bims-drudre Biomed News
on Targeted drug delivery, programmed drug release mechanisms
Issue of 2021‒01‒10
twenty-one papers selected by
Ceren Kimna
Technical University of Munich


  1. Nat Biomed Eng. 2021 Jan 04.
    Ling S, Yang S, Hu X, Yin D, Dai Y, Qian X, Wang D, Pan X, Hong J, Sun X, Yang H, Paludan SR, Cai Y.
      Therapeutic genome editing requires effective and targeted delivery methods. The delivery of Cas9 mRNA using adeno-associated viruses has led to potent in vivo therapeutic efficacy, but can cause sustained Cas9 expression, anti-Cas9 immune responses and off-target edits. Lentiviral vectors have been engineered to deliver nucleases that are expressed transiently, but in vivo evidence of their biomedical efficacy is lacking. Here, we show that the lentiviral codelivery of Streptococcus pyogenes Cas9 mRNA and expression cassettes that encode a guide RNA that targets vascular endothelial growth factor A (Vegfa) is efficacious in a mouse model of wet age-related macular degeneration induced by Vegfa. A single subretinal injection of engineered lentiviruses knocked out 44% of Vegfa in retinal pigment epithelium and reduced the area of choroidal neovascularization by 63% without inducing off-target edits or anti-Cas9 immune responses. Engineered lentiviruses for the transient expression of nucleases may form the basis of new treatments for retinal neovascular diseases.
    DOI:  https://doi.org/10.1038/s41551-020-00656-y
  2. ACS Nano. 2021 Jan 07.
    Yu Y, Xiang K, Xu M, Li Y, Cui J, Zhang L, Tang X, Zhu X, Qian L, Zhang M, Yang Y, Yu Q, Shen Y, Gan Z.
      Chemotherapy is one of the most commonly used clinical antitumor strategies. However, the therapy-induced proliferative burst, which always accompanies drug resistance and metastasis, has become a major obstacle during treatment. Except for some endogenous cellular or genetic mechanisms and some microenvironmental selection pressures, the intercellular connections in the tumor microenvironment (TME) are also thought to be the driving force for the acquired drug resistance and proliferative burst. Even though some pathway inhibitors or cell exempting strategies could be applied to partially avoid these unwanted communications, the complexity of the TME and the limited knowledge about those unknown detrimental connections might greatly compromise the efforts. Therefore, a more broad-spectrum strategy is urgently needed to relieve the drug-induced burst proliferation during various treatments. In this article, based on the possible discrepancies in metabolic activity between cells with different growth rates, several ester-bond-based prodrugs were synthesized. After screening, 7-ethyl-10-hyodroxycamptothecin-based prodrug nanoparticles were found to efficiently overcome the paclitaxel resistance, to selectively act on the malignantly proliferated drug-resistant cells and, furthermore, to greatly diminish the proliferative effect of common cytotoxic agents by blocking the detrimental intercellular connections. With the discriminating ability against malignant proliferating cells, the as-prepared prodrug nanomedicine exhibited significant anticancer efficacy against both drug-sensitive and drug-resistant tumor models, either by itself or by combining with highly potent nonselective chemotherapeutics. This work provides a different perspective and a possible solution for the treatment of therapy-induced burst proliferation.
    Keywords:  cancer chemotherapy; multidrug resistance; nanomedicine; therapy-induced proliferative burst; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsnano.0c07113
  3. Nat Biomed Eng. 2021 Jan 04.
    Simonson AW, Mongia AS, Aronson MR, Alumasa JN, Chan DC, Lawanprasert A, Howe MD, Bolotsky A, Mal TK, George C, Ebrahimi A, Baughn AD, Proctor EA, Keiler KC, Medina SH.
      Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen's channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen's cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue. These mycomembrane-templated assemblies elicit rapid mycobactericidal activity and enhance the potency of antibiotics by improving their otherwise poor diffusion across the rigid M. tuberculosis envelope with respect to agents that exploit transmembrane protein channels for antimycobacterial activity. This biomimetic strategy may aid the design of other narrow-spectrum antimicrobial peptides.
    DOI:  https://doi.org/10.1038/s41551-020-00665-x
  4. ACS Appl Mater Interfaces. 2021 Jan 06.
    Wang C, Wang X, Du L, Dong Y, Hu B, Zhou J, Shi Y, Bai S, Huang Y, Cao H, Liang Z, Dong A.
      pH-sensitive hydrophobic segments have been certificated to facilitate siRNA delivery efficiency of amphiphilic polycation vehicles. However, optimal design concepts for these vehicles remain unclear. Herein, by studying the library of amphiphilic polycations mPEG-PAMA50-P(DEAx-r-D5Ay) (EAE5x/y), we concluded a multifactor matching concept (pKa values, "proton buffering capacities" (BCs), and critical micelle concentrations (CMCs)) for polycation vehicles to improve siRNA delivery efficiency in vitro and in vivo. We identified that the stronger BCs in a pH 5.5-7.4 subset induced by EAE548/29 (pKa = 6.79) and EAE539/37 (pKa = 6.20) are effective for siRNA delivery in vitro. Further, the stronger BCs occurred in a narrow subset of pH 5.5-6.5 and the lower CMC attributed to higher siRNA delivery capacity of EAE539/37 in vivo than EAE548/29 after intravenous administration and subcutaneous injection. More importantly, 87.2% gene knockdown efficacy was achieved by EAE539/37 via subcutaneous injection, which might be useful for an mRNA vaccine adjuvant. Furthermore, EAE539/37 also successfully delivered siRRM2 to tumor via intravenous administration and received highly efficient antitumor activity. Taken together, the suitable pKa values, strong BCs occurred in pH 5.5-6.5, and low CMCs were probably the potential solution for designing efficient polycationic vehicles for siRNA delivery.
    Keywords:  CMC; pH-sensitive polycations; pKa value; proton buffering capacity; siRNA delivery
    DOI:  https://doi.org/10.1021/acsami.0c17866
  5. Cancers (Basel). 2020 Dec 30. pii: E77. [Epub ahead of print]13(1):
    Gong P, Wang Y, Zhang P, Yang Z, Deng W, Sun Z, Yang M, Li X, Ma G, Deng G, Dong S, Cai L, Jiang W.
      Despite the advances in surface bioconjugation of synthetic nanoparticles for targeted drug delivery, simple biological functionalization is still insufficient to replicate complex intercellular interactions naturally. Therefore, these foreign nanoparticles are inevitably exposed to the immune system, which results in phagocytosis by the reticuloendothelial system and thus, loss of their biological significance. Immunocyte membranes play a key role in intercellular interactions, and can protect foreign nanomaterials as a natural barrier. Therefore, biomimetic nanotechnology based on cell membranes has developed rapidly in recent years. This paper summarizes the development of immunocyte membrane-coated nanoparticles in the immunotherapy of tumors. We will introduce several immunocyte membrane-coated nanocarriers and review the challenges to their large-scale preparation and application.
    Keywords:  T-cell; biomimicry; cancer immunotherapy; dendritic cell; immunocyte membrane-coated nanoparticles; macrophage; natural killer
    DOI:  https://doi.org/10.3390/cancers13010077
  6. J Mol Med (Berl). 2021 Jan 04.
    Levy O, Rothhammer V, Mascanfroni I, Tong Z, Kuai R, De Biasio M, Wang Q, Majid T, Perrault C, Yeste A, Kenison JE, Safaee H, Musabeyezu J, Heinelt M, Milton Y, Kuang H, Lan H, Siders W, Multon MC, Rothblatt J, Massadeh S, Alaamery M, Alhasan AH, Quintana FJ, Karp JM.
      Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases. KEY MESSAGES: MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425. Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells. Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425. Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.
    Keywords:  Drug delivery; Mesenchymal stem cells; Multiple sclerosis; Ro-31-8425
    DOI:  https://doi.org/10.1007/s00109-020-02003-9
  7. Oncogene. 2021 Jan 08.
    Chen H, Bian A, Yang LF, Yin X, Wang J, Ti C, Miao Y, Peng S, Xu S, Liu M, Qiu WW, Yi Z.
      Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41388-020-01626-z
  8. ACS Biomater Sci Eng. 2019 Feb 11. 5(2): 710-723
    Zhou X, Zhang Q, Chen L, Nie W, Wang W, Wang H, Mo X, He C.
      To achieve enhanced stimulatory effects on the osteogenic differentiation of stem cells, the combination of dual factors with synergistic bioactivity has been regarded as the most effective and powerful strategy. In this study, polylysine-modified polyethylenimine (PEI-PLL) copolymers with various molecular weight PEI blocks were first synthesized and evaluated focusing on their cytotoxicity and gene transfection efficiency, and the results demonstrated that the synthesized copolymer PEI-PLL-25k (synthesized using 25 kDa PEI) exhibited lower cytotoxicity and higher in vitro transfection efficiency than commercial PEI-25k (Mw = 25 kDa). In order to effectively load and deliver plasmid DNA and osteogenic drug dexamethasone (DEX), PEI-PLL-25k copolymer and arginine-glycine-aspartate (RGD) peptide were successively anchored onto the surface of mesoporous silica nanoparticles (MSNs) to construct the dual-factor delivery system, which allows the surface adsorption of DNA and DEX loading in the mesopores of MSNs. The modification of PEI-PLL-25k copolymer and RGD on nanoparticles was successfully characterized by various techniques. The functionalized MSNs with RGD conjugation on the surface showed good cytocompatibility as evidenced by in vitro cell viability assays and cytoskeleton observation. The dual-factor delivery system could quickly release plasmid DNA (pDNA), while releasing DEX in a sustained manner. When cultured with the vector bearing bone morphogenetic protein-2 (BMP-2) pDNA, the transfected bone mesenchymal stem cells (BMSCs) were capable of expressing BMP-2 protein. With the simultaneous delivery of DEX and the BMP-2 gene, this dual-factor delivery system could significantly enhance the level of osteogenic differentiation of BMSCs, as demonstrated by in vitro results of alkaline phosphatase (ALP) activity, expression of osteo-related genes, and calcium deposition. Therefore, the versatile functionalized MSNs nanocarrier for codelivery of osteogenic gene and drug may be considered as a promising dual-delivery system to synergistically enhance the osteogenic outcomes of stem cells.
    Keywords:  copolymer; dual-factor; mesoporous silica nanoparticles; osteogenic differentiation; simultaneous delivery
    DOI:  https://doi.org/10.1021/acsbiomaterials.8b01110
  9. J Cardiovasc Transl Res. 2021 Jan 07.
    Yaakobovich H, Koren O, Chapas S, Gohari S, Zaretsky U, Rotman OM, Weiss D.
      Short peripheral catheters are ubiquitous in today's healthcare environment, enabling effective and direct delivery of fluids and medications intravenously. A commonly associated complication of their use is thrombophlebitis-thrombus formation-involved inflammation of the vein wall. A novel design of a very short peripheral catheter showed promising results in a pig model in reducing the mechanical irritation to the vein wall. Here, the kinetics of drug release through the novel catheter was compared to a standard commercial catheter using experimental and computational models. In a good agreement, in vitro and in silico models reveal the superiority of the novel catheter design with faster washout time, favorable spatial distribution within the vein, and substantially lower wall shear stress. We submit therefore that the novel design has an improved drug removal profile compared to the conventional catheter and can potentially reduce chemical irritation to the vein wall and minimize the risk for thrombophlebitis. CLINICAL RELEVANCE: Short peripheral catheters are ubiquitous in today's healthcare environment, allowing effective and direct delivery of fluids and medications intravenously. It is well known, however, that prolonged exposure to an irritant drug may lead to its absorption in the endothelial layer lining the vein wall, promoting among other, thrombophlebitis that may lead to increased morbidity, delayed treatment, and prolonged hospitalization. There have been multiple calls to consider low infusion rates with various infusion protocols and to place the catheter tip as central as possible to promote faster drug clearance and reduce the potential vessel damage, but the requisite device had not been available, and the short peripheral catheter is still, and for decades, the standard of care. Towards this end, we recently introduced a novel very short peripheral catheter design, and here, we demonstrate using experimental and computational models its favorable spatial and temporal drug-releasing profiles compared with the standard catheter. The clinically potential relevance is underscore both by the more efficient perfusion of IV drugs and lower irritation to the vein wall at the site of injection. Graphical abstract.
    Keywords:  CFD; Drug; Infusion catheter; Intravenous; Phlebitis; Thrombophlebitis
    DOI:  https://doi.org/10.1007/s12265-020-10096-3
  10. Nat Commun. 2021 01 04. 12(1): 51
    Lei H, Xu HZ, Shan HZ, Liu M, Lu Y, Fang ZX, Jin J, Jing B, Xiao XH, Gao SM, Gao FH, Xia L, Yang L, Liu LG, Wang WW, Liu CX, Tong Y, Wu YZ, Zheng JK, Chen GQ, Zhou L, Wu YL.
      Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin-Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.
    DOI:  https://doi.org/10.1038/s41467-020-20259-0
  11. Theranostics. 2021 ;11(1): 164-180
    Wang Y, Zhang K, Li T, Maruf A, Qin X, Luo L, Zhong Y, Qiu J, McGinty S, Pontrelli G, Liao X, Wu W, Wang G.
      Atherosclerosis (AS), the underlying cause of most cardiovascular events, is one of the most common causes of human morbidity and mortality worldwide due to the lack of an efficient strategy for targeted therapy. In this work, we aimed to develop an ideal biomimetic nanoparticle for targeted AS therapy. Methods: Based on macrophage "homing" into atherosclerotic lesions and cell membrane coating nanotechnology, biomimetic nanoparticles (MM/RAPNPs) were fabricated with a macrophage membrane (MM) coating on the surface of rapamycin-loaded poly (lactic-co-glycolic acid) copolymer (PLGA) nanoparticles (RAPNPs). Subsequently, the physical properties of the MM/RAPNPs were characterized. The biocompatibility and biological functions of MM/RAPNPs were determined in vitro. Finally, in AS mouse models, the targeting characteristics, therapeutic efficacy and safety of the MM/RAPNPs were examined. Results: The advanced MM/RAPNPs demonstrated good biocompatibility. Due to the MM coating, the nanoparticles effectively inhibited the phagocytosis by macrophages and targeted activated endothelial cells in vitro. In addition, MM-coated nanoparticles effectively targeted and accumulated in atherosclerotic lesions in vivo. After a 4-week treatment program, MM/RAPNPs were shown to significantly delay the progression of AS. Furthermore, MM/RAPNPs displayed favorable safety performance after long-term administration. Conclusion: These results demonstrate that MM/RAPNPs could efficiently and safely inhibit the progression of AS. These biomimetic nanoparticles may be potential drug delivery systems for safe and effective anti-AS applications.
    Keywords:  ApoE knockout mice; atherosclerosis; biomimetic; macrophage membrane; targeted delivery
    DOI:  https://doi.org/10.7150/thno.47841
  12. ACS Biomater Sci Eng. 2019 May 13. 5(5): 2610-2620
    Du X, Wu L, Yan H, Qu L, Wang L, Wang X, Ren S, Kong D, Wang L.
      A multifunctional hydrogel patch with a combination of high toughness, superior adhesion, and good antibacterial effect is a highly desired surgical material. In this study, we developed a novel hydrogel patch composed of poly(ethylene glycol) diacrylate/quaternized chitosan/tannic acid (PEGDA/QCS/TA) based on mussel-inspired chemistry. The physical and biological properties of the hydrogel patch were systematically evaluated in vitro and in vivo. The results indicated that this hydrogel patch possessed compact microstructure, low swelling ratio, tough mechanical properties, good antibacterial activities against S. aureus and E. coli, and excellent dry/wet adhesive ability to a wide range of substrates. The hydrogel patch could also be degraded and absorbed in vivo and used as a sutureless material for wound closure. All these findings demonstrate that the PEGDA/QCS/TA hydrogel patch with multifunctional properties has great potential for application in biomedical fields.
    Keywords:  antibacterial; hydrogel patch; poly(ethylene glycol) diacrylate (PEGDA); quaternized chitosan (QCS); sutureless wound closure; tannic acid
    DOI:  https://doi.org/10.1021/acsbiomaterials.9b00130
  13. Nanotheranostics. 2021 ;5(1): 113-124
    Gregoriou Y, Gregoriou G, Yilmaz V, Kapnisis K, Prokopi M, Anayiotos A, Strati K, Dietis N, Constantinou AI, Andreou C.
      Treatment of breast cancer underwent extensive progress in recent years with molecularly targeted therapies. However, non-specific pharmaceutical approaches (chemotherapy) persist, inducing severe side-effects. Phytochemicals provide a promising alternative for breast cancer prevention and treatment. Specifically, resveratrol (res) is a plant-derived polyphenolic phytoalexin with potent biological activity but displays poor water solubility, limiting its clinical use. Here we have developed a strategy for delivering res using a newly synthesized nano-carrier with the potential for both diagnosis and treatment. Methods: Res-loaded nanoparticles were synthesized by the emulsion method using Pluronic F127 block copolymer and Vitamin E-TPGS. Nanoparticle characterization was performed by SEM and tunable resistive pulse sensing. Encapsulation Efficiency (EE%) and Drug Loading (DL%) content were determined by analysis of the supernatant during synthesis. Nanoparticle uptake kinetics in breast cancer cell lines MCF-7 and MDA-MB-231 as well as in MCF-10A breast epithelial cells were evaluated by flow cytometry and the effects of res on cell viability via MTT assay. Results: Res-loaded nanoparticles with spherical shape and a dominant size of 179±22 nm were produced. Res was loaded with high EE of 73±0.9% and DL content of 6.2±0.1%. Flow cytometry revealed higher uptake efficiency in breast cancer cells compared to the control. An MTT assay showed that res-loaded nanoparticles reduced the viability of breast cancer cells with no effect on the control cells. Conclusions: These results demonstrate that the newly synthesized nanoparticle is a good model for the encapsulation of hydrophobic drugs. Additionally, the nanoparticle delivers a natural compound and is highly effective and selective against breast cancer cells rendering this type of nanoparticle an excellent candidate for diagnosis and therapy of difficult to treat mammary malignancies.
    Keywords:  breast cancer; cancer nanomedicine; drug-delivery; nanotheranostics; resveratrol
    DOI:  https://doi.org/10.7150/ntno.51955
  14. Glycobiology. 2021 Jan 05. pii: cwaa119. [Epub ahead of print]
    Uhler R, Popa-Wagner R, Kröning M, Brehm A, Rennert P, Seifried A, Peschke M, Krieger M, Kohla G, Kannicht C, Wiedemann P, Hafner M, Rosenlöcher J.
      N-glycosylated proteins produced in human embryonic kidney 293 (HEK 293) cells often carry terminal N-acetylgalactosamine (GalNAc) and only low levels of sialylation. On therapeutic proteins, such N-glycans often trigger rapid clearance from the patient bloodstream via efficient binding to asialoglycoprotein receptor (ASGP-R) and mannose receptor (MR). This currently limits the use of HEK 293 cells for therapeutic protein production. To eliminate terminal GalNAc, we knocked-out GalNAc transferases B4GALNT3 and B4GALNT4 by CRISPR/Cas9 in FreeStyle 293-F cells. The resulting cell line produced a coagulation factor VII-albumin fusion protein without GalNAc but with increased sialylation. This glyco-engineered protein bound less efficiently to both the ASGP-R and MR in vitro and it showed improved recovery, terminal half-life and area under the curve in pharmacokinetic rat experiments. By overexpressing sialyltransferases ST6GAL1 and ST3GAL6 in B4GALNT3 and B4GALNT4 knock-out cells, we further increased factor VII-albumin sialylation; for ST6GAL1 even to the level of human plasma-derived factor VII. Simultaneous knock-out of B4GALNT3 and B4GALNT4, and overexpression of ST6GAL1 further lowered factor VII-albumin binding to ASGP-R and MR. This novel glyco-engineered cell line is well-suited for the production of factor VII-albumin and presumably other therapeutic proteins with fully human N-glycosylation and superior pharmacokinetic properties.
    Keywords:  Coagulation factor VII/sialylation/N-acetylgalactosamine/asialoglycoprotein receptor/mannose receptor
    DOI:  https://doi.org/10.1093/glycob/cwaa119
  15. ACS Biomater Sci Eng. 2019 Jul 08. 5(7): 3419-3428
    Deng K, Zhao X, Liu F, Peng J, Meng C, Huang Y, Ma L, Chang C, Wei H.
      The elegant integration of an excellent light-emitting segment and a biorelevant signal-responsive moiety could generate advanced polymeric delivery systems with simultaneously favorable diagnostic and therapeutic functions with respect to cancer theranostics. Although polymeric delivery systems based on fluorescent polyfluorene (PF) or thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) have been extensively developed, the preparation of a ternary polymer formulation composed of a PF block, a PNIPAAm sequence, and a hydrophilic moiety remains rarely explored likely because of the difficulty in integrating different synthesis strategies for polymer synthesis. To this end, herein we reported the design and controlled synthesis of a PF- and PNIPAAm-based amphiphilic triblock copolymer, PF11-b-PNIPAAm120-b-poly(oligo(ethylene glycol) monomethyl ether methacrylate)17 (PF11-b-PNIPAAm120-b-POEGMA17), with a well-defined structure by a strategy of sequential click couplings between Suzuki-coupling-generated PF and atom-transfer radical polymerization (ATRP)-produced PNIPAAm and POEGMA. The as-prepared triblock copolymers can self-assemble into micelles with a core-shell-corona (CSC) structure that is composed of an inner hydrophobic core of the PF moiety for fluorescent tracking and drug encapsulation, a thermosensitive middle shell of PNIPAAm block for thermomodulated drug loading and release, and a hydrophilic outer corona of the POEGMA segment for micelle stabilization. Interestingly, the doxorubicin (DOX)-loaded micelles prepared at 25 °C had a greater drug loading capacity than the analogues fabricated at 37 °C due to the better stability of the former formulation, leading to its higher in vitro cytotoxicity in HeLa cells. Together with the integration of a localized hyperthermia-triggered drug release profile and efficiently intracellular trafficking of the nanocarriers by monitoring the fluorescence of the PF moiety, this formulation demonstrates a great potential for cancer theranostics.
    Keywords:  cell imaging; controlled drug release; poly(N-isopropylacrylamide); polyfluorene; sequential click couplings; thermo-sensitivity
    DOI:  https://doi.org/10.1021/acsbiomaterials.9b00664
  16. J Nanobiotechnology. 2021 Jan 07. 19(1): 14
    Sun C, Lu J, Wang J, Hao P, Li C, Qi L, Yang L, He B, Zhong Z, Hao N.
      BACKGROUND: Nano-drug delivery systems show considerable promise for effective cancer therapy. Polymeric micelles have attracted extensive attention as practical nanocarriers for target drug delivery and controlled drug delivery system, however, the distribution of micelles and the release of the drug are difficult to trace in cancer cells. Therefore, the construction of a redox-sensitive multifunctional drug delivery system for intelligent release of anticancer drugs and simultaneous diagnostic imaging and therapy remains an attractive research subject.RESULTS: To construct a smart drug delivery system for simultaneous imaging and cancer chemotherapy, mPEG-ss-Tripp was prepared and self-assembled into redox-sensitive polymeric micelles with a diameter of 105 nm that were easily detected within cells using confocal laser scanning microscopy based on aggregation-induced emission. Doxorubicin-loaded micelles rapidly released the drug intracellularly when GSH reduced the disulfide bond. The drug-loaded micelles inhibited tumor xenografts in mice, while this efficacy was lower without the GSH-responsive disulfide bridge. These results establish an innovative multi-functional polymeric micelle for intracellular imaging and redox-triggered drug deliver to cancer cells.
    CONCLUSIONS: A novel redox-sensitive drug delivery system with AIE property was constructed for simultaneous cellular imaging and intelligent drug delivery and release. This smart drug delivery system opens up new possibilities for multifunctional drug delivery systems.
    Keywords:  Aggregation-induced emission; Bioimaging; Drug delivery; Polymeric micelles; Redox-sensitive
    DOI:  https://doi.org/10.1186/s12951-020-00761-9
  17. Nat Cancer. 2020 May;1(5): 493-506
    Zavidij O, Haradhvala NJ, Mouhieddine TH, Sklavenitis-Pistofidis R, Cai S, Reidy M, Rahmat M, Flaifel A, Ferland B, Su NK, Agius MP, Park J, Manier S, Bustoros M, Huynh D, Capelletti M, Berrios B, Liu CJ, He MX, Braggio E, Fonseca R, Maruvka Y, Guerriero JL, Goldman M, van Allen E, McCarroll SA, Azzi J, Getz G, Ghobrial IM.
      Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK+ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14+ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.
    Keywords:  MGUS; SMM; immune microenvironment; multiple myeloma; plasma cells; single-cell RNA sequencing; tumor microenvironment
    DOI:  https://doi.org/10.1038/s43018-020-0053-3
  18. ACS Biomater Sci Eng. 2019 May 13. 5(5): 2330-2342
    Wang N, Yang Y, Wang X, Tian X, Qin W, Wang X, Liang J, Zhang H, Leng X.
      This study aimed to investigate the efficacy of polydopamine nanoparticles (Pdop-NPs) as a subcutaneous antigen delivery vehicle in antitumor therapy. The nanoparticles were prepared by self-polymerization of dopamine in an aerobic and weak alkaline solution, and the tumor model antigen-ovalbumin (OVA) was grafted onto the nanoparticles to form OVA@Pdop nanoparticles (OVA@Pdop-NPs). The particle size of OVA@Pdop-NPs was 232.8 nm with a zeta potential of -23.4 mV, and the loading capacity of OVA protein was 754 μg mg-1. OVA@Pdop-NPs were essentially noncytotoxic and even demonstrated a slightly viability effect on bone-marrow-derived dendritic cells (BMDCs). As compared to free OVA, OVA@Pdop-NPs exhibited higher cellular uptake and were easier to migrate to lymph nodes in vivo. Both in vitro and in vivo experiments showed that OVA@Pdop-NPs promoted the maturation of DCs with up-regulated expression of major histocompatibility complex (MHC), costimulatory molecules, and cytokines. When used to treat the mice bearing OVA-MC38 colon tumor, OVA@Pdop-NPs could effectively activate OVA-specific cytotoxic CD8+ T cells and induce the production of memory CD4+ and CD8+ T cells and thus led to significantly suppressed tumor growth. All the preliminary data demonstrated the application potential of OVA@Pdop-NPs as a vaccine vector in cancer immunotherapy.
    Keywords:  cancer immunotherapy; colon cancer; nanoparticles; polydopamine
    DOI:  https://doi.org/10.1021/acsbiomaterials.9b00359
  19. ACS Biomater Sci Eng. 2019 Mar 11. 5(3): 1366-1377
    Gao J, Yu B, Li C, Wang W, Xu M, Cao Z, Xie X, Liu J.
      Gene therapy is one of the promising solutions in cancer therapeutics. Ultrasound-mediated gene delivery showed great potential as a noninvasive strategy for gene therapy. However, the efficiency of gene transfection and incorporation of multiple functions remain key challenges in the development of gene delivery systems. In this study, we developed perfluoropentane (PFP) and gold nanorods (AuNRs) loading nanodroplets for photothermal-enhanced ultrasound-mediated imaging and gene transfection. The nanodroplet theranostic system was formulated with fluorinated cationic poly(aspartamide) based polymer that encapsulated PFP, AuNRs, and plasmid DNA and was stabilized with a negatively charged poly(glutamic acid)-g-MeO-poly(ethylene glycol) (PGA-g-mPEG) coating. The nanodroplets presented good stability, biocompatibility, and DNA binding stability. Upon treatment with both near-infrared and ultrasound energy, the photothermal and ultrasound-responsive system exerted a synergistic effect, in which strong adsorption of light induced hyperthermia that promoted the phase transition of PFP and the following ultrasound irradiation, generating strong acoustic cavitation and sonoporation, thus leading to enhanced ultrasound contrast imaging and gene transfection efficiency both in vitro and in vivo.
    Keywords:  gold nanorods; hyperthermia; near-infrared; phase-change agent; theranostics; ultrasound imaging; ultrasound-mediated gene delivery
    DOI:  https://doi.org/10.1021/acsbiomaterials.8b01611
  20. Cell. 2020 Dec 15. pii: S0092-8674(20)31685-8. [Epub ahead of print]
    Garcia-Beltran WF, Lam EC, Astudillo MG, Yang D, Miller TE, Feldman J, Hauser BM, Caradonna TM, Clayton KL, Nitido AD, Murali MR, Alter G, Charles RC, Dighe A, Branda JA, Lennerz JK, Lingwood D, Schmidt AG, Iafrate AJ, Balazs AB.
      Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels. Although anti-RBD immunoglobulin G (IgG) levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting cross-protection from reinfection by either strain. However, SARS-CoV-2 sera generally lacked cross-neutralization to a highly homologous pre-emergent bat coronavirus, WIV1-CoV, which has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.
    Keywords:  COVID-19; D614G; ELISA; RBD; SARS-CoV-2; WIV1-CoV; disease severity; neutralizing antibodies; pro-inflammatory cytokines; spike
    DOI:  https://doi.org/10.1016/j.cell.2020.12.015
  21. ACS Appl Mater Interfaces. 2021 Jan 06.
    Wang H, Liu H, Zhang X, Wang Y, Zhao M, Chen W, Qin J.
      Hydrogel fibers are promising carriers for biological applications due to their flexible mechanical properties, well-defined spatial distribution, and excellent biocompatibility. In particular, the droplet-filled hydrogel fibers with the controllable dimension and location of droplets display great advantages to enhance the loading capacity of multiple components and biofunctions. In this work, we proposed a new all-in-water microfluidic system that allows for one-step fabrication of aqueous-droplet-filled hydrogel fibers (ADHFs) with unique morphology and tunable configurations. In the system, the aqueous droplets with equidistance are successfully arranged within the alginate calcium fibers, relying on the design of the pump valve cycle and the select of two immiscible liquids with a stable aqueous interface. The architecture of the ADHF can be flexibly controlled by adjusting the three phase flow rates and the valve switch cycle. The produced ADHFs exhibit high controllability, uniformity, biocompatibility, and stability. The established system enabled the formation of functional human islet organoids in situ through encapsulating pancreatic endocrine progenitor cells within microfibers. The generated islet organoids within droplets exhibit high cell viability and islet-specific function of insulin secretion. The proposed approach provides a new way to fabricate multifunctional hydrogel fibers for materials sciences, tissue engineering, and regenerative medicine.
    Keywords:  all-in-water microfluidic system; aqueous-droplet-filled hydrogel fiber (ADHF); islet organoids; one-step fabrication; tissue engineering
    DOI:  https://doi.org/10.1021/acsami.0c20434