Biodegradable Nanoflowers with Abaloparatide Spatiotemporal Management of Functional Alveolar Bone Regeneration.

Post-extraction alveolar bone atrophy greatly hinders the subsequent orthodontic tooth movement (OTM) or implant placement. In this study, we synthesized biodegradable bifunctional bioactive calcium phosphorus nanoflowers (NFs) loaded with abaloparatide (ABL), namely ABL@NFs, to achieve spatiotemporal management for alveolar bone regeneration. The NFs exhibited a porous hierarchical structure, high drug encapsulation efficacy, and desirable biocompatibility. ABL was initially released to recruit stem cells, followed by sustained release of Ca2+ and PO43- for in situ interface mineralization, establishing an osteogenic "biomineralized environment". ABL@NFs successfully restored morphologically and functionally active alveolar bone without affecting OTM. In conclusion, the ABL@NFs demonstrated promising outcomes for bone regeneration under orthodontic condition, which might provide a desirable reference of man-made "bone powder" in the hard tissue regeneration field.

Recent Advances in the Modification and Improvement of Bioprosthetic Heart Valves.

Valvular heart disease (VHD) has become a burden and a growing public health problem in humans, causing significant morbidity and mortality worldwide. An increasing number of patients with severe VHD need to undergo heart valve replacement surgery, and artificial heart valves are in high demand. However, allogeneic valves from donors are lacking and cannot meet clinical practice needs. A mechanical heart valve can activate the coagulation pathway after contact with blood after implantation in the cardiovascular system, leading to thrombosis. Therefore, bioprosthetic heart valves (BHVs) are still a promising way to solve this problem. However, there are still challenges in the use of BHVs. For example, their longevity is still unsatisfactory due to the defects, such as thrombosis, structural valve degeneration, calcification, insufficient re-endothelialization, and the inflammatory response. Therefore, strategies and methods are needed to effectively improve the biocompatibility and longevity of BHVs. This review describes the recent research advances in BHVs and strategies to improve their biocompatibility and longevity.

Advanced biomaterials for cancer immunotherapy.

Immunotherapy, as a powerful strategy for cancer treatment, has achieved tremendous efficacy in clinical trials. Despite these advancements, there is much to do in terms of enhancing therapeutic benefits and decreasing the side effects of cancer immunotherapy. Advanced nanobiomaterials, including liposomes, polymers, and silica, play a vital role in the codelivery of drugs and immunomodulators. These nanobiomaterial-based delivery systems could effectively promote antitumor immune responses and simultaneously reduce toxic adverse effects. Furthermore, nanobiomaterials may also combine with each other or with traditional drugs via different mechanisms, thus giving rise to more accurate and efficient tumor treatment. Here, an overview of the latest advancement in these nanobiomaterials used for cancer immunotherapy is given, describing outstanding systems, including lipid-based nanoparticles, polymer-based scaffolds or micelles, inorganic nanosystems, and others.

Tumor-Targeting Anti-MicroRNA-155 Delivery Based on Biodegradable Poly(ester amine) and Hyaluronic Acid Shielding for Lung Cancer Therapy.

Anti-microRNA-155 (anti-miR-155), an oligonucleotide with a complimentary sequence to microRNA-155, holds great promise for lung cancer therapy, and thus some cationic materials have been used to deliver anti-miR-155 into lung tumors. Although the gene delivery capacity in vitro was favorable, the application in vivo was limited by rapid removal and significant cytotoxicity, which were mainly caused by the positive charge of the gene complexes. Therefore, it was necessary to develop a novel carrier to decrease the positive charge and increase the gene delivery capacity into the tumor site. In this paper, biodegradable poly(ester amine) (PEA) was used to condense anti-miR-155 into PEA/anti-miR-155 complexes, and natural anionic polysaccharide hyaluronic acid (HA) was modified with a lung tumor cell targeting peptide and then coated on the surface of gene complexes. The formed hyaluronic acid shielding, PEA/anti-miR-155/HA-peptide complexes were monodispersed, and the particle size and zeta potential were 362.7 nm and -10.17 mV, respectively. In addition, the PEA/anti-miR-155/HA-peptide complexes had good biocompatibility and stability in vitro, and the lung tumor growth inhibitions of PEA/anti-miR-155/HA-peptide in vitro and in vivo were also excellent. The PEA/anti-miR-155/HA-peptide complexes play an active role in tumor growth inhibition and could be useful for lung cancer therapy.

Functional Nanoparticles Activate a Decellularized Liver Scaffold for Blood Detoxification.

Extracorporeal devices have great promise for cleansing the body of virulence factors that are caused by venomous injuries, bacterial infections, and biological weaponry. The clinically used extracorporeal devices, such as artificial liver-support systems that are mainly based on dialysis or electrostatic interaction, are limited to remove a target toxin. Here, a liver-mimetic device is shown that consists of decellularized liver scaffold (DLS) populated with polydiacetylene (PDA) nanoparticles. DLS has the gross shape and 3D architecture of a liver, and the PDA nanoparticles selectively capture and neutralize the pore-forming toxins (PFTs). This device can efficiently and target-orientedly remove PFTs in human blood ex vivo without changing blood components or activating complement factors, showing potential application in antidotal therapy. This work provides a proof-of-principle for blood detoxification by a nanoparticle-activated DLS, and can lead to the development of future medical devices for antidotal therapy.

Facile Construction of Chloroquine Containing PLGA-Based pDNA Delivery System for Efficient Tumor and Pancreatitis Targeting in Vitro and in Vivo.

Chloroquine diphosphate (CQ) was ingeniously used to take place of phosphate salt in traditional calcium phosphate coprecipitation method for pDNA transfection. With multiple roles of CQ in the novel Ca-CQ-pDNA complex including pDNA compaction and assistance in lysosome escape, the transfection efficiency of the pDNA was significantly increased relative to the traditional method. CQ did not intercalate into the DNA double helix as free CQ did, which was probably ascribed to the prior mixing of the pDNA with high concentration of calcium chloride. In order to construct efficacious vector for in vivo gene delivery, Ca-CQ-pDNA-PLGA-NPs was designed and prepared. With entrapment efficiency, particle size and pDNA integrity as screening conditions, the optimal prescription was obtained and CaPi-pDNA-PLGA-NPs made with classic calcium phosphate coprecipitation method after optimization was also prepared as control to systematically study the role of CQ in the novel vector. Physical characters of the vectors were comprehensively studied using TEM, DSC, and XRD. The safety of the vector both in vitro and in vivo was evaluated using MTT, hemolysis test, and histological sections. The Ca-CQ-pDNA-PLGA-NPs dramatically enhanced the gene tranfection efficiency in Human Embryonic kidney HEK293 cells compared with the CaPi-pDNA-PLGA-NPs and presented an increasing gene transfection for up 144 h. The relative fast release of the CQ compared with pDNA from the nanoparticles was responsive for the increased transfection. The Did-labeled-Ca-CQ-pDNA-PLGA-NPs exhibited excellent tumor targeting efficiency and sustained circulation time in CT26 mouse model. The Ca-CQ-pDNA-PLGA-NP loaded with the plasmid pVITRO2 expressing mSurvivin-T34A protein gave 70% tumor inhibition rate, which was partially ascribed to CQ. The Ca-CQ-pDNA-PLGA-NPs showed high targeting efficiency in C57 acute pancreatitis model. In all, the Ca-CQ-pDNA-PLGA-NP was a promising candidate for targeted gene delivery to both tumor and pancreatitis.

Preparation and Properties of Nano-Hydroxyapatite/Gelatin/Poly(vinyl alcohol) Composite Membrane.

In this study, the bone-like composite membrane based on blends of gelatin (Gel), nano-hydroxyapatite (n-HA) and poly(vinyl alcohol) (PVA) was fabricated by solvent casting and evaporation methods. The effect of n-HA content and the ratio of Gel/PVA on the properties of the composite was investigated. The Gel/PVA and n-HA/Gel/PVA composite membranes were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), water contact angle measurement and scanning electron microscopy (SEM). The mechanical properties of the composites were determined by tensile tests. The as prepared composite membranes exhibited hydrophobility, the water contact angle of composite membrane was 126.6 when its mass ratio of n-HA/Gel/PVA was 10/50/40. The tensile strength of composite membranes was greatly increased due to the introduction of n-HA, and the tensile strength was increased to 74.92 MPa when the mass ratio of n-HA/Gel/PVA was 10/50/40. SEM observation indicated that n-HA was dispersed in the membranes and a sea-island structure was formed in the n-HA/Gel/PVA composite membranes, resulting in a significant increase in tensile strength. The as-prepared n-HA/Gel/PVA composite membranes may be applied in the field of bone tissue engineering.

Effects of bevacizumab loaded PEG-PCL-PEG hydrogel intracameral application on intraocular pressure after glaucoma filtration surgery.

PEG-PCL-PEG (PECE) hydrogel for intracameral injection as a sustained delivery system can get a stable release of the medication and achieve an effective local concentration. The injectable PECE hydrogel is thermosensitive nano-material which is flowing sol at low temperature and can shift to nonflowing gel at body temperature. This study evaluated the intracameral injection of bevacizumab combined with a PECE hydrogel drug release system on postoperative scarring and bleb survival after experimental glaucoma filtration surgery. The best result was achieved in the bevacizumab loaded PECE hydrogels group, which presented the lowest IOP values after surgery. And the blebs were significantly more persistent in this group. Histology, Massion trichrome staining and immunohistochemistry further demonstrated that glaucoma filtration surgery in combination with bevacizumab loaded PECE hydrogel resulted in good bleb survival due to scar formation inhibition. In conclusions, this study demonstrated that bevacizumab-loaded PECE hydrogel for intracameral injection as a sustained delivery system provide a great opportunity to increase the therapeutic efficacy of glaucoma filtration surgery.

A facile boronophenylalanine modified polydopamine dual drug-loaded nanoparticles for enhanced anti-tumor immune response in hepatocellular carcinoma comprehensive treatment.

Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence.

An Injectable Thermosensitive Hydrogel Containing Resveratrol and Dexamethasone-Loaded Carbonated Hydroxyapatite Microspheres for the Regeneration of Osteoporotic Bone Defects.

Bone defects in osteoporosis usually present excessive reactive oxygen species (ROS), abnormal inflammation levels, irregular shapes and impaired bone regeneration ability; therefore, osteoporotic bone defects are difficult to repair. In this study, an injectable thermosensitive hydrogel poly (D, L-lactide)-poly (ethylene glycol)- poly (D, L-lactide) (PLEL) system containing resveratrol (Res) and dexamethasone (DEX) is designed to create a microenvironment conducive to osteogenesis in osteoporotic bone defects. This PLEL hydrogel is injected and filled irregular defect areas and achieving a rapid sol-gel transition in situ. Res has a strong anti-inflammatory effects that can effectively remove excess free radicals at the damaged site, guide macrophage polarization to the M2 phenotype, and regulate immune responses. Additionally, DEX can promote osteogenic differentiation. In vitro experiments showed that the hydrogel effectively promoted osteogenic differentiation of mesenchymal stem cells, removed excess intracellular ROS, and regulated macrophage polarization to reduce inflammatory responses. In vivo experiments showed that the hydrogel promoted osteoporotic bone defect regeneration and modulated immune responses. Overall, this study confirmed that the hydrogel can treat osteoporotic bone defects by synergistically modulating bone damage microenvironment, alleviating inflammatory responses, and promoting osteogenesis; thus, it represents a promising drug delivery strategy to repair osteoporotic bone defects.

Synthesis, characterization, and application of amino-terminated poly(ethylene glycol)-block-poly(epsilon-caprolactone) copolymer for paclitaxel.

In this paper, we successfully synthesized amino-terminated poly(ethylene glycol)-block-poly (epsilon-caprolactone) (NH2-PEG-PCL) block copolymer from polyethylene glycol 2000, epsilon-caprolactone (epsilon-CL) and hydrazine hydrate. The obtained copolymer was characterized by nuclear magnetic resonance (1H-NMR), the molecular weight and distribution of NH2-PEG-PCL were characterized by Gel permeation chromatography (GPC). The NH2-PEG-PCL copolymer could self-assemble into micelles in water. Paclitaxel (PTX) loaded NH2-PEG-PCL (PNPP) micelles were prepared by solid dispersion technique without organic solvent. The micelles were characterized by XRD, TEM and Malvern laser particle size. The results of this work indicated that PNPP micelles were uniform and spherical shapes in solution. The average size and zeta potential of PNPP (DL = 8%) in water was about 97.1 +/- 1.2 nm, +13.9 +/- 0.6 mV, respectively. The in vitrodrug release profile of PNPP micelles showed a clear slow-release effect. The results suggested that NH2-PEG-PCL copolymer might be an excellent carrier for hydrophobic drugs such as PTX. In particular, the NH2-PEG-PCL polymer has potential value for modifying with ligands to work as active targeting drug delivery carriers, which has great significance for cancer therapeutics.

RGD peptide modified platinum nanozyme Co-loaded glutathione-responsive prodrug nanoparticles for enhanced chemo-photodynamic bladder cancer therapy.

Bladder cancer is one of the most common malignant tumors in the urinary system worldwide. The poor permeability and uncontrollable release of drug and hypoxia of tumor tissues were the main reasons leading to poor therapeutic effect of chemo-photodynamic therapy for bladder cancer. To solve the above problems, a tumor-targeting peptide Arg-Gly-Asp (RGD) modified platinum nanozyme (PtNP) co-loaded glutathione (GSH)-responsive prodrug nanoparticles (PTX-SS-HPPH/Pt@RGD-NP) was constructed. Firstly, a GSH-responsive prodrug (PTX-SS-HPPH) was prepared by introducing a disulfide bond between paclitaxel (PTX) and photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), which could realize the GSH-responsive release of the drug at the tumor sites. Also, the distearoylphosphoethanolamine-poly (ethylene glycol)-RGD peptide (DSPE-PEG-RGD) modified the prodrug to enhance the targeting and permeability ability to bladder cancer cells. Besides, to alleviate the hypoxia of tumor tissues, PtNP was introduced to produce oxygen (O2) and improve photodynamic therapy efficiency. The results showed that the PTX-SS-HPPH/Pt@RGD-NP could achieve GSH-responsive drug release in tumor microenvironment, enhance the drug accumulation time and permeability at tumor sites in T24 subcutaneous tumor model and T24 orthotopic bladder tumor model, and alleviate hypoxia in tumor tissues, thus realizing enhanced chemo-photodynamic therapy for bladder cancer, and providing new strategies and methods for clinical treatment of bladder cancer.

Hierarchically Porous Implants Orchestrating a Physiological Viscoelastic and Piezoelectric Microenvironment for Bone Regeneration.

The extracellular matrix microenvironment of bone tissue comprises several physiological cues. Thus, artificial bone substitute materials with a single cue are insufficient to meet the demands for bone defect repair. Regeneration of critical-size bone defects remains challenging in orthopedic surgery. Intrinsic viscoelastic and piezoelectric cues from collagen fibers play crucial roles in accelerating bone regeneration, but scaffolds or implants providing integrated cues have seldom been reported. In this study, it is aimed to design and prepare hierarchically porous poly(methylmethacrylate)/polyethyleneimine/poly(vinylidenefluoride) composite implants presenting a similar viscoelastic and piezoelectric microenvironment to bone tissue via anti-solvent vapor-induced phase separation. The viscoelastic and piezoelectric cues of the composite implants for human bone marrow mesenchymal stem cell line stimulate and activate Piezo1 proteins associated with mechanotransduction signaling pathways. Cortical and spongy bone exhibit excellent regeneration and integration in models of critical-size bone defects on the knee joint and femur in vivo. This study demonstrates that implants with integrated physiological cues are promising artificial bone substitute materials for regenerating critical-size bone defects.

Polyethylenimine functionalized magnetic nanoparticles as a potential non-viral vector for gene delivery.

Polyethylenimine (PEI) functionalized magnetic nanoparticles were synthesized as a potential non-viral vector for gene delivery. The nanoparticles could provide the magnetic-targeting, and the cationic polymer PEI could condense DNA and avoid in vitro barriers. The magnetic nanoparticles were characterized by Fourier transform infrared spectroscopy, X-ray powder diffraction, dynamic light scattering measurements, transmission electron microscopy, vibrating sample magnetometer and atomic force microscopy. Agarose gel electrophoresis was used to asses DNA binding and perform a DNase I protection assay. The Alamar blue assay was used to evaluate negative effects on the metabolic activity of cells incubated with PEI modified magnetic nanoparticles and their complexes with DNA both in the presence or absence of an external magnetic field. Flow cytometry and fluorescent microscopy were also performed to investigate the transfection efficiency of the DNA-loaded magnetic nanoparticles in A549 and B16-F10 tumor cells with (+M) or without (-M) the magnetic field. The in vitro transfection efficiency of magnetic nanoparticles was improved obviously in a permanent magnetic field. Therefore, the magnetic nanoparticles show considerable potential as nanocarriers for gene delivery.

Polysaccharide hydrogels: Functionalization, construction and served as scaffold for tissue engineering.

Polysaccharide hydrogels have been widely utilized in tissue engineering. They interact with the organismal environments, modulating the cargos release and realizing of long-term survival and activations of living cells. In this review, the potential strategies for modification of polysaccharides were introduced firstly. It is not only used to functionalize the polysaccharides for the consequent formation of hydrogels, but also used to introduce versatile side groups for the regulation of cell behavior. Then, techniques and underlying mechanisms in inducing the formation of hydrogels by polysaccharides or their derivatives are briefly summarized. Finally, the applications of polysaccharide hydrogels in vivo, mainly focus on the performance for alleviation of foreign-body response (FBR) and as cell scaffolds for tissue regeneration, are exemplified. In addition, the perspectives and challenges for further research are addressed. It aims to provide a comprehensive framework about the potentials and challenges that the polysaccharide hydrogels confronting in tissue engineering.

Recent advances in toxicological research and potential health impact of microplastics and nanoplastics in vivo.

As emerging pollutants, direct and indirect adverse impacts of micro(nano)plastics (MPs/NPs) are raising an increasing environmental concern in recent years due to their poor biodegradability and difficulty in recycling. MPs/NPs can act as carriers of bacteria, viruses, or pollutants (such as heavy metals and toxic organic compounds), and may potentially change the toxicity and bioavailability of pollutants. Ingested or attached MPs/NPs can also be transferred from low-trophic level organisms to high-nutrient organisms or even the human body through the food chain transfer process. This article reviews the emerging field of micro- and nanoplastics on organisms, including the separate toxicity and toxicity of compound after the adsorption of organic pollutants or heavy metals, as well as possible mechanism of toxicological effects and evaluate the nano- and microplastics potential adverse effects on human health. The inherent toxic effects MPs/NPs mainly include the following: physical injury, growth performance decrease and behavioral alteration, lipid metabolic disorder, induced gut microbiota dysbiosis and disruption of the gut's epithelial permeability, neurotoxicity, damage of reproductive system and offspring, oxidative stress, immunotoxicity, etc. Additionally, MPs/NPs may release harmful plastic additives and toxic monomers such as bisphenol A, phthalates, and toluene diisocyanate. The vectors' effect also points out the potential interaction of MPs/NPs with pollutants such as heavy metals, polycyclic aromatic hydrocarbons, organochlorine pesticides, polychlorinated biphenyls, perfluorinated compounds, pharmaceuticals, and polybrominated diphenyl ethers. Nevertheless, these potential consequences of MPs/NPs being vectors for contaminants are controversial.

Cancer-Cell-Biomimetic Nanoparticles for Targeted Therapy of Multiple Myeloma Based on Bone Marrow Homing.

Multiple myeloma (MM) is the second most common hematological malignancy. It is characterized by abnormal transformation and uncontrolled clonal proliferation of malignant plasma cells in the bone marrow (BM), which can destroy bone structure and inhibit hematopoiesis. Although there are new therapeutic methods, they are not curative, mainly because it is difficult to deliver an effective amount of drug to BM, leading to a failure to eradicate MM cells inside the BM. BM homing is an important and unique characteristic of MM cells and it is mainly affected by surface molecules on the tumor cell membrane. Inspired by this mechanism, an MM-mimicking nanocarrier is developed by coating bortezomib (BTZ)-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) nanoparticles with the MM cell membrane. The MM-mimicking nanoparticles can enter the BM based on BM homing as a "Trojan horse" and target the tumor cells through homologous targeting. In this way, drug availability at the myeloma site is enhanced so as to inhibit MM growth. In addition, these MM-mimicking nanoparticles can escape phagocytosis by the MPS and have a long circulation effect. The in vivo therapeutic results demonstrate an excellent treatment efficacy for MM. Accordingly, this strategy may be a promising platform for the treatment of MM.

Tumor microenvironment-responsive Ag2S-PAsp(DOX)-cRGD nanoparticles-mediated photochemotherapy enhances the immune response to tumor therapy.

Chemotherapy drugs play important roles in clinical treatment, and most first-line regimens of cancer therapy contain chemotherapy drugs. In particular, some chemotherapeutic drugs can also produce ICD effect and enhance the immune response of the body. However, most chemotherapy drugs do not specifically target tumors or the complex tumor microenvironment, which renders their curative effect insufficient. Therefore, we constructed a tumor microenvironment-responsive drug delivery system (Ag2S-PAsp-cRGD) combined with doxorubicin (DOX) for tumor therapy. Firstly, Ag2S nanoparticles (NPs) were modified with polymer aspartic acid (PAsp) to construct the drug-loading platform. Then, an active targeting ligand (cRGD) was coupled through an amide reaction to enhance the functional targeting ability of the drug delivery system. In vivo imaging of the system showed that the nanoparticles accumulated in the tumor site, which facilitated the delivery of the chemotherapy drug DOX to the targeted tumor site. Furthermore, the photothermal effect of Ag2S NPs can effectively killed tumor cells, and also helped the release of DOX from nanoparticles into tumor tissue, thus enhancing the chemotherapeutic effect. Moreover, combined with the ICD effect jointly induced by photothermal therapy (PTT) and DOX, the treatment further activated the host immune response against tumors by enhancing the presentation of antigens and promoting the differentiation of T cells. This strategy of photo-chemo-immunotherapy showed excellent antitumor effect, not only eliminating the primary tumor but also preventing recurrence and inhibiting metastasis.

A Transformable Amphiphilic and Block Polymer-Dendron Conjugate for Enhanced Tumor Penetration and Retention with Cellular Homeostasis Perturbation via Membrane Flow.

Efficient penetration and retention of therapeutic agents in tumor tissues can be realized through rational design of drug delivery systems. Herein, a polymer-dendron conjugate, POEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), is presented, which allows a cathepsin-B-triggered stealthy-to-sticky structural transformation. The compositions and ratios are optimized through dissipative particle dynamics simulations. GFLG-DP displays tumor-specific transformation and the consequently released dendron-Ppa is found to effectively accumulate on the tumor cell membrane. The interaction between the dendron-Ppa and the tumor cell membrane results in intracellular and intercellular transport via membrane flow, thus achieving efficient deep penetration and prolonged retention of therapeutic agents in the solid tumor tissues. Meanwhile, the interaction of dendron-Ppa with the endoplasmic reticulum disrupts cell homeostasis, making tumor cells more vulnerable and susceptible to photodynamic therapy. This platform represents a versatile approach to augmenting the tumor therapeutic efficacy of a nanomedicine via manipulation of its interactions with tumor membrane systems.

Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine-plasmid interleukin-15 complexes in murine models of lung metastasis.

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin-polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin-15 (IL15) and investigated the effects HPEI-plasmid IL15 (HPEI-pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI-pIL15 complexes on lung metastases of B16-F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI-pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K-pIL15 and PEI25K-pIL15, and mice treated with HPEI-pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor-α and interferon-γ in the serum also increased in the pIL15-treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI-pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI-pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol.