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1.
Macromol Biosci ; : e2100025, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769670

RESUMO

pH-sensitive polyelectrolytes provide enormous opportunity for siRNA delivery. Especially, their tertiary amine structures can not only bind genes but also act as pH-sensitive hydrophobic structure to control genes release. However, the influence of molecular structures on siRNA delivery still remains elusive, especially for the asymmetric alkyl substituents of the tertiary amine groups. Herein, a library of N-methyl-N-alkyl aminoethyl methacrylate monomers (MsAM) with asymmetric alkyl substituents on the tertiary amine group is synthesized and used to prepare a series of tri-block polycationic copolymers poly(aminoethyl methacrylate)-block-poly (N-methyl-N-alkyl aminoethyl methacrylate)-block-poly(ethylene glycol methacrylate) (PAMA-PMsMA-PEG). And the properties of these polycations and their self-assembled micelles are characterized, including molecular structure, proton buffering capacity, pH-sensitivity, size, and zeta potential. With the length increase of one alkyl substituent, the proton buffering capacity of both monomers and polycations is demonstrated to be narrowed down. The siRNA delivery efficiency and cytotoxicity of these micelles are also evaluated on HepG2 cells. In particular, poly(aminoethyl methacrylate)-block-poly(N-methyl-N-ethyl aminoethyl methacrylate)-block-poly(ethylene glycol methacrylate) (PAMA-PMEMA-PEG) elicited the best luciferase knockdown efficiency and low cytotoxicity. Besides, PAMA-PMEMA-PEG/siRRM2 also induced significant anti-tumor activity in vitro. These results indicated PAMA-PMEMA-PEG has potential for further use in the design of gene vehicles with the improved efficiency of siRNA delivery.

3.
Nano Lett ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596656

RESUMO

Efficient endosomal escape is the most essential but challenging issue for siRNA drug development. Herein, a series of quaternary ammonium-based amphiphilic triblock polymers harnessing an elaborately tailored pH-sensitive hydrophobic core were synthesized and screened. Upon incubating in an endosomal pH environment (pH 6.5-6.8), mPEG45-P(DPA50-co-DMAEMA56)-PT53 (PDDT, the optimized polymer) nanomicelles (PDDT-Ms) and PDDT-Ms/siRNA polyplexes rapidly disassembled, leading to promoted cytosolic release of internalized siRNA and enhanced silencing activity evident from comprehensive analysis of the colocalization and gene silencing using a lysosomotropic agent (chloroquine) and an endosomal trafficking inhibitor (bafilomycin A1). In addition, PDDT-Ms/siPLK1 dramatically repressed tumor growth in both HepG2-xenograft and highly malignant patient-derived xenograft models. PDDT-Ms-armed siPD-L1 efficiently blocked the interaction of PD-L1 and PD-1 and restored immunological surveillance in CT-26-xenograft murine model. PDDT-Ms/siRNA exhibited ideal safety profiles in these assays. This study provides guidelines for rational design and optimization of block polymers for efficient endosomal escape of internalized siRNA and cancer therapy.

4.
ACS Appl Mater Interfaces ; 13(2): 2218-2229, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33406826

RESUMO

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.


Assuntos
Polieletrólitos/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Animais , Linhagem Celular , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , RNA Interferente Pequeno/genética
5.
Biomaterials ; 268: 120579, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33278683

RESUMO

Immunotherapy has revolutionized cancer treatment; however, only a limited portion of patients show responses to currently available immunotherapy regimens. Here, we demonstrate that RNA interference (RNAi) combined with immunogenic chemotherapy can elicit potent antitumor immunity against melanoma. Specially, we developed cationic polymer-lipid hybrid nanovesicles (P/LNVs) as a new delivery system for doxorubicin and small interfering RNA (siRNA) with extensive cytotoxicity and gene silencing efficiency towards B16 cells. The deployment of doxorubicin-loaded P/LNVs augmented the expression and presentation of endogenous tumor antigens directly in situ by inducing the immunogenic cell death of B16 cells through poly(ADP-ribose) polymerase 1-dependent (PARP1) apoptosis pathway; thereby, eliciting remarkable antitumor immune responses in mice. Leveraging dying B16 cells as a vaccination strategy in combination with RNAi-based programmed cell death ligand 1 (PD-L1) knockdown showed efficacy in both prophylactic and metastasis melanoma settings. Strikingly, PD-L1 blockade synergized with a sub-therapeutic dose of doxorubicin triggered robust therapeutic antitumor T-cell responses and eradicated pre-established tumors in 30% of mice bearing B16 melanoma. Our findings indicated that this combination treatment provided a new powerful immunotherapy modality, characterized by markedly increased infiltration of effector CD8+ T cells and effective alleviation of the immunosuppressive microenvironment in tumors. P/LNVs is a versatile and highly scalable carrier that can enable a broad combination of nanomedicine and RNAi, providing new therapeutic strategies for advanced cancers.

6.
Biomacromolecules ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33226784

RESUMO

The amphiphilic cationic polymers that mimic antimicrobial peptides have received increasing attention due to their excellent antibacterial activity. However, the relationship between the structure of cationic polymers and its antibacterial effect remains unclear. In our current work, a series of PEG blocked amphiphilic cationic polymers composed of hydrophobic alkyl-modified and quaternary ammonium salt (QAS) moieties have been prepared. The structure-antibacterial activity relationship of these cationic polymers was investigated against E. coli and S. aureus, including PEGylation, random structure, molecular weights, and the content and lengths of the hydrophobic alkyl side chains. The results indicated that PEGylated random amphiphilic cationic copolymer (mPB35/T57) showed stronger antibacterial activity and better biocompatibility than the random copolymer without PEG (PB33/T56). Furthermore, mPB35/T57 with appropriate mole fraction of alkyl side chains (falkyl = 0.38), degree of polymerization (DP = 92), and four-carbon hydrophobic alkyl moieties was found to have the optimal structure that revealed the best antibacterial activities against both E. coli (MIC = 8 µg/mL, selectivity > 250) and S. aureus (MIC = 4 µg/mL, selectivity > 500). More importantly, mPB35/T57 could effectively eradicate E. coli biofilms by killing the bacteria embedded in the biofilms. Therefore, the structure of mPB35/T57 provided valuable information for improving the antibacterial activity of cationic polymers.

7.
J Mater Chem B ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33245311

RESUMO

Bacterial infection is a serious clinical threat. The misuse of antibiotics has already resulted in the emergence of antibiotic-resistant strains of pathogenic bacteria. Efficient membrane-destructive antibacterial agents are considered as an alternative, promising solution against bacterial infection. Herein, we prepared a new type of comb-like cationic, polyethylene glycol (PEG) block polycarbonates with polyquaternium arms (G-CgQAs). The amphiphilic G-CgQAs could self-assemble into about 60 nm sized nanoparticles (NPs) with positive charges (20~30 mV). G-CgQA-3 NPs with an appropriate hydrophobic-hydrophilic balance in the polyquaternium arms showed antibacterial activity against Gram-negative, Gram-positive, and drug-resistant strains at low concentrations (MIC 64-128 µg mL-1) and low hemolysis (HC50 > 2000 µg mL-1). In vivo anti-infection tests indicated G-CgQA-3 NPs could highly inhibit the growth of vancomycin-resistant bacteria by spraying on wounds. Collectively, G-CgQA NPs hold great promise for the prevention of infection, serving as new antibacterial agents. This study also highlights the significance of a hydrophobic block in positive polyquaternium arms to facilitate the antibacterial activity of cationic, quaternized polymers. The design of comb-like amphiphilic cationic polycarbonates provides a new method for manufacturing antibacterial nano-agents.

8.
Mater Sci Eng C Mater Biol Appl ; 116: 111250, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32806305

RESUMO

Various nanoparticles as drug delivery system provide significant improvements in the cancer treatment. However, their clinical success remains elusive in large part due to their inability to overcome both systemic and tumor tissue barriers. The nanosystems with nanoproperty-transformability (surface, size, stability and target) hold great promise for achieving enhanced delivery efficacy. However, currently available systems that are mainly polymer-based assemblies usually suffer from the intrinsic drawbacks of poor stability, premature leakage and low drug loading as well as limited transformability. In this study, we designed a facile strategy to build a novel multi-transformable MSNs@GO nanosystem for efficient doxorubicin (DOX) loading and delivery. This novel nanosystem was well characterized and investigated in vitro. The results indicated that the MSNs@GO can realize a very high drug loading ability due to the large pore surface area of MSNs and the demonstrated donor-acceptor (boron­nitrogen) coordination interactions between phenylboronic acid-containing nanocarriers and electron donor-containing DOX. More importantly, the novel nanocarriers can simultaneously achieve charge reversal, size reduction and ligand reemergence by shielding/deshielding transition via acid-cleavable dynamic boronate bonds under in vitro simulated acidic microenvironment of tumor tissues, opening a new avenue for improving delivery efficiency of chemotherapeutics.

9.
Biomaterials ; 255: 120210, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32592871

RESUMO

The redox status of cancer cells is well regulated by the balance between the reactive oxygen species (ROS) generation and elimination. Thus, the overall elevation of ROS level above the cellular tolerability threshold would lead to apoptotic or necrotic cell death. Herein, cinnamaldehyde (CA), a kind of oxidative stress amplified agent, was combined with photosensitizer pheophorbide A (PA) to promote the generation of ROS though synergistically endogenous and exogenous pathways. Firstly, acid-responsive polygalactose-co-polycinnamaldehyde polyprodrug (termed as PGCA) was synthesized, which could self-assemble into stable nanoparticles for the delivery of PA (termed as PGCA@PA NPs). The abundant expression of galactose receptor on tumor cells facilitated the positive targeting and cellular uptake efficiency of PGCA@PA NPs, after which PA could be synchronously released in company with the intracellular disassembly of PGCA NPs, due to the detaching of CA moieties under acidic microenvironment in endo/lysosomal compartment. Significantly increased ROS level was induced by the combined action of CA and PA with light irradiation, resulting in dramatically enhanced apoptosis of cancer cells. Importantly, intravenous injection of PGCA@PA NPs potently inhibited the tumor growth in hepatocellular carcinoma with negligible adverse effects. Moreover, combined with anti-programmed cell death protein 1 (anti-PD-1) therapy, PGCA@PA NPs treatment elicited anti-melanoma T-cell immune response and significantly promoted T cells infiltration in tumors. Hence, this novel polyprodrug nano delivery system was able to target and modulate the unique redox regulatory mechanisms of cancer cells through endogenous and exogenous pathways, providing a feasible approach to achieve synergetic therapeutic activity and selectivity.

10.
Soft Matter ; 16(24): 5750-5758, 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32529197

RESUMO

We synthesized amino-modified poly(ε-caprolactone) PCN-b-PEG-b-PCN (PECN) triblock copolymers and studied the contribution of the introduced amino groups to the drug delivery efficiency of PECN nanoparticles (NPs) and their injectable thermosensitive hydrogels. PECN15 with an optimal amino group content was obtained. Firstly, the hydrophobic drug paclitaxel (PTX) was loaded into PECN15 up to 5.91% and formed PTX/PECN NPs 90 nm in size and with a slightly positive charge (7.3 mV). Furthermore, the injectable PTX/PECN NPs aqueous solution (25 wt%) at ambient temperature could undergo fast gelation at 37 °C and sustainedly release PTX/PECN NPs in 10 days. More importantly, compared with our previously reported PECT NPs, the PECN NPs without an increase in toxicity could improve the cell uptake and enhance intracellular drug release by responding to the acidic environment of the endosome. Thus, the PTX/PECN NPs presented a lower IC50 of 3.14 µg mL-1 than that of the PTX/PECT NPs (7.67 µg mL-1) and free PTX (4.65 µg mL-1). Moreover, through peritumoral injection, the PTX/PECNGel showed 94.27% inhibition rate of tumor growth on day 19, higher than PTX/PECTGel (72.28%) and Taxol® (47.03%). Therefore, the PECN NPs hydrogel provided a more effective injectable platform to enhance local cancer chemotherapy, and also provided the possibility of further functionalization by the reactive amino groups.

11.
Biomater Sci ; 8(12): 3301-3309, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32356855

RESUMO

The degradation behavior of hydrogel scaffolds is closely related to the controlled release of bioactive agents and matching with the proliferative demands of newly generated tissues. However, the current methods cannot provide precise localization and track the degradation of individual hydrogel scaffolds in vivo, despite superficial or volumetric information. Here, for the first time, we presented the use of 19F magnetic resonance imaging (19F MRI) to precisely monitor the localization and quantify the degradation rate of implantable or injectable hydrogels in a real-time and noninvasive manner, with no interference of endogenous background signals and limitation of penetration depth. The total voxel and content in the region of interest (ROI) were linearly correlated to the injection amount, providing exact three-dimensional (3D) stereoscopic and two-dimensional (2D) anatomical information in the meantime. Moreover, a computational algorithm was established to present the real-time degradation rate in vivo as a function of time, which was implemented directly from the 19F MRI dataset. In addition, labelling with a zwitterionic 19F contrast agent demonstrated a facile and general applicability for multiple types of materials with no influence on their original gelation properties as well as 19F NMR properties in the hydrogel matrix. Therefore, this 19F MRI method offers a new approach to non-invasively track the degradation rate of hydrogel scaffolds in vivo in a precise localization and accurate quantification way, which will suffice the need for the evaluation of implants at deep depths in large animals or human objects.

12.
Macromol Biosci ; 20(7): e2000143, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32401412

RESUMO

Owing to the biodegradability and good biocompatibility polycarbonates show the versatile class of applications in biomedical fields. While their poor functional ability seriously limited the development of functional polycarbonates. Herein, a new Br-containing cyclic carbonate (MTC-Br) and a polycarbonate atom transfer radical polymerization (ATRP) macro-initiator (PEG-PMTC-Br) is synthesized. Then, by initiating the side-chain ATRP of 2-(dimethyl amino)ethyl methacrylate (DMAEMA) on PEG-PMTC-Br, a series of comb-like amphiphilic cationic polycarbonates, PEG-b-(PMTC-g-PDMAEMA) (GMDMs), with different lengths of cationic branches are successfully prepared. All these poly(ethylene glycol)-b-(poly((5-methyl-2-oxo-1,3-dioxane-5-yl) methyl 2-bromo-2-methylpropanoate/1,3-dioxane-2-one)-g-poly(2-dimethyl aminoethyl methacrylate) (GMDMs) self-assembled nanoparticles (NPs) (≈180 nm, +40 mV) can well bind siRNA to form GMDM/siRNA NPs. The gene silence efficiency of GMDM/siRNA high to 80%, which is even higher than the commercial transfection reagent lipo2000 (76%). But GMDM/siRNA shows lower cell uptake than lipo2000. So, the high gene silence ability of GMDM/siRNA NPs can be attributed to the strong intracellular siRNA trafficking capacity. Therefore, GMDM NPs are potential siRNA vectors and the successful preparation of comb-like polycarbonates also provides a facile way for diverse side-chain functional polycarbonates, expanding the application of polycarbonates.

13.
Int J Biol Macromol ; 155: 153-162, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32224179

RESUMO

Bacterial infections caused by S. aureus are prevalent all over the world. Antibiotic-loaded hydrogel has been reported as a promising drug delivery system for the treatment. However, the direct incorporation of antibiotics into the hydrogel leads to quick initial burst release, which results in a sub-inhibition concentration of antibiotics in local environment and induces the antibiotic resistance of bacteria. In this work, a novel dual-crosslinked nanocomposite hydrogel (imine bond and nanoparticle crosslinking) was prepared based on quaternized chitosan and clindamycin-loaded hyperbranched nanoparticles. Dual-crosslinked nanocomposite structure endowed the hydrogel with considerable mechanical and injectable properties. Dual pH responses were introduced into the hydrogel, and a controlled clindamycin release was observed in the acidic environment, which might avoid inducing the antibiotic resistance of bacteria. What's more, the antibacterial results demonstrated an excellent antibacterial activity of the hydrogel for not only E. coli and S. aureus, but also Methicillin-resistant S. aureus (MRSA). Nearly 90% of bacteria was killed after contacting with the hydrogel. In addition, the in vitro cell cytotoxicity test results showed that the hydrogel owned good biocompatibility. The in vitro cell viability was >90%. Above all, this dual-crosslinked nanocomposite hydrogel owned possibility for potential antibacterial applications.

14.
Biomater Sci ; 8(5): 1442-1454, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-31960834

RESUMO

An efficient theranostic nanoplatform responding to tumour microenvironments with characters of simple and flexible combinations owns great potential in cancer diagnosis and therapy. Herein, a series of triblock copolymers, mPEG-b-PDPA-b-P(nBMA-r-cystamine) (EPB), were synthesized and among them, the structure of EPB-3 was optimized for both fluorescence imaging-guided cancer diagnosis and multi-modal therapy with good biocompatibility. (1) The self-assembled nanoparticles of EPB-3-ICG1 obtained by conjugating one ICG on EPB-3 via S-S bonds effectively performed reduction-sensitive OFF/ON fluorescence signal transition, thus inducing tumour cell-specific amplified fluorescence imaging in vitro and in vivo. (2) By entrapping Au nanorods into the co-assembled NPs of EPB-3 and EPB-3-ICG1, EPB-3-ICG1@Au NPs could synchronously induce strong tumour fluorescence imaging and high local photothermal effect, indicating the potential of imagine-guided photothermal therapy. (3) EPB-3 NPs could efficiently co-load paclitaxel (PTX) and ICG to form stable EPB-3@PTX@ICG NPs, which provided long periods of intracellular pH-sensitive sustainable drug release and highly enhanced apoptosis of 4T1 cells in vitro by the chemo-photothermal effect. Excitingly, a single intravenous injection of EPB-3@PTX@ICG NPs followed by a one-time local near-infrared light (NIR, 808 nm) irradiation treatment for 10 min could lead to significant inhibition of tumour growth, avoiding tumor metastasis and extending the survival of mice. All the above-mentioned results suggest that EPB-3 provides a nanoplatform with the characters of simple structure, convenience of use and flexible combination, holding potential for multi-modal diagnosis and therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Imagem Óptica , Paclitaxel/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Polímeros/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corantes/química , Terapia Combinada , Ensaios de Seleção de Medicamentos Antitumorais , Verde de Indocianina/química , Camundongos , Estrutura Molecular , Nanopartículas/química , Paclitaxel/química , Técnicas Fotoacústicas , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Polímeros/síntese química , Polímeros/química
15.
Macromol Rapid Commun ; 41(4): e1900570, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894599

RESUMO

Covalent organic frameworks (COFs) as drug delivery systems have shown great promise, but their pharmaceutical applications are often limited by complex building blocks, tedious preparations, irregular shape, and uncontrolled drug release within target cells. Herein, a facile strategy is developed to prepare PEGylated redox-responsive nanoscale COFs (denoted F68@SS-COFs) for efficiently loading and delivering doxorubicin (DOX) by use of FDA-approved Pluronic F68 and commercially available building blocks. The obtained F68@SS-COFs with controlled size, high stability, and good biocompatibility can not only achieve a very high DOX-loading content (about 21%) and very low premature leakage at physiological condition but can also rapidly respond to the tumor intracellular microenvironment and efficiently release DOX to kill tumor cells. Considering the readily available raw materials, simple preparation process, and desirable redox-responsiveness, the strategy provided here opens up a promising avenue to develop well-defined COFs-based nanomedicines for cancer therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Portadores de Fármacos/análise , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/ultraestrutura , Nanopartículas/ultraestrutura , Oxirredução , Tamanho da Partícula , Polietilenoglicóis/química
16.
Biomaterials ; 230: 119649, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791843

RESUMO

Immunotherapy in solid tumors is limited by the poor immunogenicity of tumors and limited T-cell immune response, resulting in low patient response rate. To increase the efficiency of cancer immunotherapy, a unique synergistic combination cancer immunotherapy by co-localized delivery of cancer nanomedicine for enhancing the tumor immunogenicity and nanovaccine for augmenting the antitumor T-cell immunity was developed for post-surgical tumor treatment. The thermo-responsive, curcumin-loaded polymer nanoparticles (nanomedicine)-assembled hydrogel enabled the complete coverage of the surgical bed of primary tumor and the spatio-temporal delivery of cognate nanomedicines and encapsulated nanovaccines. Importantly, the nanomedicine efficiently induced the immunogenic cell death (ICD) of residual cancer cells, and consequently enhanced the tumor immunogenicity and sensitized the tumor to antitumor T-cell immunity. The cancer nanovaccine composed of antigenic peptide, CpG-ODN and cationic polymer nanoparticle significantly triggered the maturation of dendritic cells (DCs) and elicited potent vaccine-specific T-cell immune responses. Using highly malignant postoperative breast carcinoma 4T1 models, we found that the combination immunotherapy strategy strikingly amplified the level of systemic host T-cell immunity, promoted the infiltration of CD8+ T lymphocytes in tumor, and thus efficaciously attenuated the local tumor recurrence and pulmonary metastasis. Collectively, this work provided an advanced synergistic combination approach for post-surgical tumor immunotherapy. The self-assembled hydrogel should enable a broader combination of immunomodulating nanomedicines and vaccines for cancer immunotherapy.

17.
J Mater Chem B ; 7(47): 7490-7493, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31763663

RESUMO

Bortezomib, dietary tannic acid and an FDA-approved excipient poloxamer were used as building blocks without any chemical syntheses and modifications to construct a dynamic self-delivery nanodrug with high drug loading, outstanding stability, tunable size and pH-controlled release. This strategy with high druggability, reproducibility and productivity might be desirable and useful for pharmaceutical formulations of bortezomib.


Assuntos
Bortezomib/química , Portadores de Fármacos/química , Nanopartículas/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Bortezomib/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Tamanho da Partícula , Poloxâmero/química , Poloxâmero/farmacologia , Inibidores de Proteassoma/química , Inibidores de Proteassoma/metabolismo , Taninos/química , Taninos/farmacologia
18.
J Mater Chem B ; 7(39): 6024-6034, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31545333

RESUMO

A versatile coating strategy, which is suitable for the anti-corrosion and anti-fouling modification of chemically distinct substrates, is crucial in many industries. The immobilization of zwitterionic polymers onto the surface has been proven to be an excellent approach for the improvement of antibiofouling potency. However, the anti-corrosion property has not always been considered simultaneously. Herein, a layer-by-layer (LBL) zwitterionic surface modification strategy was proposed: the surface was first coated with a polydopamine (PDA) layer for anti-corrosion; then, by self-assembling a monolayer of 3-aminopropyl triethoxysilane (APTES), the anti-corrosion ability was further enhanced and the efficiency of grafting was improved; thereafter, by immobilizing the zwitterionic polysulfobetaine (PSB) polymer brush layer, the surface could effectively repel biofouling. The surface chemical composition and morphology characterization was performed by using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM), atomic force microscopy (AFM), and water contact angle measurements, demonstrating that the modification was stepwise introduced onto the surface. The thickness of coating was observed and measured by SEM cross-sectional analysis. In vitro studies revealed that the PSB coated surfaces dramatically reduced the adhesion of bovine serum albumin (BSA), bovine plasma fibrinogen (Fg), bovine γ-globulin (γ-GL), the mixture of these proteins, fibroblasts, E. coli and S. aureus with superior cytocompatibility and hemocompatibility. Moreover, the electrochemical impedance spectroscopy and acidic corrosion studies indicated that an excellent and durable anti-corrosion property was established successfully on the surfaces of stainless steel, cotton textile and wood plates, confirming the feasibility of the LBL surface modification strategy. Significantly, this LBL surface chemistry may be widely applied for the modification of other materials, such as biosensors, biomedical implants and/or devices, and marine equipment.


Assuntos
Incrustação Biológica/prevenção & controle , Indóis/química , Indóis/farmacologia , Polímeros/química , Polímeros/farmacologia , Células 3T3-L1 , Animais , Aderência Bacteriana/efeitos dos fármacos , Corrosão , Escherichia coli/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Teste de Materiais , Camundongos , Propilaminas/química , Silanos/química , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície
19.
ACS Appl Mater Interfaces ; 11(35): 31743-31754, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31389686

RESUMO

One tough question induced by the hypoxia in cancer tissue is resistance to anticancer drugs basing on the reactive oxygen species (ROS) mechanism. Furthermore, the hypoxic regions locate in the center of tumor where tumor cells are easily residual and survival due to the poor drug-delivery efficiency even with nanocarriers. In this paper, these problems were well addressed through the rational combination of the enhanced penetration, self-inducing high level of intracellular ROS, and synchronously pH-sensitive drug release, realized by a simple structural and accessible copolymer, poly(poly(ethylene glycol) methyl ether methacrylate-co-(2-methylpropenoic acid-glycerol-cinnamaldehyde)) (PgEMC). For one thing, PgEMC could self-assemble into stable nanoparticles with PEG shell and optimizing diameters of 60 nm to simultaneously facilitate long blood circulation and deep tumor penetration. Second, cinnamylaldehyde moieties could detach from PgEMC NPs in intracellular acidic environment and trigger high level of ROS to allay the doxorubicin (DOX) resistance induced by hypoxia in solid malignancies. Furthermore, the DOX payload in PgEMC NPs could be synchronously released with the intracellular disassembly of PgEMC NPs due to the detaching of cinnamylaldehyde moieties. In 4T1 cells treated with PgEMC/DOX NPs, remarkable elevation of ROS level and enhanced DOX sensitivity in hypoxia environment were observed in in vitro studies. The results of tumor spheroid penetration indicated that 60 nm sized DOX-loaded PgEMC NPs (PgEMC60/DOX) could distribute into deep site of tumor at a high intensity. In vivo studies using a 4T1 breast tumor model, PgEMC60/DOX NPs, showed significant inhibition over 95.4% of the tumor growth. These results reveal that integrating optimizing size, self-inducing ROS, and pH-sensitive drug release into one small-sized nanoparticle can efficiently overcome the poor tumor penetration and hypoxia-induced chemotherapy resistance.


Assuntos
Antineoplásicos , Neoplasias da Mama , Doxorrubicina , Portadores de Fármacos , Nanopartículas , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Feminino , Xenoenxertos , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
20.
ACS Appl Mater Interfaces ; 11(37): 33667-33675, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31414601

RESUMO

In an attempt to develop an imaging probe with ultra-high sensitivity for a broad range of tumors in vivo and inspired by the concept of chemical synthetic nanoreactors, we designed a type of glutathione-priming fluorescent nanoreactor (GPN) with an albumin-coating shell and hydrophobic polymer core containing disulfide bonds, protonatable blocks, and indocyanine green (ICG), a near-infrared fluorophore. The albumin played multiple roles including biocompatible carriers, hydrophilic stabilizer, "receptor" of the fluorophores, and even targeting molecules. The protonation of the hydrophobic core triggered the outside-to-core transport of acidic glutathione (GSH), as well as the core-to-shell transference of ICGs after the disulfide bond cleavage by GSH, which induced strong binding of fluorophores with albumins on the GPN shell, initiating intensive fluorescence signals. As a result, the GPNs demonstrated extremely high response sensitivity and imaging contrast, proper time window, and broad cancer specificity. In fact, an orthogonal activation pattern was found in vitro with an ON/OFF ratio up to 24.7-fold. Furthermore, the nanoprobes specifically amplified the tumor signals in five cancer-bearing mouse models and actualized tumor margin delineation with a contrast up to 20-fold, demonstrating much better imaging efficacy than the other four commercially available probes. Therefore, the GPNs provide a new paradigm in developing high-performance bioresponsive nanoprobes.


Assuntos
Portadores de Fármacos , Glutationa/metabolismo , Verde de Indocianina , Nanopartículas , Neoplasias Experimentais/diagnóstico por imagem , Imagem Óptica , Animais , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Feminino , Células HT29 , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacocinética , Verde de Indocianina/farmacologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia
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