Timin, Alexander S.Postovalova, Alisa S.Karpov, Timofey E.Antuganov, Dmitrii...
11页
查看更多>>摘要：Considering the clinical limitations of individual approaches against metastatic lung cancer, the use of combined therapy can potentially improve the therapeutic effect of treatment. However, determination of the appropriate strategy of combined treatment can be challenging. In this study, combined chemo-and radionuclide therapy has been realized using radionuclide carriers (Lu-177-labeled core-shell particles, Lu-177-MPs) and chemotherapeutic drug (cisplatin, CDDP) for treatment of lung metastatic cancer. The developed core-shell particles can be effectively loaded with Lu-177 therapeutic radionuclide and exhibit good radiochemical stability for a prolonged period of time. In vivo biodistribution experiments have demonstrated the accumulation of the developed carriers predominantly in lungs. Direct radiometry analysis did not reveal an increased absorbance of radiation by healthy organs. It has been shown that the radionuclide therapy with Lu-177-MPs in mono-regime is able to inhibit the number of metastatic nodules (untreated mice = 120 +/- 12 versus Lu-177-MPs = 50 +/- 7). The combination of chemo-and radionuclide therapy when using Lu-177-MPs and CDDP further enhanced the therapeutic efficiency of tumor treatment compared to the single therapy (Lu-177-MPs = 50 +/- 7 and CDDP = 65 +/- 10 versus Lu-177-MPs + CDDP = 37 +/- 5). Thus, this work is a systematic research on the applicability of the combination of chemo-and radionuclide therapy to treat metastatic lung cancer.
Stie, Mai BayKalouta, KleopatraVetri, ValeriaFodera, Vito...
14页
查看更多>>摘要：Protein-based materials have found applications in a wide range of biomedical fields because of their biocompatibility, biodegradability and great versatility. Materials of different physical forms including particles, hydrogels, films, fibers and microneedles have been fabricated e.g. as carriers for drug delivery, factors to promote wound healing and as structural support for the generation of new tissue. This review aims at providing an overview of the current scientific knowledge on protein-based materials, and selected preclinical and clinical studies will be reviewed in depth as examples of the latest progress within the field of protein-based materials, specifically focusing on non-and minimally invasive strategies mainly for topical application.
Cho, Young SeokKim, Gui ChulLee, Hye MinKim, Byoungmo...
13页
查看更多>>摘要：Despite recent breakthroughs in the development of direct KRAS inhibitors and modulators, no drugs targeting pan-KRAS mutant cancers are clinically available. Here, we report a novel strategy to treat pan-KRAS cancers using a caspase-3 cleavable peptide-drug conjugate that exploits enhanced albumin metabolism in KRAS altered cancers to deliver a cytotoxic agent that can induce a widespread bystander killing effect in tumor cells. Increased albumin metabolism in KRAS mutant cancer cells induced apoptosis via the intracellular uptake of albumin-bound MPD1. This allowed caspase-3 upregulation activated MPD1 to release the payload and exert the non-selective killing of neighboring cancer cells. MPD1 exhibited potent and durable antitumor efficacy in mouse xenograft models with different KRAS genotypes. An augmentation of anti-cancer efficacy was achieved by the bystander killing effect derived from the caspase-3 mediated activation of MPD1. In summary, albumin metabolism-induced apoptosis, together with the bystander killing effect of MPD1 boosted by caspase-3 mediated activation, intensified the efficacy of MPD1 in KRAS mutant cancers. These findings suggest that this novel peptide-drug conjugate could be a promising breakthrough for the treatment in the targeting of pan-KRAS mutant cancers.
Isaacson, Kyle J.Van Devener, Brian R.Steinhauff, Douglas B.Jensen, M. Martin...
11页
查看更多>>摘要：Various polymers used in controlled release applications exhibit solution-based thermal responses. Unfortunately, very few characterization and imaging techniques permit resolution of individual polymers during their thermally-triggered phase transitions. Here, we demonstrate the use of temperature-ramp liquid-cell transmission electron microscopy (LCTEM) for real-time evaluation of the solution and interfacial behavior of elastinlike polypeptides (ELPs) and their self-assembled nanostructures over a temperature range incorporating their intrinsic lower critical solution temperatures (LCSTs). Individual polymers and supramolecular assemblies were discriminated dependent upon solubility states. The recombinant polymers were shown to adsorb to the silicon nitride chip window from the buffered saline solution and desorb in a temperature-dependent manner. Silkelastinlike protein block copolymers (SELPs) (composed of repeat peptide motifs of silk and elastin) differed from ELPs in thermal behavior. While both polymers were shown to cluster, only SELPs formed robust amyloidlike fibers upon heating.
Parhiz, HamidehBrenner, Jacob S.Patel, Priyal N.Papp, Tyler E....
12页
查看更多>>摘要：Current nucleoside-modified RNA lipid nanoparticle (modmRNA-LNP) technology has successfully paved the way for the highest clinical efficacy data from next-generation vaccinations against SARS-CoV-2 during the COVID-19 pandemic. However, such modmRNA-LNP technology has not been characterized in common pre-existing inflammatory or immune-challenged conditions, raising the risk of adverse clinical effects when administering modmRNA-LNPs in such cases. Herein, we induce an acute-inflammation model in mice with lipopolysaccharide (LPS) intratracheally (IT), 1 mg kg(-1), or intravenously (IV), 2 mg kg(-1), and then IV administer modmRNA-LNP, 0.32 mg kg (-1), after 4 h, and screen for inflammatory markers, such as pro-inflammatory cytokines. ModmRNA-LNP at this dose caused no significant elevation of cytokine levels in naive mice. In contrast, shortly after LPS immune stimulation, modmRNA-LNP enhanced inflammatory cytokine responses, Interleukin-6 (IL-6) in serum and Macrophage Inflammatory Protein 2 (MIP-2) in liver significantly. Our report identifies this phenomenon as inflammation exacerbation (IE), which was proven to be specific to the LNP, acting independent of mRNA cargo, and was demonstrated to be time-and dose-dependent. Macrophage depletion as well as TLR3 -/-and TLR4-/- knockout mouse studies revealed macrophages were the immune cells involved or responsible for IE. Finally, we show that pretreatment with anti-inflammatory drugs, such as corticosteroids, can partially alleviate IE response in mice. Our findings characterize the importance of LNP-mediated IE phenomena in gram negative bacterial inflammation, however, the generalizability of modmRNA-LNP in other forms of chronic or acute inflammatory and immune contexts needs to be addressed.
Widjaya, Andy SamuelLiu, YunhuYang, YueyingYin, Weiwei...
18页
查看更多>>摘要：Low levels of accumulation and permeability in tumors are two primary reasons for the limited efficacy of conventional antineoplastic nanodrugs. In the present study, based on an original corosolic acid liposome (CALP) carrier with the functions of cell penetration, tumor permeability and anti-inflammation developed by our previous work, a versatile PTX/CALP was achieved by CALP loading paclitaxel (PTX). Compared to conventional PTX liposomes (PTX/LP) prepared by cholesterol and phospholipid, PTX/CALP exhibited extremely increasing cellular uptake and cytotoxicity in vitro, and in vivo enhancing the accumulation and permeability of tumor, thus significantly improving the antitumor efficacy. Further evidence indicated that PTX/CALP conspicuously promoted the recruitment of CD8(+) T cells as well as reduced the infiltration of regulatory T cells and M2 macrophages into tumor by inducing enhanced immunogenic cell death (ICD) and down-regulating the inflammation level. Therefore, the improvement of efficacy was also attributed to the superiorities of PTX/CALP in modulating the inflammatory and immunosuppressive tumor microenvironment. Overall, the smart PTX liposomes based on the multi-functional CALP carrier without any modification could overcome the harsh tumor biological barriers, enhance the induction of ICD and then achieve satisfactory efficacy, suggesting its promising potentials in industrial transfer and clinical application.
查看更多>>摘要：In 2021, mRNA vaccines against COVID-19 were approved by the Food and Drug Administration. mRNA vaccines are important for preventing severe COVID-19 and returning to normal life. The development of RNA-delivery technology, including mRNA vaccines, has been investigated worldwide for ~30 years. Lipid nanoparticles (LNPs) are a breakthrough technology that stably delivers RNA to target organs, and RNA-loaded LNP-based nanomedicines have been studied for the development of vaccines and nanomedicines for RNA-, gene-, and cell based therapies. Recently, microfluidic devices and technologies have attracted attention for the production of LNPs, particularly RNA-loaded LNPs. Microfluidics provides many advantages for RNA-loaded LNP production, including precise LNP size controllability, high reproducibility, high-throughput optimization of LNP formulation, and continuous LNP-production processes. In this review, we summarize microfluidic-based RNA-loaded LNP production and its applications in RNA-based therapy and genome editing.
查看更多>>摘要：Drug-controlled release is recognized as effective for improving compliance with treatment and obtaining better therapeutic efficacy with less toxicity in cancer treatment. However, few reports in this area are involved in nucleic acids delivery, especially in RNA therapeutics delivery. In this study, an injectable hydrogel Methacry-lated gelatin (GM) scaffold was introduced into a dual-RNA hybrid delivery complex hybrid lipid particle (HLP) to form a G-HLP/RNAs system. This system can control the release of both siRNA and mRNA and was found to be efficient for protecting these RNAs from biodegradation and retaining their therapeutic effect over 7 days. Further, a tumor environment (TME)-activation function after peritumoral injection of mocked GM scaffold was observed. Then, matured DC cells and activated T-cells were detected by the addition of HLP/RNAs complex, thus verifying the immunoactivation function of GM scaffold and its ability to reserve immune cells and antigens. Finally, two doses of G-HLP/RNAs treatment efficiently suppressed C26 tumor growth in mice with a tumor weight inhibition rate of 71.9%. Owing to its ability to achieve RNA drug-controlled release, alter TME, and induce tumor apoptosis, the G-HLP/RNAs system may become a valuable tool for cancer gene therapy.
查看更多>>摘要：ABS T R A C T Drug-eluting implants are one of the leading implant technologies to facilitate the healing capacity of bones by eliminating implant-associated infections. Treatment of the infections like osteomyelitis, prevention of pathogen growth in the bone, and elimination of residual cancer cells, have become the predominant need of the ortho-pedic industry. Moreover, the mechanical compatibility of the implants to retain their strength under the cor-rosive environment of the body is one of the vital critical components needed to balance with biological properties. The drawbacks of permanent implants have already shifted the attention towards biodegradable materials due to various advantages, i.e., 1) eliminate the need for a second surgery and 2) Degradation rate, which will slowly transfer the load to the healing bone and reduces the problem of stress-shielding. However, implant-related infections are still a matter of concern despite these properties. The review focuses on high-lighting various drug-loaded implant technologies investigated previously.The effects of different drugs to overcome the repercussions of bacterial colonies formed due to adherence of different bacteria over the surface of the bone are also highlighted. Gentamicin, vancomycin, and tobramycin are the frequently used antibiotics for such functions to act as an anti-inflammatory and antimicrobial agent and are evaluated through this study. Different in-vitro and in-vivo studies were performed to analyze the cyto-compatibility, hemolytic behavior, release rate of drugs, and anti-bacterial properties of the implant materials against different pathogens such as S. Aureus, E.Coli, S. Epidermidisare covered under this review.
查看更多>>摘要：Tumor peptide vaccines contain only key amino acid sequences of tumor neoantigens, and therefore can provide precise activation of immune responses. Recent research has found that short peptide vaccines restricted to MHC-I epitopes are insufficient to activate effective CD8(+) T cell responses for tumor elimination, and assistance from CD4(+) T cell immunity could significantly improve the therapeutic outcome. Herein, we proposed an innovative peptide vaccine strategy to simultaneously activate CD8(+) and CD4(+) T cell responses by combining MHC-I and MHC-II epitopes into one long peptide antigen. To further strengthen the anti-tumor immune response induced by this dual-epitope peptide, we engineered a PEG derivative (PpASE) stabilized aluminum nanoparticle for delivering the synthetic long peptides (ANLs). The synthesized nanovaccine with a diameter of similar to 100 nm showed good stability and enhanced antigen uptake by antigen-presenting cells (APCs). As a result, ANLs promoted the presentation of MHC-I epitope in APCs and induced stronger activation and proliferation of CD8(+) T cells as compared to aluminum nanoparticle loaded with MHC-I epitope restricted peptides (ANSs). After subcutaneous vaccination, the developed nanovaccine significantly inhibited tumor growth and prolonged mouse survival in both B16-OVA and B16F10 tumor models. Finally, ANLs were also able to elevate the maturation level of human dendritic cells (DCs), showing a great possibility of clinical translation.
NSTL
Elsevier