs. From this basis, the fluorescence detection of NO2- was implemented, which showed a linear relationship between 0 nM and 110 nM with a detection limit of 2.3 nM. Furthermore, e-PNPs were used as nanoprobes to monitor the NO2- levels in HeLa cells by fluorescence imaging, demonstrating the ability of discrimination from different concentrations of NO2-. The proposed method can be applied to a wide range of other ESIPT modules to integrate into polymer nanoparticles and offer highly sensitive nanosensing platform for bioanalysis and molecular imaging.

Perfluorohexane-Loaded Polymeric Nanovesicles with Oxygen Supply for Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT), as a new method of non-invasive tumor treatment developed from photodynamic therapy (PDT), can overcome the disadvantage of poor laser penetration while retaining the function of PDT. However, the lack of efficient sonosensitizer accumulation and the hypoxic environment in tumor sites limited the therapeutic efficacy of SDT. Here, we constructed a highly efficient liquid fluorocarbon-encapsulated polymeric nanovesicle for enhanced sonodynamic efficacy as well as tumor hypoxia relief. This multifunctional nanovesicle was constructed by fluorinated cationic polymer C9F17-PAsp(DET) with PEG-conjugated protoporphyrin IX (PEG-PpIX) modification, which could yield the simultaneous loading of perfluorohexane (PFH) and oxygen. We found that the PAsp(DET)-PpIX-PEG@PFH nanovesicles could not only generate the reactive oxygen species (ROS) under ultrasound irradiation after intravenous (i.v.) injection but also could generate and prolong the ROS under nanovesicle preparation by ultrasonication in vitro, so-called the ″exogenous ROS", which might result in enhanced cytotoxicity in tumor tissue. Furthermore, oxygen-loaded PAsp(DET)-PpIX-PEG nanovesicles could not only reduce therapeutic resistance by relieving tumor hypoxia but also increase ROS production for enhanced sonodynamic therapy. An in vivo study revealed that the nanovesicles could accumulate in the tumor site after i.v. injection and achieved remarkable tumor growth inhibition in both with and without preloaded oxygen groups, which indicated that the nanovesicle system could efficiently achieve oxygen loading during in vivo circulation and provide a better solution for SDT application.

Mesoporous polydopamine carrying sorafenib and SPIO nanoparticles for MRI-guided ferroptosis cancer therapy.

Iron-based nanomaterials as the main ferroptosis-inducing platforms are more promising because iron itself is a key component in the Fenton reaction to produce ROS. However, the Fe dose needs to be very high in order to induce ferroptosis-based cancer treatment using the SPIO NPs. Therefore, it is still of great challenge to enhance the efficacy of ferroptosis-based cancer therapy by associating the iron-based nanomaterials with other components and therapeutic modalities. In this study, sorafenib (SRF) and ultrasmall SPIO nanoparticles were loaded into the mesopores and onto the surface of MPDA NPs to form SRF@MPDA-SPIO nanoparticles. SPIO loading endowed the system with iron-supply for ferroptosis and made the system MRI-visible. Meanwhile, SRF was able to induce ferroptosis in cancer cells with lower Fe dose. Furthermore, the heat generated by MPDA NPs upon laser irradiation offered a moderate PTT to boost the ferroptosis effect. The SRF@MPDA-SPIO exhibited biocompatibility highly desirable for in vivo application and superior anticancer therapy via the combination of ferroptosis and photothermal therapy.

Enzymatic synthesis of PEG-poly(amine-co-thioether esters) as highly efficient pH and ROS dual-responsive nanocarriers for anticancer drug delivery.

Novel multifunctional drug nanocarriers have been successfully fabricated from a new type of enzymatically synthesized, biodegradable block copolymer, PEG-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-thiodipropionate) (PEG-PPMT), which was responsive to tumor-relevant acidic pH (5.0-6.5) and intracellular reactive oxygen species (ROS) of tumor cells. The PEG-PPMT copolymers could self-assemble to form nano-scaled particles in aqueous solutions, which are stable in physiological solutions, but swell substantially upon reducing the pH from 7.4 to 5.0 and/or in the presence of ROS on account of the protonation of the tertiary amino groups and oxidation of the thioether groups, causing a hydrophobic to hydrophilic transition in the nanoparticle cores. Consistently, docetaxel (DTX) encapsulated in PEG-PPMT nanoparticles can be triggered in a synergistic manner by acidic pH and a high-ROS environment in tumor cells to release the hydrophobic drug at accelerated rates for efficient tumor growth inhibition. In particular, DTX encapsulated in PEG-PPMT-11% PDL and PEG-PPMT-28% PDL nanoparticles exhibit extraordinarily enhanced potency (95% and 93% tumor-inhibiting efficiency, respectively) in inhibiting the growth of ROS-rich CT-26 tumors xenografted in mice. Importantly, biosafety analyses show minimal toxicity of DTX-loaded PEG-PPMT nanoparticles toward normal organs including liver and kidneys during the in vivo antitumor treatments. These results demonstrate that the PEG-PPMT nanoparticles are promising pH and ROS dual-responsive multifunctional nanocarriers for tumor site specific, controlled release of anticancer drugs to treat ROS-rich tumors.

Ultrasound triggered phase-change nanodroplets for doxorubicin prodrug delivery and ultrasound diagnosis: An in vitro study.

Ultrasound-triggered delivery system is among the various multifunctional and stimuli-responsive strategies that hold great potential as a robust solution to the challenges of localized drug delivery and gene therapy. In this work, we developed an ultrasound-triggered delivery system PFP/C9F17-PAsp(DET)/CAD/PGA-g-mPEG nanodroplet, which combined ultrasound responsive phase-change contrast agent, acid-cleavable doxorubicin prodrug and cationic amphiphilic fluorinated polymer carrier, aiming to achieve both high imaging contrast and preferable ultrasound-triggered anti-cancer therapeutic effect. The optimized nanodroplets were characterized as monodispersed particles with a diameter of about 400 nm, slightly positive surface charge and high drug-loading efficiency. The functional augmenter PGA-g-mPEG provided the nanodroplets good sustainability, low cytotoxicity and good serum compatibility, as confirmed by stability and biocompatibility tests. In ultrasound imaging study, the nanodroplets produced significant contrast with ultrasound irradiation (3.5 MHz, MI = 0.08) at 37 ℃. Cell uptake and cytotoxicity studies in HepG2 and CT-26 cells showed the enhanced drug uptake and therapeutic effect with the combination of nanodroplets and ultrasound irradiation. These results suggest that the PFP/CAD-loaded phase change nano-emulsion can be utilized as an efficient theranostic agent for both ultrasound contrast imaging and drug delivery.

Intrinsically fluorescent and highly functionalized polymer nanoparticles as probes for the detection of zinc and pyrophosphate ions in rabbit serum samples.

Intrinsically fluorescent polymer nanoparticles (F-PNPs) were synthetized from 2-hydroxy-5-methylisophthalaldehyde and melamine by solvothermal method. F-PNPs can emit strong yellow green fluorescence at 542 nm without the conjugation to any external fluorescent agent and surface modification. Owing to the abundant amino and hydroxyl groups on their surface, the F-PNPs possess multiple binding sites, good biocompatibility and excellent water-solubility. Addition of Zn2+ to the F-PNPs solution resulted in a blue shift (Δλ=40 nm) with obvious enhancement in the fluorescence intensity at 502 nm; while there was negligible change in the presence of other metal ions. The subsequent treatment with pyrophosphate (PPi) can cause fluorescence recovery of F-PNPs by pulling the Zn2+ out of the coordination cavity of F-PNPs-Zn2+ nanocomposites. No interference was observed from other anions and nucleotides, making the F-PNPs-Zn2+ ensembles highly sensitive and selective nanoprobes for PPi. The detection limit is 2.75 × 10-8 M/L and 7.63 × 10-8 M/L for Zn2+ and PPi, respectively. The proposed nanoprobes were then used for detecting the recovery of Zn2+ and PPi in rabbit serum samples, which were found to be 99.4-104.2% and 98.6-104.7%, respectively. The present strategy for the fabrication of nanoparticles may offer a new sight for the preparation of polymer nanostructures. The F-FNPs based probes can provide an accurate method for the detection of Zn2+ and PPi in serum samples.

pH and redox dual-responsive multifunctional gene delivery with enhanced capability of transporting DNA into the nucleus.

Stimuli-responsive gene delivery vectors based on physiologically triggered structure changing have been recently recognized as a new therapeutic agent for their excellent performance in vivo. Herein, we present an intelligent gene delivery system based on the octa-arginine peptides (R8)-conjugated polyamino acid derivatives noted as PPCRC (PVIm-(PAsp-Cystamine-R8)-Cholesteryl), which processed pH responsive, surface charge-switching, intracellular redox-responsive and enhanced nucleus import of gene together. Due to the imidazole group in the PPCRC backbone, the DNA/PPCRC polyplexes not only exhibited the enhanced buffering capacity in the endosome after endocytosis, but also displayed the reversible surface charge from negative to positive with decreasing the pH value form pH 7.4 to pH 6.5-6.8, which would promote the cell membrane binding and cellular uptake. The disulfide bond for R8 peptides conjugation in the polymer side chain could be rapidly cleaved under reductive conditions, facilitating DNA release in the cytoplasm. Subsequently, the DNA would be still associated with the R8 peptides, which would promote the intracellular nucleus import of DNA. The luciferase gene expression level of COS-7 cells transfected by DNA/PPCRC polyplexes was almost 2000 folds higher than cells transfected by DNA/PPCC polyplexes (without R8 peptides modification) in growth-arrested cell model. Nearly 10 folds enhanced gene transfection efficiency was found on human bone mesenchymal stem cells (hBMSCs) using the same strategy, which revealed that this intelligent vector can be also utilized in transfection of non-dividing cells. Intravenous injection of the DNA/PPCRC polyplexes also achieved the effective transfection in subcutaneous tumor model. Taken together, PPCRC vector has great potential for both dividing and non-dividing cells transfection and in vivo gene delivery application.

Stimuli-Responsive Polymeric Nanocarriers for Efficient Gene Delivery.

Gene therapy provides an alternative and effective method for treatment of genetic diseases and cancers that are refractory to conventional therapeutics. The success of gene therapy is largely dependent on the development of safe and effective gene delivery vectors for transporting genetic material from the blood stream to the cytoplasm or nucleus. Current gene vectors can be divided into viral and non-viral vectors. Although non-viral gene delivery carriers can offer some advantages, such as safety and facile fabrication, they do not possess the same high gene transfection efficiency as viral vectors due to a lack of functionality to overcome extra- and intracellular gene delivery obstacles. On the basis of these disadvantages, researchers are developing "smart" non-viral gene-delivery carriers in order to overcome the physiological barriers and realize efficient gene transfection. These "smart" stimuli-responsive carriers can undergo physical or chemical reactions in response to internal tumor-specific environments, such as pH conditions, redox potentials, enzymatic activations and thermal gradients, as well as external stimulations, such as ultrasound, light, magnetic fields, and electrical fields. Furthermore, "smart" carriers can also be triggered by dual or multiple combinations of different stimuli. In this review, we highlight the recent stimuli-sensitive polymeric nanocarriers for gene delivery, and we discuss the potential of combining multiple stimuli-responsive strategies for future gene therapy applications.

Enzymatic PEG-Poly(amine-co-disulfide ester) Nanoparticles as pH- and Redox-Responsive Drug Nanocarriers for Efficient Antitumor Treatment.

We have designed and constructed novel multifunctional nanoparticle drug-delivery systems that are stable under physiological conditions and responsive to tumor-relevant pH and intracellular reduction potential. The nanoparticles were fabricated from enzymatically synthesized poly(ethylene glycol) (PEG)-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PPMD) and PEG-poly(ε-caprolactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PCMD) block copolymers via self-assembly processes in aqueous solution. At acidic pH and in the presence of a reductant (e.g., d,l-dithiothreitol or glutathione), the nanosized micelle particles rapidly swell and disintegrate due to the protonation of amino groups and reductive cleavage of disulfide bonds in the micelle cores. Consistently, docetaxel (DTX)-loaded PEG-PPMD and PEG-PCMD micelles can be triggered synergistically by acidic endosomal pH and a high intracellular reduction potential to rapidly release the drug for efficient killing of cancer cells. The drug formulations based on PEG-PPMD and PEG-PCMD copolymers exhibited a substantially higher potency than free DTX in inhibiting tumor growth in mice, whereas their therapeutic effects on important organ tissues were minimal. These results demonstrate that PEG-PPMD and PEG-PCMD nanoparticles have a great potential to serve as site-specific, controlled drug-delivery vehicles for safe and efficient antitumor treatment.

Codelivery of sorafenib and GPC3 siRNA with PEI-modified liposomes for hepatoma therapy.

Hepatocellular carcinoma (HCC) is one of the most common malignancies imposing a serious threat to human health worldwide. To date, the effect of HCC chemotherapy has been limited due to drug resistance. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy that may improve anticancer effects by synergistic actions. The current study was aimed at achieving better HCC treatment via combination therapy, in which PEI-modified liposomes prepared by a thin-film hydration method were used to codeliver sorafenib (SF) and siRNA targeting GPC3 gene (siGPC3). Under optimized experimental conditions, SF and siGPC3 were effectively loaded into liposomes (SF-PL/siGPC3). SF-PL/siGPC3 with selected sizes and zeta potentials effectively accumulated at tumor sites and entered HCC cells. The two codelivered therapeutic agents exerted good anticancer effects by jointly suppressing the expression of the anti-apoptotic GPC3 gene and the proliferative cyclin D1 gene in HCC. Consequently, the intravenous injection of SF-PL/siGPC3 into nude mice bearing subcutaneous human HepG2 xenografts effectively inhibited tumor growth and also increased the survival rates of animals. These results revealed the great potential of the PEI-modified liposomal nanomedicine carrying SF and siGPC3 to improve HCC treatment.

Enzymatic PEGylated Poly(lactone-co-ß-amino ester) Nanoparticles as Biodegradable, Biocompatible and Stable Vectors for Gene Delivery.

We have developed new, efficient gene delivery systems based on PEGylated poly(lactone-co-ß-amino ester) block copolymers that are biodegradable, stable and low in toxicity. The PEG-poly[PDL-co-3-(4-(methylene)piperidin-1-yl)propanoate] (PEG-PPM) diblock and PPM-PEG-PPM triblock copolymers with various compositions were synthesized in one step via lipase-catalyzed copolymerization of ω-pentadecalactone (PDL) and ethyl 3-(4-(hydroxymethyl)piperidin-1-yl)propanoate (EHMPP) with an appropriate PEG (MeO-PEG-OH or HO-PEG-OH). The amphiphilic block copolymers are capable of condensing DNA in aqueous medium via a self-assembly process to form polyplex micelle nanoparticles with desirable particle sizes (70-140 nm). These micelles possess low CMC values and are stable in the medium containing serum protein molecules (FBS). Among the PEG-PPM and PPM-PEG-PPM micelles, the PEG-PPM-15% PDL micelle particles exhibited high DNA-binding ability, the fastest cellular uptake rate and highest gene transfection efficacy. Flow cytometry analysis shows that LucDNA/PEG-PPM-15% PDL polyplex micelles can effectively escape from endosomal degradation after cellular uptake likely due to the presence of the tertiary amine groups in the copolymer chains that act as proton sponges. In vitro cytotoxicity and hemolysis assay experiments indicate that all copolymer samples are nonhemolytic and have minimal toxicity toward COS-7 cells within the polymer concentration range (≤200 µg/mL) used for the gene transfection. These results demonstrate that the PEGylated poly(lactone-co-ß-amino ester) block copolymers are promising new vectors for gene delivery applications.

Drug and gene co-delivery systems for cancer treatment.

Cancer remains a major killer and a leading cause of death in the world; thus, a growing number of new treatments have been focused on cancer therapy over the past few decades. Chemotherapy, which is thought to be a powerful strategy for cancer treatment, has been widely used in clinical therapy in recent years. However, due to the complexity of cancer, a single therapeutic approach is insufficient for the suppression of cancer growth and migration. Therefore, increasing attention has been paid to the use of smart multifunctional carriers and combinatorially delivers chemotherapeutic drugs and functional genes in order to maximize therapeutic efficiency. Combination therapy using selected drugs and genes can not only overcome multidrug resistance and inhibit the cellular anti-apoptotic process but also achieve a synergistic therapeutic effect. Because multifunctional nanocarriers are important for achieving these goals, this review will illustrate and discuss some advanced biomaterial nanocarriers for co-delivering therapeutic genes and drugs, including multifunctional micelles, liposomes, polymeric conjugates and inorganic nanoparticles. In addition, the challenges and future perspectives for co-delivery systems, containing therapeutic drugs and genes to achieve better therapeutic effects for cancer treatment will be discussed.