Sericin microparticles enveloped with metal-organic networks as a pulmonary targeting delivery system for intra-tracheally treating metastatic lung cancer.
ABSTRACT: Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer. However, systemic chemotherapy is limited by poor therapeutic efficiency and severe toxic side effects, due to the extremely low delivery efficacy and non-specificity of anticancer drugs. Herein, we report a sericin microparticles enveloped with metal-organic networks as a pulmonary delivery system for treating lung metastasis of breast cancer in an animal model. The sericin microparticles (SMPs) were prepared using water in oil (w/o) emulsification method. After doxorubicin (DOX) loading, tannic acid (TA)/ferric irons (Fe3+) based metal organic networks (MON) were coated on the particles to obtain DOX-loaded microparticles (DOX@SMPs-MON). The SMPs-MON with good biocompatibility could effectively encapsulate DOX and sustainably unload cargos in a pH-dependent manner. The DOX-loaded microparticles could be uptaken by 4T1 cells, and effectively kill the cancer cells. In vivo, DOX@SMPs-MON was deposited in the lungs and remained for over 5 days after pulmonary administration. In contrast to conventional DOX treatment that did not show significantly inhibitory effects on lung metastatic tumor, DOX@SMPs-MON markedly decreased the number and size of metastatic nodules in lungs, and the lung weight and appearance were similar to those of healthy mice. In summary, the sericin microparticles with MON wrapping might be a promising pulmonary delivery system for treating lung metastatic cancer.
Project description:Drug resistance is the major challenge facing cancer chemotherapy and nanoscale delivery systems based on natural materials, such as sericin, are a promising means of overcoming drug resistance. Yet, no attempt of introducing synthetic poly(?-benzyl-L-glutamate) (PBLG) onto sericin polypeptide to fabricate a facile biocompatible and biodegradable micelle has been tried. Here, we prepared a polypeptide-based amphiphilic polymer containing hydrophilic sericin polypeptide backbone and PBLG side chains via ring-opening polymerization (ROP) strategy. The introduction of PBLG side chains remarkably enhances the stability of sericin micelles in water. Meanwhile, the micelles exhibited a high loading capacity and pH-responsive release ability for antitumor drug doxorubicin (DOX), called sericin-PBLG-DOX. Owing to the excellent cell membrane penetration of sericin-PBLG, the cellular uptake of DOX when loaded into micelles was improved. Subsequently, sericin-PBLG-DOX was transferred into perinuclear lysosomes, where the release rate of DOX was accelerated. Compared to the same dose of DOX, sericin-PBLG-DOX could induce a more efficient anti-tumor effect both in vitro and in vivo, and these micelles have promise for future clinical applications in overcoming cancer drug resistance with good biosafety, enhanced cellular uptake, pH-triggered drug release, efficient anti-tumor effects, and minimized systemic toxicity.
Project description:Silk sericin, a water-soluble glue-like protein, is extensively used as a biomaterial due to its biocompatibility, hydrophilicity, biodegradability, and adequate resource. In addition, hydroxyapatite-based drug carriers are functionally efficient for drug or gene delivery due to their biodegradability, biocompatibility and easy metabolism in vivo. Herein, for the first time, this study used sericin, from a wild silkworm called Antheraea pernyi (A. pernyi), as a template to nucleate hydroxylapatite (HAp) nano-needles and form porous sericin-HAp nanocomposite microspheres as an anticancer drug carrier. Specifically, A. pernyi sericin (AS) was incubated in 1.5× simulated body fluid to induce the formation of porous AS/HAp microspheres in situ. Doxorubicin (DOX) loading and release assays proved that the microspheres exhibited pH-dependent controlled and sustained release of DOX. In particular, the microspheres can selectively release DOX at a higher rate at the acidic conditions typical for tumor microenvironment than at the physiological conditions typical for normal tissues, which will potentially reduce the side effect of the cancer drugs in normal tissues. Cancer cell toxicity assay, cancer cell imaging and intracellular DOX distribution assay provided further evidence to support the pH-dependent controlled and sustained release of DOX to cancer cells from the microspheres. Our work has demonstrated a biomimetic strategy for the design and synthesis of silk protein-based drug carriers that can be potentially employed in drug delivery and regenerative medicine.
Project description:In recent times, the co-delivery therapeutics have garnered enormous interest from researchers in the treatment of cancers with multidrug resistance (MDR) due to their efficient delivery of multiple agents, which result in synergistic effects and capable of overcoming all the obstacles of MDR in cancer. However, an efficient delivery platform is required for the conveyance of diverse agents that can successfully devastate MDR in cancer.Initially, short-interfering RNA-loaded chitosan (siRNA-CS) nanoparticles were synthesized using the ionic gelation method. Further, the siRNA-CS nanoparticles and doxorubicin hydrochloride (DOX) were co-loaded in poly-L-lactide porous microparticles (PLLA PMs) (nano-embedded porous microparticles, [NEPMs]) by the supercritical anti-solvent (SAS) process.The NEPM formulation exhibited an excellent aerodynamic performance and sustained release of DOX, which displayed higher anticancer efficacy in drug-resistant cells (human small cell lung cancer, H69AR cell line) than those treated with either free DOX and DOX-PLLA PMs due to the siRNA from CS nanoparticles silenced the MDR gene to DOX therapy.This eco-friendly process provides a convenient way to fabricate such innovative NEPMs co-loaded with a chemotherapeutic agent and a gene, which can devastate MDR in cancer through the co-delivery system.
Project description:Lung is one of the most common sites to which almost all other primary tumors metastasize. The major challenges in the chemotherapy of lung metastases include the low drug concentration found in the tumors and high systemic toxicity upon systemic administration. In this study, we combine local lung delivery and the use of nanocarrier-based systems for improving pharmacokinetics and biodistribution of the therapeutics to fight lung metastases. We investigate the impact of the conjugation of doxorubicin (DOX) to carboxyl-terminated poly(amidoamine) dendrimers (PAMAM) through a bond that allows for intracellular-triggered release, and the effect of pulmonary delivery of the dendrimer-DOX conjugate in decreasing tumor burden in a lung metastasis model. The results show a dramatic increase in efficacy of DOX treatment of the melanoma (B16-F10) lung metastasis mouse model upon pulmonary administration of the drug, as indicated by decreased tumor burden (lung weight) and increased survival rates of the animals (male C57BL/6) when compared to iv delivery. Conjugation of DOX further increased the therapeutic efficacy upon lung delivery as indicated by the smaller number of nodules observed in the lungs when compared to free DOX. These results are in agreement with the biodistribution characteristics of the DOX upon pulmonary delivery, which showed a longer lung accumulation/retention compared to iv administration. The distribution of DOX to the heart tissue is also significantly decreased upon pulmonary administration, and further decreased upon conjugation. The results show, therefore, that pulmonary administration of DOX combined to conjugation to PAMAM dendrimer through an intracellular labile bond is a potential strategy to enhance the therapeutic efficacy and decrease systemic toxicity of DOX.
Project description:Bombyx mori (B. mori) silk fibroin and sericin can act as a great candidate in delivering drugs or other bioactive substances. Silica also has a great application in the field of drug delivery. To the best of our knowledge, there has been no report on the design of a nanocomposite made of silk protein and silica for drug delivery. Here, for the first time, we used B. mori silk fibroin (SF) and sericin (SS), self-assembled into nanospheres and nanofibers in situ in the aqueous solution, respectively, as a biotemplate to regulate the nucleation and self-assembly of silica for designing anticancer drug delivery. SF and SS mediated the nucleation and assembly of silica into monodispersed nanospheres (termed Si/SF) and nanofibers (termed Si/SS), respectively. The size and topography of the silica assemblies were dependent on the concentration of SF or SS as well as reaction conditions. Both Si/SF nanospheres and Si/SS nanofibers showed a high loading capability and sustained release profile of an anticancer drug, doxorubicin (DOX), in vitro. Si/SF nanospheres were found to be efficiently internalized in human cervical carcinoma (HeLa) cells and accumulate around the cell nuclei. Si/SS nanofibers could only adhere to the surface of the cancer cells. This indicates that DOX-loaded Si/SF nanospheres and Si/SS nanofibers are more effective in cancer therapy than free DOX. Our results suggest that the self-assembled Si/SF spheres and Si/SS nanofibers are potential effective anticancer drug carriers.
Project description:Cancer metastasis is the main cause for the high mortality in breast cancer patients. In this work we developed a polymer POEG-st-Pmor for targeted co-delivery of IL-36? expression plasmid and doxorubicin (Dox) to lung metastasis of breast cancer. The polymer readily formed micelles that were effective in loading Dox and simultaneously forming complexes with IL-36? plasmid. Interestingly, particles co-loaded with Dox and plasmid was significantly smaller and more stable than the particles loaded with Dox only. Gene transfection in both lungs and s.c. tumors was significantly higher with our polymer compared to PEI. In addition, the Dox?+?IL-36?/POEG-st-Pmor not only could bring improved anti-metastatic effect but synergistically enhance the type I immune response by increasing the IFN-? positive CD4+ and CD8+ T cells and simultaneously decreasing the immunosuppressive myeloid-derived suppressor cells in the lung. POEG-st-Pmor may represent a simple and effective delivery system for an optimal chemo-gene combination therapy.
Project description:We developed a novel, pH-sensitive drug delivery microparticle based on N-palmitoyl chitosan (NPCS) to transport the superparamagnetic iron oxide (SPIO) and anticancer drug doxorubicin (DOX). The characteristics of NPCS were characterized through nuclear magnetic resonance. Our results based on testing of volume swelling in multiple pH aqueous solutions revealed that the modified chitosan had a pH-sensitive property. The morphology and size of the DOX-SPIO/NPCS microparticles were investigated using transmission electron microscopy and scanning electron microscopy. The statistical result of microparticles had diameter of 185 ± 87 nm. Surface chemical moieties of DOX-SPIO/NPCS microparticles were confirmed using attenuated total reflection Fourier transform infrared spectroscopy and indicated the existence of mostly hydrophilic groups such as -OH, -C=O, and -C-O-C-. Transmission electron microscopy revealed the dark contrast of SPIO dots encapsulated in the NPCS matrix. Nuclear magnetic resonance T2-weighted magnetic resonance imaging confirmed that the produced DOX-SPIO/NPCS microparticles still exhibited T2 relaxation durations as short as 37.68 ± 8.69 ms (under administration of 2.5 ?g/mL), which is comparable to the clinically required dosage. In the drug release profile, the DOX-SPIO/NPCS drug delivery microparticle was accelerated in an acidic environment (pH 6.5) compared with that in a basic environment. Microparticles in a cytotoxicity assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay) revealed that DOX-SPIO/NPCS microparticles had better antitumor ability than did free-form of DOX. Additionally, microparticles loaded with 0.5-5 ?g/mL DOX in an acidic environment (pH 6.5) demonstrated higher efficacy against Hep G2 cell growth, possibly because of the swelling effect of NPCS, resulting in volume expansion and easy drug release. Accordingly, these large DOX-SPIO/NPCS microparticles showed potential for application as a pH-sensitive drug delivery system and as chemoembolization particles for hepatic carcinoma therapy.
Project description:Cell-derived microparticles, which are recognized as nanosized phospholipid bilayer membrane vesicles, have exhibited great potential to serve as drug delivery systems in cancer therapy. However, for the purpose of comprehensive therapy, microparticles decorated with multiple therapeutic components are needed, but effective engineering strategies are limited and still remain enormous challenges. Herein, Bi2Se3 nanodots and doxorubicin hydrochloride (DOX) co-embedded tumor cell-derived microparticles (Bi2Se3/DOX@MPs) are successfully constructed through ultraviolet light irradiation-induced budding of parent cells which are preloaded with Bi2Se3 nanodots and DOX via electroporation. The multifunctional microparticles are obtained with high controllability and drug-loading capacity without unfavorable membrane surface destruction, maintaining their excellent intrinsic biological behaviors. Through membrane fusion cellular internalization, Bi2Se3/DOX@MPs show enhanced cellular internalization and deepened tumor penetration, resulting in extreme cell damage in vitro without considering endosomal escape. Because of their distinguished photothermal performance and tumor homing target capability, Bi2Se3/DOX@MPs exhibit admirable dual-modal imaging capacity and outstanding tumor suppression effect. Under 808 nm laser irradiation, intravenous injection of Bi2Se3/DOX@MPs into H22 tumor-bearing mice results in remarkably synergistic antitumor efficacy by combining photothermal therapy with low-dose chemotherapy in vivo. Furthermore, the negligible hemolytic activity, considerable metabolizability, and low systemic toxicity of Bi2Se3/DOX@MPs imply their distinguished biocompatibility and great potential for tumor theranostics.
Project description:Bombyx mori (B. mori) silk sericin is a protein with features desirable as a biomaterial, such as increased hydrophilicity and biodegradation, as well as resistance to oxidation, bacteria, and ultraviolet light. In contrast to other widely studied B. mori silk proteins such as fibroin, sericin is still unexplored as a building block for fabricating biomaterial, and thus a facile technique of processing it into a material is needed. Here, electrospinning technology was used to fabricate it into biomaterials from two forms of B. mori silk sericin with different molecular weights, one is a low (12.0 kDa) molecular sericin (LS) form and another is a high (66.0 kDa) molecular weight sericin (HS) form. Circular dichroism (CD) spectra showed that LS in hexafluoroacetone (HFA) solvent adopted a predominantly random coil conformation, whereas HS tended to form a ?-sheet structure along with a large content of random coils. In addition, LS and HS in HFA solvent were found to form cylinder-like smaller nanoparticles and larger irregular aggregates before electrospinning, respectively. As a result, biomaterials based on microparticles and nanofibers were successfully fabricated by electrospinning of LS and HS dissolved in HFA, respectively. The cell viability and differentiation assay indicated that nanofibers and microparticles improved cell adhesion, growth, and differentiation, proving that the scaffolds electrospun from sericin are biocompatible regardless of its molecular weight. The microparticles, not common in electrospinning of silk proteins reported previously, were found to promote the osteogenic differentiation of mesenchymal stem cells in comparison to the nanofibers. This study suggested that molecular weight of sericin mediates its secondary structure and assembly structure, which in turn leads to a control of final morphology of the electrospun materials. The microparticles and nanofibers of sericin can be potentially used as building blocks for fabricating the scaffolds for tissue engineering.
Project description:Nonsmall-cell lung cancer is a severe disease with high morbidity and mortality. However, the systemic administration of anticancer drugs generally leads to serious toxicity and low anti-lung cancer efficiency because of very limited drug distribution in the lung. In our previous research, we have confirmed the high anti-lung cancer effect of inhalable oridonin microparticles in spite of their long and complicated preparation process. Here, we develop a novel, simple, and quick method for preparing inhalable oridonin-loaded poly(d,l-lactic-co-glycolic)acid (PLGA) porous microspheres using the electrospraying technique. The formulation and preparation processes were screened. The electrospraying porous microspheres (EPMs) were rough, porous, and suitable for pulmonary delivery. Most of the oridonin was released from the EPMs within 20 h based on drug diffusion and via PLGA erosion. The EPMs exhibited efficient lung deposition in vitro and in vivo because of their ideal aerodynamic diameters. Chemical carcinogens were used to prepare primary lung cancer rat models by direct pulmonary delivery. The EPMs showed high anti-lung cancer effect after pulmonary delivery according to CT images and pathology. Inhibition of angiogenesis and enhancement of lung cancer cell apoptosis could be the major anticancer mechanism. Electrospraying is an efficient method for the preparation of inhalable drug-loaded porous microspheres. The oridonin-loaded EPMs are promising dry powder inhalers for the local therapy of primary lung cancer.