Zwitterionic Modification of Polyethyleneimine for Efficient In Vitro siRNA Delivery.

Polyethylenimine (PEI) has been widely used in gene delivery. However, its high cytotoxicity and undesired non-specific protein adsorption hinder the overall delivery efficacy and the practical applications of PEI-based gene delivery systems. In this study, we prepared hydrophobically modified PEIs (H-PEIs) via the reaction of octanal with 40% of primary amines in PEI25k and PEI10k, respectively. Two common zwitterionic molecules, 1,3-propanesultone and ß-propiolactone, were then used for the modification of the resulting H-PEIs to construct polycationic gene carriers with zwitterionic properties (H-zPEIs). The siRNA delivery efficiency and cytotoxicity of these materials were evaluated in Hela-Luc and A549-Luc cell lines. Compared with their respective parental H-PEIs, different degrees of zwitterionic modification showed different effects in reducing cytotoxicity and delivery efficiency. All zwitterion-modified PEIs showed excellent siRNA binding capacity, reduced nonspecific protein adsorption, and enhanced stability upon nuclease degradation. It is concluded that zwitterionic molecular modification is an effective method to construct efficient vectors by preventing undesired interactions between polycationic carriers and biomacromolecules. It may offer insights into the modification of other cationic carriers of nucleic acid drugs.

Atorvastatin Promotes Macrocalcification, But Not Microcalcification in Atherosclerotic Rabbits: An 18F-NaF PET/CT Study.

INTRODUCTION: Our study aimed to investigate the effect of atorvastatin on plaque calcification by matching the results obtained by 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/computed tomography (CT) with data from histologic sections. METHODS AND RESULTS: The rabbits were divided into 2 groups as follows: an atherosclerosis group (n = 10) and an atorvastatin group (n = 10). All rabbits underwent an abdominal aortic operation and were fed a high-fat diet to induce atherosclerosis. Plasma samples were used to analyze serum inflammation markers and blood lipid levels. 18F-NaF PET/CT scans were performed twice. The plaque area, macrophage number and calcification were measured, and the data from the pathological sections were matched with the 18F-NaF PET/CT scan results. The mean standardized uptake value (0.725 ± 0.126 vs. 0.603 ± 0.071, P < 0.001) and maximum standardized uptake value (1.024 ± 0.116 vs. 0.854 ± 0.091, P < 0.001) significantly increased in the atherosclerosis group, but only slightly increased in the atorvastatin group (0.616 ± 0.103 vs. 0.613 ± 0.094, P = 0.384; 0.853 ± 0.099 vs.0.837 ± 0.089, P < 0.001, respectively). The total calcium density was significantly increased in rabbits treated with atorvastatin compared with rabbits not treated with atorvastatin (1.64 ± 0.90 vs. 0.49 ± 0.35, P < 0.001), but the microcalcification level was significantly lower. There were more microcalcification deposits in the areas with increased radioactive uptake of 18F-NaF. CONCLUSIONS: Our study suggests that the anti-inflammatory activity of atorvastatin may promote macrocalcification but not microcalcification within atherosclerotic plaques. 18F-NaF PET/CT can detect plaque microcalcifications.

Highly Efficient Modular Construction of Functional Drug Delivery Platform Based on Amphiphilic Biodegradable Polymers via Click Chemistry.

Amphiphilic copolymers with pendant functional groups in polyester segments are widely used in nanomedicine. These enriched functionalities are designed to form covalent conjugates with payloads or provide additional stabilization effects for encapsulated drugs. A general method is successfully developed for the efficient preparation of functional biodegradable PEG-polyester copolymers via click chemistry. Firstly, in the presence of mPEG as initiator, Sn(Oct)2-catalyzed ring-opening polymerization of the α-alkynyl functionalized lactone with D,L-lactide or ε-caprolactone afforded linear mPEG-polyesters bearing multiple pendant alkynyl groups. Kinetic studies indicated the formation of random copolymers. Through copper-catalyzed azide-alkyne cycloaddition reaction, various small azido molecules with different functionalities to polyester segments are efficiently grafted. The molecular weights, polydispersities and grafting efficiencies of azido molecules of these copolymers were investigated by NMR and GPC. Secondly, it is demonstrated that the resulting amphiphilic functional copolymers with low CMC values could self-assemble to form nanoparticles in aqueous media. In addition, the in vitro degradation study and cytotoxicity assays indicated the excellent biodegradability and low cytotoxicity of these copolymers. This work provides a general approach toward the preparation of functional PEG-polyester copolymers in a quite efficient way, which may further facilitate the application of functional PEG-polyesters as drug delivery materials.

Hydrophobic Domain Structure of Linear-Dendritic Poly(ethylene glycol) Lipids Affects RNA Delivery of Lipid Nanoparticles.

In this work, a series of linear-dendritic poly(ethylene glycol) (PEG) lipids (PEG-GnCm) were synthesized through a strategy using sequential aza- and sulfa-Michael addition reactions. The effect of modulating the hydrophobic domain of linear-dendritic PEG lipids was systematically investigated for in vitro and in vivo small RNA delivery as the surface-stabilizing component of 5A2-SC8 dendrimer lipid-based nanoparticles (DLNPs). The lipid alkyl lengths (C8, C12, and C16) and dendrimer generations (G1, G2, and G3) were altered to create PEG-GnCm with different physical properties and anchoring potential. The tail chemical structure of PEG-GnCm did not affect the formulation of 5A2-SC8 DLNPs, including the nanoparticle size, RNA encapsulation, and stability. However, the tail chemical structure did dramatically affect the RNA delivery efficacy of the formed 5A2-SC8 DLNPs with different PEG-GnCm. First-generation PEG lipids (PEG-G1C8, PEG-G1C12, and PEG-G1C16) and a second-generation PEG lipid (PEG-G2C8) formed 5A2-SC8 DLNPs that could deliver siRNAs effectively in vitro and in vivo. 5A2-SC8 DLNPs formulated with second-generation PEG lipids (PEG-G2C12 and PEG-G2C16) and all three third-generation PEG lipids (PEG-G3C8, PEG-G3C12, and PEG-G3C16) lost the ability to deliver siRNA effectively in vitro and in vivo. Overall, we determined that the hydrophobic domain chemical structure of linear-dendritic poly(ethylene glycol) lipids affected the RNA delivery of DLNPs by impacting the escape of 5A2-SC8 DLNPs from endosomes at early cell incubation times, thereby indicating how PEG lipid anchoring and chemical structure can modulate in vitro and in vivo siRNA delivery efficacies.

Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells.

Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.

Systemic mRNA Delivery to the Lungs by Functional Polyester-based Carriers.

Messenger RNA (mRNA) has recently come into focus as an emerging therapeutic class with great potential for protein replacement therapy, cancer immunotherapy, regenerative medicine, vaccines, and gene editing. However, the lack of effective and safe delivery methods impedes the broad application of mRNA-based therapeutics. We report a robust approach to develop efficient polymeric delivery carriers for mRNA. Lead polyesters were identified by in vitro screening of a 480-member combinatorially modified poly(trimethylolpropane allyl ether-co-suberoyl chloride) library for the delivery of luciferase encoding mRNA (Luc mRNA) to IGROV1 cells. The formulation of mRNA polyplex nanoparticles (NPs) with Pluronic F127 decreased the surface charge. Although this improved the stability of mRNA nanoparticles, the delivery potency decreased with increased F127 content. Thus, we determined that NP stabilization with 5% F127 could balance the protective effects and delivery potency. 5% F127 formulated PE4K-A17-0.33C12 mRNA NPs enabled luciferase expression predominantly in the lungs after intravenous injection into mice. The efficient mRNA delivery specifically to lungs by degradable carriers suggests the potential for the treatment of pulmonary diseases.

Rapid Synthesis of a Lipocationic Polyester Library via Ring-Opening Polymerization of Functional Valerolactones for Efficacious siRNA Delivery.

The ability to control chemical functionality is an exciting feature of modern polymer science that enables precise design of drug delivery systems. Ring-opening polymerization of functional monomers has emerged as a versatile method to prepare clinically translatable degradable polyesters.1 A variety of functional groups have been introduced into lactones; however, the direct polymerization of tertiary amine functionalized cyclic esters has remained elusive. We report a strategy that enabled the rapid synthesis of >130 lipocationic polyesters directly from functional monomers without protecting groups. These polymers are highly effective for siRNA delivery at low doses in vitro and in vivo.

Novel aromatic moieties-modified poly(glycidyl amine)s with potent siRNA delivery and cancer treatment effect.

The development of safe and effective delivery systems is critical for the clinical applications of siRNA-based therapeutics. Polymer-based vectors have garnered significant attention owing to their structural flexibility and functional tunability. Polyethyleneimine (PEI) has been extensively studied for nucleic acid delivery; nevertheless, its high cytotoxicity has posed challenges for clinical applications. In this study, we have reported poly(glycidyl amine) (PGAm), a linear PEI analogue, demonstrating remarkable siRNA delivery efficacy and improved biocompatibility. By introducing three aromatic moieties (tyrosine, p-hydroxybenzenepropanoic acid, and phenylalanine) at varying ratios to further modify PGAms, we successfully constructed a library comprising 36 PGAm-based carriers. In vitro evaluations revealed that PGAm-based carriers exhibited significantly enhanced biocompatibility and reduced non-specific protein absorption in comparison to PEI25k. Among them, 10 modified PGAms achieved a knockdown of target gene expressions exceeding 80%, and 26 modified PGAms maintained over 70% cell viability when utilized for the in vitro delivery of siRNA to HeLa cells. Explorations into the structure-activity relationship of PGAm-based polyplex nanoparticles (NPs) indicated that the siRNA delivery efficacy of NPs depended on factors such as the molecular weight of PGAm precursors, the type of modifying moieties, and the modification ratio. Furthermore, it was demonstrated that two top-performing NPs, namely 2T100/siLuc and 2A50/siLuc, exhibited potent silencing of target genes in tumors following i.v. injection into mice bearing HeLa-Luc xenografts. The in vivo efficacy of the selected NPs was further validated by a remarkable anti-cancer effect when employed for the delivery of siRNA targeting polo-like kinase 1 (siPLK1) to mice with PC-3 xenograft tumors. The intravenous administration of NPs resulted in a substantial inhibition of tumor growth without significant toxicity. These findings demonstrate the feasibility of employing PGAm in siRNA delivery and provide valuable insights for the development of efficient siRNA carriers based on PGAm.

Flash Nanoprecipitation Fabrication of PEI@Amorphous Calcium Carbonate Hybrid Nanoparticles for siRNA Delivery.

RNA interference (RNAi) is a promising approach for disease treatments. But the development of safe and effective delivery carriers remains a major challenge. Organic-inorganic hybrid nanoparticles (NPs), with the integration of functions from distinct materials, show great potential in small interfering RNA (siRNA) delivery. Herein, pH responsive amorphous calcium carbonate NPs (ACC NPs) are prepared using flash nanoprecipitation and hybrid NPs are constructed by coating ACC NPs with polyethyleneimine (PEI) for efficient siRNA delivery. PEI/ACC NPs show robust pH responsiveness and stability as well as effective siRNA loading and protection. Furthermore, siRNA-loaded PEI/ACC NPs demonstrate enhanced cellular uptake and efficient endosomal escape, mediating improved siRNA delivery compared to pure PEI. These findings suggest that PEI/ACC NPs may have great potential in siRNA delivery for RNAi-based therapy.

Branched hydrophobic tails in lipid nanoparticles enhance mRNA delivery for cancer immunotherapy.

Efficient and safe delivery of vulnerable mRNA is a long-standing challenge for the broad application of the emerging mRNA-based therapeutics. Herein, a combinatorial library containing 119 novel lipids was constructed via sequential aza-Michael addition reactions of arylates and varying amines to tackle the ongoing challenge in mRNA delivery. Through in vitro screening of the lipid library on IGROV 1 cells, we identified several synthetic lipids with superior mRNA delivery efficacy. The delivery capability of these lipids was verified by the potent expression of luciferase in BALB/c mice upon intravenous administration of luciferase-encoding mRNA lipid nanoparticles (LNPs). Further investigations on the structure-activity relationship revealed that lipids with branched hydrophobic tails were better at delivering mRNA than those containing linear tails at the similar total number of carbons. In comparison to linear tails, the branched tails endowed LNPs with less inner hydrophobicity, fewer surface charges, and proper stability, which benefits the cellular uptake of LNPs and the intracellular trafficking of mRNA, thus improves the delivery efficacy of mRNA. The therapeutical potential of the lead LNPs was evaluated by delivering ovalbumin (OVA)-encoding mRNA to mice bearing B16-OVA melanoma tumors. The results demonstrated that the administration of OVA mRNA LNPs significantly activated CD8+ T cells in tumor microenvironment and substantially prohibited the growth of the aggressive B16-OVA tumors. The robust antitumor efficacy highlights the great potential of these LNPs in cancer immunotherapy.

Multimerization and aggregation of native-state insulin: effect of zinc.

The aggregation of insulin is complicated by the coexistence of various multimers, especially in the presence of Zn(2+). Most investigations of insulin multimerization tend to overlook aggregation kinetics, while studies of insulin aggregation generally pay little attention to multimerization. A clear understanding of the starting multimer state of insulin is necessary for the elucidation of its aggregation mechanism. In this work, the native-state aggregation of insulin as either the Zn-insulin hexamer or the Zn-free dimer was studied by turbidimetry and dynamic light scattering, at low ionic strength and pH near pI. The two states were achieved by varying the Zn(2+) content of insulin at low concentrations, in accordance with size-exclusion chromatography results and literature findings (Tantipolphan, R.; Romeijn, S.; Engelsman, J. d.; Torosantucci, R.; Rasmussen, T.; Jiskoot, W. J. Pharm. Biomed. 2010, 52, 195). The much greater aggregation rate and limiting turbidity (τ(∞)) for the Zn-insulin hexamer relative to the Zn-free dimer was explained by their different aggregation mechanisms. Sequential first-order kinetic regimes and the concentration dependence of τ(∞) for the Zn-insulin hexamer indicate a nucleation and growth mechanism, as proposed by Wang and Kurganov (Wang, K.; Kurganov, B. I. Biophys. Chem. 2003, 106, 97). The pure second-order process for the Zn-free dimer suggests isodesmic aggregation, consistent with the literature. The aggregation behavior at an intermediate Zn(2+) concentration appears to be the sum of the two processes.

Structural Exploration of Polycationic Nanoparticles for siRNA Delivery.

RNA interference (RNAi) is a promising approach to the treatment of genetic diseases by the specific knockdown of target genes. Functional polymers are potential vehicles for the effective delivery of vulnerable small interfering RNA (siRNA), which is required for the broad application of RNAi-based therapeutics. The development of methods for the facile modulation of chemical structures of polymeric carriers and an elucidation of detailed delivery mechanisms remain important areas of research. In this paper, we synthesized a series of methacrylate-based polymers with controllable structures and narrow distributions by atom transfer radical polymerization using various combinations of cationic monomers (2-dimethylaminoethyl methacrylate, 2-diethylaminoethyl methacrylate, and 2-dibutylaminoethyl methacrylate) and hydrophobic monomers (2-butyl methacrylate (BMA), cyclohexyl methacrylate, and 2-ethylhexyl methacrylate). These polymers exhibited varying hydrophobicities, charge densities, and pKa values, enabling the discovery of effective carriers for siRNA by in vitro delivery assays. For the polymers with BMA segments, 50% of cationic segments were beneficial to the formation of siRNA nanoparticles (NPs) and the in vitro delivery of siRNA. The optimal ratio varied for different combinations of cationic and hydrophobic segments. In particular, 20k PMB 0.5, PME 0.5, and PEB 1.0 showed >75% luciferase knockdown. Efficacious delivery was dependent on high siRNA binding, the small size of NPs, and balanced hydrophobicity and charge density. Cellular uptake and endosomal escape experiments indicated that carboxybetaine modification of 20k PMB 0.5 did not remarkably affect the internalization of corresponding NPs after incubation for 6 h but significantly reduced the endosomal escape of NPs, which leads to the notable decrease in delivery efficacy of polymers. These results provide insights into the mechanism of polymer-based siRNA delivery and may inspire the development of novel polymeric carriers.

Construction of Degradable and Amphiphilic Triblock Polymer Carriers for Effective Delivery of siRNA.

The development of effective and safe delivery carriers is one of the prerequisites for the clinical translation of siRNA-based therapeutics. In this study, a library of 144 functional triblock polymers using ring-opening polymerization (ROP) and thiol-ene click reaction is constructed. These triblock polymers are composed of hydrophilic poly (ethylene oxide) (PEO), hydrophobic poly (ε-caprolactone) (PCL), and cationic amine blocks. Three effective carriers are discovered by high-throughput screening of these polymers for siRNA delivery to HeLa-Luc cells. In vitro evaluation shows that siLuc-loaded nanoparticles (NPs) fabricated with leading polymer carriers exhibit sufficient knockdown of luciferase genes and relatively low cytotoxicity. The chemical structure of polymers significantly affects the physicochemical properties of the resulting siRNA-loaded NPs, which leads to different cellular uptake of NPs and endosomal escape of loaded siRNA and thus the overall in vitro siRNA delivery efficacy. After systemic administration to mice with xenograft tumors, siRNA NPs based on P2-4.5A8 are substantially accumulated at tumor sites, suggesting that PEO and PCL blocks are beneficial for improving blood circulation and biodistribution of siRNA NPs. This functional triblock polymer platform may have great potential in the development of siRNA-based therapies for the treatment of cancers.

Improved paclitaxel delivery with PEG-b-PLA/zein nanoparticles prepared via flash nanoprecipitation.

Polymeric micelle is a promising vehicle to improve the bioavailability and clinical outcomes of paclitaxel (PTX) which has been proven effective in the treatment of a wide range of cancers. However, conventional PTX formulation with the amphiphilic PEG-b-PLA usually suffers from insufficient PTX loading, low stability of PTX-micelles, and rapid PTX release due to low compatibility between PTX and PLA, limiting its clinical application. In this study, a novel nanoparticle platform was developed to improve the stability of PTX-loaded nanoparticles (NPs) and the delivery efficacy of PTX by integrating the flash nanoprecipitation (FNP) technique and a combination of amphiphilic PEG-PLA and super hydrophobic zein. The incorporation of zein led to the formation of distinct hydrophobic interiors of NPs which enhanced the interaction between PTX and NPs, therefore improving the encapsulation efficiency of PTX and sustained drug release compared with PEG-PLA micelles without zein. In addition, FNP allowed facile fabrication of PTX-NPs with smaller sizes and higher stability. These PTX-NPs showed superior sustained release of PTX and good cancer cell-killing in vitro. Among them, PTX-5k-16k-1Z NPs exhibited excellent biosafety and anti-tumor efficacy in a xenograft tumor model in mice, suggesting great potential in the delivery of hydrophobic drugs for cancer therapy.

PEI fluorination reduces toxicity and promotes liver-targeted siRNA delivery.

Polyethyleneimine (PEI) has been extensively investigated as an efficient carrier for nucleic acid delivery. Yet, it suffers from a high toxicity profile that hinders clinical translation. Fluorination has proven to be a valid approach to reduce the cytotoxicity of PEI and improve the in vitro siRNA delivery potency. Hydrophobicity and lipophobicity can be controllably introduced into the side chains of PEI. However, the effect of fluorination on siRNA delivery in vivo, particularly the biodistribution of siRNA polyplex nanoparticles with fluorinated PEIs, has not been extensively explored. Here, we introduce two series of fluorinated PEIs via amidation with ethyl trifluoroacetate and perfluorobutyryl chloride. Fluorination substantially improved the performance of PEI for siRNA delivery by reducing the cytotoxicity to MDA-MB-231 cells. Importantly, fluorinated PEI enabled the major accumulation of siRNA polyplex nanoparticles in the liver while non-fluorinated PEI delivered siRNA nanoparticles mainly to the lungs after intravenous administration to mice. It is envisioned that fluorination may be an important general strategy for lowering toxicity of cationic polymers, and that the fluorination-induced alteration of biodistribution may be applicable for improved delivery to different organs. Graphical abstract.

Fabrication of Charge-Conversion Nanoparticles for Cancer Imaging by Flash Nanoprecipitation.

Traditional charge-conversion nanoparticles (NPs) need the breakage of acid-labile groups on the surface, which impedes the rapid response to the acidic microenvironment. Here, we developed novel rodlike charge-conversion NPs with amphiphilic dextran- b-poly(lactic- co-glycolic acid), poly(2-(dimethylamino) ethylmethylacrylate)- b-poly(ε-caprolactone), and an aggregation-induced emission-active probe through flash nanoprecipitation (FNP). These NPs exhibit reversible negative-to-positive charge transition at a slightly acidic pH relying on the rapid protonation/deprotonation of polymers. The size and the critical charge-conversion pH can be further tuned by varying the flow rate and polymer ratio. Consequently, the charge conversion endows NPs with resistance to protein adsorption at physiological pH and enhanced internalization to cancer cells under acidic conditions. Ex vivo imaging on harvest organs shows that charge-conversion NPs were predominantly distributed in tumors after intravenous administration to mice due to the robust response of NPs to the acidic microenvironment in tumor tissue, whereas control NPs or free probes were broadly accumulated in tumor, liver, kidney, and lung. These results suggest the great potential of the current FNP strategy in the facile and generic fabrication of charge-conversion NPs for tumor-targeting delivery of drugs or fluorescent probes.

High-Contrast Fluorescence Detection of Metastatic Breast Cancer Including Bone and Liver Micrometastases via Size-Controlled pH-Activatable Water-Soluble Probes.

Breast cancer metastasis is the major cause of cancer death in women worldwide. Early detection would save many lives, but current fluorescence imaging probes are limited in their detection ability, particularly of bone and liver micrometastases. Herein, probes that are capable of imaging tiny (<1 mm) micrometastases in the liver, lung, pancreas, kidneys, and bone, that have disseminated from the primary site, are reported. The influence of the poly(ethylene glycol) (PEG) chain length on the performance of water-soluble, pH-responsive, near-infrared 4,4'-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) probes is systematically investigated to demonstrate that PEG tuning can provide control over micrometastasis tracking with high tumor-to-background contrast (up to 12/1). Optimized probes can effectively visualize tumor boundaries and successfully detect micrometastases with diameters <1 mm. The bone-metastasis-targeting ability of these probes is further enhanced by covalent functionalization with bisphosphonate. This improved detection of both bone and liver micrometastases (<2 mm) with excellent tumor-to-normal contrast (5.2/1). A versatile method is thus introduced to directly synthesize modular water-soluble probes with broad potential utility. Through a single intravenous injection, these materials can image micrometastases in multiple organs with spatiotemporal resolution. They thus hold promise for metastasis diagnosis, image-guided surgery, and theranostic PEGylated drug therapies.

Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors.

Tremendous progress has been made in the development of delivery carriers for small RNA therapeutics. However, most achievements have focused on the treatment of liver-associated diseases because conventional lipid and lipidoid nanoparticles (LNPs) readily accumulate in the liver after intravenous (i.v.) administration. Delivering RNAs to other organs and tumor tissues remains an ongoing challenge. Here, we utilized a 540-member combinatorial functional polyester library to discover nanoparticles (NPs) that enable efficacious siRNA delivery to A549 lung cancer cells in vitro and in vivo. PE4K-A13-0.33C6 and PE4K-A13-0.33C10 NPs were efficiently internalized into A549-Luc cells within 4 h. The addition of PEG 2000 DMG lipid or Pluronic F-127 onto the surface of the polyplexes reduced the surface charge of NPs, resulting in an increase of serum stability. We then explored aerosol delivery of stabilized PE4K-A13-0.33C6 and PE4K-A13-0.33C10 NPs to implanted orthotopic lung tumors. We found that by altering the administration route from i.v. to aerosol, the NPs could avoid liver accumulation and instead be specifically localized only in the lungs. This resulted in significant gene silencing in the A549 orthotopic lung tumors. Due to the ability to deliver siRNA to non-liver targets, this approach provides a privileged route for gene silencing in the lungs.

Can Platforms Affect the Safety and Efficacy of Drug-Eluting Stents in the Era of Biodegradable Polymers?: A Meta-Analysis of 34,850 Randomized Individuals.

OBJECTIVE: In the era of bare metal stents (BMSs), alloys have been considered to be better materials for stent design than stainless steel. In the era of biodegradable polymer drug-eluting stents (BP-DESs), the safety and efficacy of BP-DESs with different metal platforms (stainless steel or alloys) have not yet been reported, although their polymers are eventually absorbed, and only the metal platforms remain in the body. This study sought to determine the clinical safety and efficacy of BP-DESs with different platforms compared with other stents (other DESs and BMSs). METHODS: PubMed, Embase and Clinical Trials.gov were searched for randomized controlled trials (RCTs) that compared BP-DESs with other stents. After performing pooled analysis of BP-DESs and other stents, we performed a subgroup analysis using two classification methods: stent platform and follow-up time. The study characteristics, patient characteristics and clinical outcomes were abstracted. RESULTS: Forty RCTs (49 studies) comprising 34,850 patients were included. Biodegradable polymer stainless drug-eluting stents (BP-stainless DESs) were superior to the other stents [mainly stainless drug-eluting stents (DESs)] in terms of pooled definite/probable stent thrombosis (ST) (OR [95% CI] = 0.76[0.61-0.95], p = 0.02), long-term definite/probable ST (OR [95% CI] = 0.73[0.57-0.94], p = 0.01), very late definite/probable ST (OR [95% CI] = 0.56[0.33-0.93], p = 0.03) and long-term definite ST. BP-stainless DESs had lower rates of pooled, mid-term and long-term target vessel revascularization (TVR) and target lesion revascularization (TLR) than the other stainless DESs and BMSs. Furthermore, BP-stainless DESs were associated with lower rates of long-term death than other stainless DESs and lower rates of mid-term myocardial infarction than BMSs. However, only the mid-term and long-term TVR rates were superior in BP-alloy DESs compared with the other stents. CONCLUSION: Our results indirectly suggest that BP-stainless DESs may offer more benefits than BP-alloy DESs in the era of BP-DESs. Further well-designed RCTs comparing BP-stainless with BP-alloy DESs are needed to confirm which platform is better.

Sustained and extended release with structural and activity recovery of lysozyme from complexes with sodium (sulfamate carboxylate) isoprene/ethylene oxide block copolymer.

The complexation of lysozyme and sodium (sulfamate carboxylate) isoprene/ethylene oxide (SCIEO) at pH = 7.4 and the release of lysozyme from the complexes in the presence of NaCl were investigated. Through electrostatic and hydrophobic interactions, lysozyme and SCIEO form stable complex nanoparticles. The complexation partially disturbs the structure of lysozyme. Some of the hydrophobic residues of lysozyme are exposed to bind with SCIEO. The complexation leads to loss of most of the lysozyme activity. In the presence of NaCl, lysozyme can be released from the complexes. The released lysozyme molecules recover their native structure and activity completely. In the condition of physiological pH and ionic strength, a sustained and extended release of lysozyme was achieved.