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1.
J Colloid Interface Sci ; 672: 350-362, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38850862

RESUMO

To overcome the biological barriers in the journey of systemic gene delivery, a multifaceted genomic synthetic nanomedicine was elaborated and strategically equipped with a multiple of intriguing responsiveness. Particularly, core-shell plasmid DNA condensates were created based on polyionic complexation with block copolymer of polyethylene glycol (PEG)-polylysine (PLys), namely, the nanoscaled PLys&pDNA nanoparticle tethered with the biocompatible PEG surroundings. Furthermore, redox-reversible disulfide crosslinking was introduced into PLys&pDNA nanoparticle to accomplish adequate structural stabilities, and thermal-responsive polypropylacrylamide (PNIPAM) was introduced as the secondary intermediate surroundings onto the pre-formulated PLys&pDNA nanoparticle with the aim of preventing the potential enzymatic degradation from the environmental nucleases. Hence, hundreds of times prolonged survival and retention was determined in pertinent to the blood circulation properties. Additionally, the installation of a guide ligand at the distal end of PEG segments was proposed to encourage selective tumor uptake. A linear peptide of GPLGVRG, which is selectively susceptible to digestion by the tumor-enriched matrix metalloproteinase 2 (MMP-2), was used as the linkage between the shell and core. This peptide has been shown to detach the bio-inert PEGylation, resulting in further facilitated cell endocytosis and intracellular trafficking activities. Hence, the precisely defined synthetic nanomedicine, which exhibits desirable characteristics, efficient expression of the therapeutic gene in the affected cells, and contributed to potent therapeutic efficacy in systemic treatment of intractable tumors by encapsulating the anti-angiogenic gene.

2.
Acta Biomater ; 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38838905

RESUMO

Anti-angiogenesis has emerged a promising strategy against colorectal cancer (CRC). However, the efficacy of anti-angiogenic therapy is greatly compromised by the up-regulated autophagy levels resulting from the evolutionary resistance mechanism and the presence of Fusobacterium nucleatum (F. nucleatum) in CRC. Herein, we report a cationic polymer capable of blocking autophagic flux to deliver plasmid DNA (pDNA) encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) for enhanced anti-angiogenic therapy against F. nucleatum-associated CRC. The autophagy-inhibiting cationic polymer, referred to as PNHCQ, is synthesized by conjugating hydroxychloroquine (HCQ) into 3,3'-diaminodipropylamine-pendant poly(ß-benzyl-L-aspartate) (PAsp(Nors)), which can be assembled and electrostatically interacted with sFlt-1 plasmid to form PNHCQ/sFlt-1 polyplexes. Hydrophobic HCQ modification not only boosts transfection efficiency but confers autophagy inhibition activity to the polymer. Hyaluronic acid (HA) coating is further introduced to afford PNHCQ/sFlt-1@HA for improved tumor targeting without compromising on transfection. Consequently, PNHCQ/sFlt-1@HA demonstrates significant anti-tumor efficacy in F. nucleatum-colocalized HT29 mouse xenograft model by simultaneously exerting anti-angiogenic effects through sFlt-1 expression and down-regulating autophagy levels exacerbated by F. nucleatum challenge. The combination of anti-angiogenic gene delivery and overall autophagy blockade effectively sensitizes CRC tumors to anti-angiogenesis, providing an innovative approach for enhanced anti-angiogenic therapy against F. nucleatum-resident CRC. STATEMENT OF SIGNIFICANCE: Up-regulated autophagy level within tumors is considered responsible for the impaired efficacy of clinic antiangiogenic therapy against CRC colonized with pathogenic F. nucleatum. To tackle this problem, an autophagy-inhibiting cationic polymer is developed to enable efficient intracellular delivery of plasmid DNA encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) and enhance anti-angiogenic therapy against F. nucleatum-associated CRC. HA coating that can be degraded by tumor-enriching hyaluronidase is further introduced for improved tumor targeting without compromising transfection efficiency. The well-orchestrated polyplexes achieve considerable tumor accumulation, efficient in vivo transfection, and effectively reinforce the sensitivity of CRC to the sFlt-1-derived anti-angiogenic effects by significantly blocking overall autophagy flux exacerbated by F. nucleatum challenge, thus harvesting robust antitumor outcomes against F. nucleatum-resident CRC.

3.
Angew Chem Int Ed Engl ; 63(9): e202316487, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38197735

RESUMO

The concept of molecular design, integrating diagnostic and therapeutic functions, aligns with the general trend of modern medical advancement. Herein, we rationally designed the smart molecule ER-ZS for endoplasmic reticulum (ER)-targeted diagnosis and treatment in cell and animal models by combining hemicyanine dyes with ER-targeted functional groups (p-toluenesulfonamide). Owing to its ability to target the ER with a highly specific response to viscosity, ER-ZS demonstrated substantial fluorescence turn-on only after binding to the ER, independent of other physiological environments. In addition, ER-ZS, being a small molecule, allows for the diagnosis of nonalcoholic fatty liver disease (NAFLD) via liver imaging based on high ER stress. Importantly, ER-ZS is a type I photosensitizer, producing O2 ⋅- and ⋅OH under light irradiation. Thus, after irradiating for a certain period, the photodynamic therapy inflicted severe oxidative damage to the ER of tumor cells in hypoxic (2 % O2 ) conditions and activated the unique pyroptosis pathway, demonstrating excellent antitumor capacity in xenograft tumor models. Hence, the proposed strategy will likely shed new light on integrating molecular optics for NAFLD diagnosis and cancer therapy.


Assuntos
Carbocianinas , Neoplasias , Hepatopatia Gordurosa não Alcoólica , Fotoquimioterapia , Animais , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piroptose , Corantes/metabolismo , Viscosidade , Fígado/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Neoplasias/patologia
4.
Acta Biomater ; 173: 432-441, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37984629

RESUMO

Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn-infected CRC. STATEMENT OF SIGNIFICANCE: The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn-induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn-infected colorectal cancer.


Assuntos
Anti-Infecciosos , Neoplasias Colorretais , Pró-Fármacos , Humanos , Espécies Reativas de Oxigênio , Ácido Oleico , Platina , Fusobacterium nucleatum , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Polímeros , Nanopartículas Magnéticas de Óxido de Ferro , Antibacterianos/farmacologia , Peroxidases , Linhagem Celular Tumoral , Microambiente Tumoral
6.
Bioact Mater ; 25: 580-593, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37056275

RESUMO

Pyroptosis, a unique lytic programmed cell death, inspired tempting implications as potent anti-tumor strategy in pertinent to its potentials in stimulating anti-tumor immunity for eradication of primary tumors and metastasis. Nonetheless, rare therapeutics have been reported to successfully stimulate pyroptosis. In view of the intimate participation of reactive oxygen species (ROS) in stimulating pyroptosis, we attempted to devise a spectrum of well-defined subcellular organelle (including mitochondria, lysosomes and endoplasmic reticulum)-targeting photosensitizers with the aim of precisely localizing ROS (produced from photosensitizers) at the subcellular compartments and explore their potentials in urging pyroptosis and immunogenic cell death (ICD). The subsequent investigations revealed varied degrees of pyroptosis upon photodynamic therapy (PDT) towards cancerous cells, as supported by not only observation of the distinctive morphological and mechanistic characteristics of pyroptosis, but for the first-time explicit validation from comprehensive RNA-Seq analysis. Furthermore, in vivo anti-tumor PDT could exert eradication of the primary tumors, more importantly suppressed the distant tumor and metastatic tumor growth through an abscopal effect, approving the acquirement of specific anti-tumor immunity as a consequence of pyroptosis. Hence, pyroptosis was concluded unprecedently by our proposed organelles-targeting PDT strategy and explicitly delineated with molecular insights into its occurrence and the consequent ICD.

7.
ACS Appl Mater Interfaces ; 15(10): 12864-12881, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36856003

RESUMO

Tumors managing to exempt from immune clearance are attributable to their overexpressed immune suppressive molecules (CD47, PD-L1, etc.). Leadingly, the checkpoint blockade-based chemoimmunotherapy by means of knockdown of these immunosuppressive checkpoints, together with immunogenetic chemotherapeutics, is perceived to be a valid therapeutic strategy for improving anti-tumor outcomes. Herein, chemotherapeutic camptothecin was covalently introduced into an intriguing multifaceted nanomedicine. Note that the elaborated nanomedicine was chemically engineered to enable targeted transportation to the tumors via systemic administration, possessing intelligent responsiveness to sequential extracellular and intracellular microenvironments in the targeted tumors for prompted transcellular endocytosis owing to enzymolysis by the tumor-enriched matrix metalloproteinases and the selective liberation of cytocidal camptothecin in the cell interiors owing to thiolysis by glutathione. In addition, this chemotherapeutic nanomedicine allowed facile encapsulation of the negatively charged RNA interference payloads. Consequently, aiming for treatment of intractable triple-negative breast tumors, we attempted the small interfering RNA (siRNA) payloads aiming for CD47 and PD-L1 into the aforementioned nanomedicine. The subsequent investigations demonstrated drastic knockdown of these vital immune suppressive checkpoints by this siRNA-encapsulating chemotherapeutic nanomedicine, conducing to the reversal of the immune checkpoint suppressive microenvironment of triple-negative 4T1 tumors. Namely, the inhibited proceedings of the innate and adaptive anti-tumor immunities were revived, as supported by observation of the activated infiltration and retention of CD68+ macrophages and CD4+ and CD8+ lymphocytes into the tumors. Eventually, most potent anti-tumor efficacies were accomplished by systemic administration of this chemoimmunotherapeutic nanomedicine, which verified the amplified contribution from anti-tumor immunities by means of knockdown of the immune suppressive molecules to the ultimate anti-tumor efficacies. Note that the upregulation of the immune suppressive molecules was constantly reported in a variety of clinical therapies; hence, our facile chemoimmunotherapeutic platform should be emphasized in clinical translation for seeking improved therapeutic outcomes.


Assuntos
Antígeno CD47 , Pró-Fármacos , Antígeno B7-H1 , Pró-Fármacos/farmacologia , Microambiente Tumoral , Nanomedicina , Biomarcadores , Imunoterapia , Linhagem Celular Tumoral , RNA Interferente Pequeno
8.
Chem Commun (Camb) ; 59(17): 2493-2496, 2023 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-36752717

RESUMO

A crucial endogenous signaling chemical, hydrogen sulfide, is involved in many physiological actions. In this work, we created the fluorescent probe ER-Nap-NBD using a naphthalimide fluorophore as the signal reporter, a 7-nitro-1,2,3-benzoxadiazole amine as the responsive moiety, and a sulfonamide part for endoplasmic reticulum targeting. ER-Nap-NBD could be detected the H2S levels in solution and in living systems (cells and zebrafish).


Assuntos
Sulfeto de Hidrogênio , Neoplasias , Animais , Humanos , Corantes Fluorescentes , Peixe-Zebra , Espectrometria de Fluorescência , Retículo Endoplasmático , Células HeLa
9.
J Colloid Interface Sci ; 634: 388-401, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36542969

RESUMO

Proteins have been appreciated to be a superlative modality of therapeutics in view of their direct roles in regulating diverse sets of biological events, nonetheless, the clinical applications of the proteinic therapeutics have been strictly limited to act on the cell surface receptors owing to their inherent cell-impermeable character of the proteins. To this obstacle, we contrived carboxylation reaction upon the proteins (RNase A) into the overall negatively charged pro-RNase, followed by elaboration of intelligent pH-responsive pro-RNase delivery nanocolloids based on co-precipitation of pro-RNase and Arg-Gly-Asp (RGD)-functionalized poly(ethylene glycol) (PEG)-block-polyanion with aids of inorganic calcium phosphate (CaP). The resulting nanocolloids appeared to actively accumulate into glioma due to the specific binding affinities of RGD and glioma-enriched αVß3 and αVß5 integrins. Furthermore, the pH responsiveness to the acidic endolysosomal microenvironment of all compositions of nanocolloids (including: decarboxylation of pro-RNase composition to restore the native RNase A, ionization of CaP composition to elicit osmotic pressure, and charge reversal of PEG-block-polyanion into membrane-disruptive polycation) could stimulate not only efficient endolysosomal escape for translocation into the cytosol but also structural disassembly for ready liberation of the RNase A payloads, eventually exerting non-specific RNA degradation for apoptosis of the affected cells. Systemic dosage of the proposed nanocolloids demonstrated potent anti-tumor efficacies towards xenograft glioma due to massive RNA degradation. Therefore, our proposed RNase A prodrug nanocolloids could represent as a versatile platform for engineering transcellular protein delivery systems, which are expected to spur thriving emergence of a spectrum of proteins in precision intervention of intractable diseases.


Assuntos
Glioma , Nanopartículas , Humanos , Linhagem Celular Tumoral , Ribonuclease Pancreático , Polietilenoglicóis/química , Glioma/tratamento farmacológico , Oligopeptídeos/química , Proteínas , Concentração de Íons de Hidrogênio , Nanopartículas/química , Microambiente Tumoral
10.
Chem Commun (Camb) ; 58(81): 11438-11441, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36135099

RESUMO

We report a mitochondria-targeted nitroreductase (NTR)-activated near-infrared fluorescent probe: CS-NO2. Overexpressed NTR in mitochondria was measured with high sensitivity. More importantly, the probe CS-NO2 successfully monitored NTR activity in solid tumors and a hind-limb model of ischemia in mice. This novel finding indicates the promising function of our probe for the diagnosis of solid tumors and hypoxia-associated diseases.


Assuntos
Corantes Fluorescentes , Neoplasias , Animais , Isquemia/diagnóstico por imagem , Camundongos , Mitocôndrias , Dióxido de Nitrogênio , Nitrorredutases
11.
J Agric Food Chem ; 70(35): 10762-10770, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36000580

RESUMO

The low efficiency of RNA interference (RNAi) in insects via the oral administration of double-stranded RNA (dsRNA) is a considerable obstacle preventing its application in insect pest control. The instability of dsRNA and insufficient dsRNA uptake are known to limit the RNAi efficiency. To overcome these limitations, the block copolymer poly(ethylene glycol)-polylysine(thiol) [PEG-PLys(SH)] was designed in this study to form well-defined, core-shell nanoparticles to protect dsRNA from premature degradation and to facilitate its movement through various physiological barriers. The developed material had excellent structural stability and dsRNA-protecting capacity, thereby enabling the prolonged survival of dsRNA in the digestive tract for endocytosis into the midgut cells of the migratory locust, Locusta migratoria. After encapsulation of a dsLmCHS2 payload (a midgut gene), a 60% down-regulation of LmCHS2, accompanied with observations of amorphous and discontinuous linings of the peritrophic matrix and abnormal phenotypes, was observed. In addition, the elaborated nanoscale dsRNA condensates appeared to readily extravasate through the narrow fenestrations in the linings of midgut epithelial cells into the hemolymph and be distributed throughout the body. After encapsulation of a dsLmCHS1 payload (a cuticle gene), a distinctive lethal phenotype with molting failure was observed as a result of a 50% down-regulation in LmCHS1. The persistent leaf adherence of these dsRNA constructs was also capable of resisting continuous rinsing. Therefore, these dsRNA constructs represent a robust type of RNAi pesticide, which has potential as a versatile pesticide against a variety of molecular targets for the control of destructive insects and insects resistant to conventional pesticides.


Assuntos
Locusta migratoria , Praguicidas , Animais , Hemolinfa , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Insetos/metabolismo , Locusta migratoria/genética , Locusta migratoria/metabolismo , Praguicidas/metabolismo , Interferência de RNA , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo
12.
ACS Appl Mater Interfaces ; 14(27): 30493-30506, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35657733

RESUMO

We have tailored multifaceted chemistries into the manufacture of artificial virus-like delivery vehicles mimicking viral "intelligent" transportation pathways through sequential biological barriers; these vehicles can acquire the ability to dynamically "program transfer" to their target sites. To accomplish this, we created anionic pro-proteins, which facilitate charge reversal when subject to acidic endosomal pH; in this way, carboxylation reactions are performed on proteins with amine-reactive cis-aconitic anhydride. Electrostatic associations then initiate the envelopment of these pro-proteins into multilayered nanoarchitectural vehicles composed of multiple-segmental block copolycationic cyclic Arg-Gly-Asp (RGD)-poly(ethylene glycol)(PEG)-GPLGVRG-polylysine(thiol). Therefore, upon the pro-proteins' initial binding to the tumors via the protruding RGD ligands, the bio-inert PEG surroundings are detached through the enzymolysis of the intermediate GPLGVRG linkage by tumor-enriched matrix metalloproteinases, unveiling the cationic polylysine palisade and imparting intimate affinities to the anionic cytomembranes of the targeted tumors. Essentially, through their active endocytosis into the subcellular endosomal compartments, the pro-proteins are made capable of retrieving the original amine groups through a charge reversal decarboxylation process, consequently eliciting augmented charge densities (charge nonstoichiometric protein@polylysine(disulfide)) to disrupt the anionic endosomal membranes to facilitate translocation into the cytosol. Eventually, the active protein payloads can be liberated from nonstoichiometric protein@polylysine(thiol) by the disassembly of polylysine palisade upon the cleavage of disulfide crosslinking in response to the very high level of glutathione in the cytosol, thereby contributing toward extreme cytotoxic potency. Hence, our elaborated virus-mimicking platform has demonstrated potent antitumor efficacy through the systemic administration of ribonucleases, which will consequently lead to an innovative new therapeutic method by which proteins could reach intracellular targets.


Assuntos
Glioma , Nanocápsulas , Aminas , Dissulfetos , Glioma/tratamento farmacológico , Humanos , Concentração de Íons de Hidrogênio , Polietilenoglicóis , Polilisina , Proteínas , Ribonucleases , Compostos de Sulfidrila
13.
J Colloid Interface Sci ; 622: 938-949, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35561612

RESUMO

Cytoplasmic transportation of therapeutic nucleic acids is deemed as an onerous task with aim of precise knockdown towards the targeted genes. Pertaining to the programed functionalities of natural virus in circumventing the biological barriers, we tailored multifaceted chemistries into manufacture of synthetic siRNA delivery vehicles in resembling the functionalities of viral vectors to dynamically tackle with a sequential of biological obstacles encountered in the journey of systemic anti-tumor RNAi therapy. Once harnessing ligands with RGD motif for specific internalization into subcellular endosomal compartments of the tumor cells, the architecture of the proposed delivery vehicles was subjected to facile transformation responsive to pH stimuli in acidic endosomal compartments. The external biocompatible PEGylation palisade was consequently detached, unveiling the cytomembrane-lytic cationic components to commit disruptive potencies to the anionic endosomal membranes for translocation of siRNA conjugates into cytosol. Eventually, liberation of active siRNA could be accomplished due to its responsiveness to the strikingly high level of glutathione in cytosol, thereby contributing to potent RNAi. Hence, our elaborated virus-mimicking platform has demonstrated significant anti-tumor efficacy through systemic administration of anti-angiogenic RNAi payloads, which inspired prosperous potentials in a variety of therapeutic applications.


Assuntos
Nanopartículas , Neoplasias , Ácidos Nucleicos , Humanos , Neoplasias/terapia , Interferência de RNA , RNA Interferente Pequeno/genética , Microambiente Tumoral
14.
Biomacromolecules ; 23(5): 2138-2149, 2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35471918

RESUMO

Proteins have been perceived as being an intriguing modality of therapeutics for the treatment of intractable diseases in view of their superlative precision and versatility. Nonetheless, proteins' intrinsic characters, particularly their being hydrophilic macromolecules with unmethodical charges, have imposed the exceeding challenge of seeking transcellular trafficking into cells' interiors. To circumvent this drawback, we have attempted to employ triple-functional amine-reactive 4-(2-((2-(((4-nitrophenoxy)carbonyl)oxy)ethyl)disulfaneyl)ethoxy)-4-oxobutanoic acid for the efficient incorporation of the anionic carboxyl moiety into amine-enriched enzymes, resulting in overall negatively charged pro-enzymes. The resulting pro-enzymes could be readily electrostatically assembled with cationic species [for instance: block copolymers of poly(ethylene glycol)-polylysine] into core-shell architectural delivery nanoparticles for their facilitated endocytosis into cells. Noteworthy is the aforementioned carboxylation chemistry designed to allow facile reversal of the pro-enzymes to the original amine groups due to the thiolysis of intermediate disulfide linkage for subsequent cascade reactions in response to the cytosol-enriched glutathione. Therefore, cytosol-selective structural disassembly for the liberation and activation of the pro-enzymes was accomplished. Our subsequent investigations utilizing ribonuclease A and catalase as the model enzymes demonstrated appreciable transcellular transportation of the active enzymes to the cell interiors, exerting overwhelming cytotoxic potencies and H2O2 scavenging capacities, respectively. Hence, we reported an unprecedented redox-stimulated charge reversal strategy in engineering cytosol-activatable pro-enzymes, manifesting a simple and efficient approach in the manufacture of transcellular proteinic therapeutics, which should be highlighted to promote their wide availability for use with diverse functional proteins as molecular biological tools and precision therapeutics.


Assuntos
Peróxido de Hidrogênio , Nanopartículas , Aminas , Glutationa , Nanopartículas/química , Polietilenoglicóis/química , Polilisina/química , Proteínas
15.
Int J Pharm ; 607: 120979, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34371151

RESUMO

The aim of this investigation is to clarify the effect of D-α-tocopheryl succinate (vitamin E succinate, VES) and distearoylphosphatidyl ethanolamine-poly(ethylene glycol) (DSPE-PEG) on the encapsulation and controlled release of doxorubicin (DOX) in nano-assemblies and their consequences on the anti-tumor efficacy of DOX. DOX molecules were successfully loaded into the hybrid micelles with VES and DSPE-PEG (VDPM) via thin-film hydration method, exhibiting a small hydrodynamic particle size (~30 nm) and a weak negative zeta potential of around -5 mv. The obtained DOX-loaded VDPM2 displayed retarded DOX release at pH of 7.4, while substantially accelerated drug release at acidic pH of 5.0. Furthermore, the DOX-loaded VDPM2 exhibited substantially slower drug release rate at pH 7.4 compared with the drug-loaded VDPM1 or DPM preparation, benefiting for decreasing the premature DOX release during blood circulation. In vitro cell experiment indicated that DOX-loaded micelles (DPM, VDPM1 and VDPM2) improved the cellular uptake of DOX in 4T1 and MDA-MB-231 cells. The existence of VES component in the structure of DOX-loaded micelles had no obvious influence on the subcellular distribution of the encapsulated DOX molecules. Furthermore, the DOX-loaded VDPM2 exhibited more pronounced cytotoxicity to 4T1 and MDA-MB-231 cancerous cells compared with DOX-loaded DPM and free DOX solution. The hybrid nanocarriers including VES and DSPE-PEG selectively induced intracellular ROS accumulation and increased level of cytoplasmic calcium ion in cancerous cells by interacting with mitochondria and endoplasmic reticulum, bringing about the improved cytotoxicity of DOX. In vivo antitumor efficacy investigation of DOX-loaded VDPM2 against 4T1 xenograft-bearing mice displayed satisfied therapeutic activity with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The proposed DOX-loaded VDPM preparation, as a mulifunctional chemotherapeutic nanomedicine system, holds great potential and bright prospect for clinical tumor therapy.


Assuntos
Micelas , alfa-Tocoferol , Animais , Linhagem Celular Tumoral , Doxorrubicina , Camundongos , Fosfolipídeos , Polietilenoglicóis , Succinatos
16.
J Control Release ; 337: 343-355, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324894

RESUMO

Molecular insights into tumorigenesis have uncovered intimate correlation of SNAI1 with tumor malignancy. Herein, to explore merits of SNAI1-knockdown in tumor therapy, we harnessed RNA interference tool (shSNAI1), together with chemotherapeutic doxorubicin. Owing to abundant hydroxyl groups, pullulan was attempted to be covalently conjugated with a multiple of functional moieties, including positively-charged oligoethylenimine components for electrostatic entrapment of polyanionic shSNAI1 and hydrophobic components for entrapment of lipophilic doxorubicin. Notably, the aforementioned covalent conjugations were tailored to be detachable in response to intracellular reducing microenvironment owing to redox disulfide linkage, thereby accounting for selective intracellular liberation of the therapeutic payloads. Moreover, the surface of nanomedicine was modified with hyaluronic acid, endowing not only excellent biocompatibilities but active tumor-targeting function due to its receptors (CD44) overexpressed on tumor cells. Subsequent investigations approved appreciably targeted co-delivery of shSNAI1 and doxorubicin into solid lung tumors via systemic administration and demonstrated critical contribution of SNAI1-knockdown in amplifying chemotherapeutic potencies.


Assuntos
Nanomedicina , Nanopartículas , Doxorrubicina , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Ácido Hialurônico
17.
Bioconjug Chem ; 32(5): 909-915, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33890782

RESUMO

Polymeric small interfering RNA (siRNA) conjugate was elaborated to sequentially circumvent the predefined biological barriers encountered in the journey of transcellular delivery of siRNA into cytosol. Herein, classic ring-opening polymerization was employed for synthesis of well-defined poly(amino acid) derivatives possessing an array of carboxyl groups in an attempt to resemble the structural characteristics of hyaluronan. Furthermore, the hyaluronan-like synthetic was conjugated with a multiple of siRNA through a glutathione (GSH)-responsive disulfide linkage. The siRNA conjugate appeared to utilize the hyaluronan-specific receptors of CD44 for cell internalization, indicating similar functionalities to our hyaluronan-mimicking synthetic. Furthermore, the carboxyl groups of hyaluronan-like synthetics were designed to be selectively detached in subcellular acidic endosomes/lysosomes and transform into the cytomembrane-disruptive flanking ethylenediamine moieties, which appeared to be crucial in facilitating translocation of siRNA payloads from entrapment and degradation in lysosomes toward the cytosol. Eventually, active siRNA could be smoothly released from the synthetic due to the GSH cleavage disulfide linkage (disulfide), consequently accounting for potent RNA knockdown activities (>90%) toward cancerous cells. In addition, appreciable knockdown of parathyroid hormone was also achieved from our proposed siRNA conjugates in parathyroid cells. Hence, the elaborated siRNA conjugate showed tremendous potential in treatment of hyperparathyroidism, and could be developed further for systemic RNA interference (RNAi) therapeutics. Moreover, this study could also be the first example of a synthetic mimic to hyaluronan acquiring its functionalities, which could have important implications for further development of biomimic materials in pursuit of biomedical applications.


Assuntos
Portadores de Fármacos/química , Hormônio Paratireóideo/biossíntese , Polímeros/química , Interferência de RNA , Transporte Biológico , Linhagem Celular , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética
18.
J Control Release ; 334: 263-274, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33930477

RESUMO

Surgical assailment at the vulnerable subcellular organelles (e.g. mitochondria) by photodynamic therapy (PDT) is perceived as the most devastating approach to eradicate the tumors. Herein, we programmed a novel near-infrared (NIR) PDT construct illustrating appreciable hierarchical zoom-in targeting scenario, namely, primary cell-level targeting to carcinoma post systemic dosage and subcellular level targeting to mitochondria. Pertaining to tumor-targeting function, charge reversal chemistry selectively responsive to acidic tumoral microenvironments (pH 6.8) was implemented as the external corona of PDT constructs. This charge transformative exterior entitled minimal biointerfacial reactions in systemic retention but intimate affinities to cytomembranes selectively in tumoral microenvironments, thereby resulting in preferential uptake by tumors. Furthermore, the proposed PDT constructs were equipped with mitochondria targeting triphenylphosphonium (TPP) motif, which appeared to propel intriguing 88% colocalization with mitochondria. Therefore, overwhelming cytotoxic potencies were accomplished by our carefully engineered photodynamic constructs. Another noteworthy is the photodynamic constructs characterized to be excited at tissue-penetrating NIR (980 nm) based on energy transfer between their internal components of anti-Stoke upconversion nanoparticles (UCN, donor) and photodynamic chlorin e6 (Ce6, acceptor). Therefore, practical applications for photodynamic treatment of intractable solid carcinoma were greatly facilitated and complete tumor eradication was achieved by systemic administration of the ultimate multifunctional NIR photodynamic constructs.


Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Raios Infravermelhos , Fármacos Fotossensibilizantes/uso terapêutico
19.
Bioconjug Chem ; 32(5): 1008-1016, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33882675

RESUMO

In light of immune facilities trafficking toward the pathological sites along upward gradient of immunostimulatory cytokines, a localized resiquimod (Toll-like receptor 7/8 agonist) release depot was manufactured for pursuit of precision immunostimulation toward intractable triple-negative breast carcinoma. In principle, resiquimod/poly(lactic-co-glycolic acid) microspheres were fabricated and embedded into injectable and biodegradable poly(ethylene glycol) (PEG)-based hydrogel. The subsequent investigations approved persistent retention of immunostimulatory resiquimod in tumors upon peritumoral administration, which consequently led to localized and consistent secretion of immunostimulatory cytokines. Initially, not only innate tumor phagocytosis but also adaptive antitumor immunities were successfully cultivated for in situ suppression of the growth of primary solid tumors, more importantly, capable of inhibiting distant pulmonary metastasis, as evidenced by observation of enormous lymphocytes selectively gathering in the pulmonary artery. Hence, our presented study provided an important clinical indication of using immunostimulatory drugs to activate potent innate and adaptive antitumor immunities for precision antitumor therapy. Further immunomodulatory strategies, such as checkpoint blockage and tumor immunogenicity, could also be complementary for development of advanced antitumor immunotherapeutics in treatment of a number of intractable tumors.


Assuntos
Adjuvantes Imunológicos/metabolismo , Imidazóis/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adjuvantes Imunológicos/farmacologia , Linhagem Celular Tumoral , Preparações de Ação Retardada , Humanos , Imidazóis/farmacologia , Metástase Neoplásica , Medicina de Precisão , Neoplasias de Mama Triplo Negativas/imunologia
20.
ACS Appl Mater Interfaces ; 13(5): 6053-6068, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33525873

RESUMO

Nanomedicine developed to date by means of directly encapsulating cytotoxins suffers from crucial drawbacks, including premature release and detoxification prior to arrival at pharmaceutics targets. To these respects, redox-responsive polymeric prodrugs of platinum (Pt) and camptothecin (CPT), selectively and concomitantly activated in the cytoplasm, were elaborated in manufacture of dual prodrug nanomedicine. Herein, multiple CPTs were conjugated to poly(lysine) (PLys) segments of block copolymeric poly(ethylene glycol) (PEG)-PLys through the redox responsive disulfide linkage [PEG-PLys(ss-CPT)] followed by reversible conversion of amino groups from PLys into carboxyl groups based on their reaction with cis-aconitic anhydride [PEG-PLys(ss-CPT&CAA)]. On the other hand, Pt(IV) in conjugation with dendritic polyamindoamine [(G3-PAMAM-Pt(IV)] was synthesized for electrostatic complexation with PEG-PLys(ss-CPT&CAA) into dual prodrug nanomedicine. Subsequent investigations proved that the elaborated nanomedicine could sequentially respond to intracellular chemical potentials to overcome a string of predefined biological barriers and facilitate intracellular trafficking. Notably, PEG-PLys(ss-CPT&CAA) capable of responding to the acidic endosomal microenvironment for transformation into endosome-disruptive PEG-PLys(ss-CPT), as well as release of G3-PAMAM-Pt(IV) from nanomedicine, prompted transclocation of therapeutic payloads from endosomes into cytosols. Moreover, concurrent activation and liberation of cytotoxic CPT and Pt(II) owing to their facile responsiveness to the cytoplasmic reducing microenvironment have demonstrated overwhelming cytotoxic potencies. Eventually, systemic administration of the dual prodrug construct exerted potent tumor suppression efficacy in treatment of intractable solid breast adenocarcinoma, as well as an appreciable safety profile. The present study illustrated the first example of nanomedicine with a dual prodrug motif, precisely and concomitantly activated by the same subcellular stimuli before approaching pharmaceutic action targets, thus shedding important implication in development of advanced nanomedicine to seek maximized pharmaceutic outcomes.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Citotoxinas/farmacologia , Nanomedicina , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Propriedades de Superfície , Células Tumorais Cultivadas
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