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1.
J Control Release ; 361: 64-76, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37532143

RESUMO

Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained 'off' status in circulation but rapidly switched 'on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration, c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors.


Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Antígeno B7-H1 , Neoplasias/tratamento farmacológico , Linfócitos T , Imunoterapia , Adjuvantes Imunológicos , Microambiente Tumoral
2.
Sci China Life Sci ; 66(1): 67-80, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35881219

RESUMO

Group 2 innate lymphoid cells (ILC2s) play important tissue resident roles in anti-parasite immunity, allergic immune response, tissue homeostasis, and tumor immunity. ILC2s are considered tissue resident cells with little proliferation at steady state. Recent studies have shown that a subset of small intestinal ILC2s could leave their residing tissues, circulate and migrate to different organs, including lung, liver, mesenteric LN and spleen, upon activation. However, it remains unknown whether other ILC populations with migratory behavior exist. In this study, we find two major colon ILC2 populations with potential to migrate to the lung in response to IL-25 stimulation. One subset expresses IL-17A and resembles inflammatory ILC2s (iILC2s) but lacks CD27 expression, whereas the other expresses CD27 but not IL-17A. In addition, the IL-17A+ ILC2s express lower levels of CD127, CD25, and ST2 than CD27+ ILC2s, which express higher levels of IL-5 and IL-13. Surprisingly, we found that both colon ILC2 populations still maintained their colonic features of preferential expression of IL-17A and CD27, IL-5/IL-13, respectively. Together, our study identifies two migratory colon ILC2 subsets with unique surface markers and cytokine profiles which are critical in regulating lung and colon immunity and homeostasis.


Assuntos
Imunidade Inata , Interleucina-13 , Interleucina-5 , Linfócitos , Pulmão/patologia , Citocinas
3.
Macromol Rapid Commun ; 44(4): e2200706, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36353903

RESUMO

Herein novel multicompartment nanoparticles (MCNs) that combine high stability and cargo loading capacity are developed. The MCNs are fabricated by crystallization-driven self-assembly (CDSA) of a tailor-made 21 arm star polymer, poly(L-lactide)[poly(tert-butyl acrylate)-block-poly(ethylene glycol)]20 [PLLA(PtBA-b-PEG)20 ]. Platelet-like or spherical MCNs containing a crystalline PLLA core and hydrophobic PtBA subdomains are formed and stabilized by PEG. Hydrophobic cargos, such as Nile Red and chemotherapeutic drug doxorubicin, can be successfully encapsulated into the collapsed PtBA subdomains with loading capacity two orders of magnitude higher than traditional CDSA nanoparticles. Depolarized fluorescence measurements of the Nile Red loaded MCNs suggest that the free volume of the hydrophobic chains in the nanoparticles may be the key for regulating their drug loading capacity. In vitro study of the MCNs suggests excellent cytocompatibility of the blank nanoparticles as well as a dose-dependent cellular uptake and cytotoxicity of the drug-loaded MCNs.


Assuntos
Nanopartículas , Polímeros , Polímeros/química , Portadores de Fármacos/química , Cristalização , Polietilenoglicóis/química , Nanopartículas/química , Micelas
4.
Angew Chem Int Ed Engl ; 61(52): e202214992, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36331428

RESUMO

Agonists of innate pattern recognition receptors such as toll-like receptors (TLRs) prime adaptive anti-tumor immunity and hold promise for cancer immunotherapy. However, small-molecule TLR agonists cause immune-related adverse effects (irAEs) after systemic administration. Herein, we report a polymeric nano-immunomodulator (cN@SS-IMQ) that is inactive until it is selectively metabolized to an active immunostimulant within the tumor. cN@SS-IMQ was obtained via self-assembly of a cyclo(Arg-Gly-Asp-D-Phe-Lys)-modified amphiphilic copolymeric prodrug. Upon systemic administration, cN@SS-IMQ preferentially accumulated at tumor sites and responded to high intracellular glutathione levels to release native imidazoquinolines for dendritic cell maturation, thereby enhancing the infiltration of T lymphocytes. Collectively, cN@SS-IMQ tends to activate the immune system without irAEs, thus suggesting its promising potential for safe systemic targeting delivery.


Assuntos
Neoplasias , Receptor 7 Toll-Like , Humanos , Receptor 7 Toll-Like/metabolismo , Células Dendríticas/metabolismo , Neoplasias/patologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Fatores Imunológicos , Imunidade
5.
J Nanobiotechnology ; 20(1): 369, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953798

RESUMO

BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.


Assuntos
Camptotecina , Neoplasias , Camptotecina/farmacologia , Linhagem Celular Tumoral , Humanos , Imunoterapia , Micelas , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico , Receptor 7 Toll-Like , Microambiente Tumoral
6.
Adv Healthc Mater ; 11(12): e2102781, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35285581

RESUMO

In situ anti-tumor vaccination is an attractive type of cancer immunotherapy which relies on the effectiveness of dendritic cells (DCs) to engulf tumor antigens, become activated, and present antigens to T cells in lymphoid tissue. Here, a multifunctional nanocomplex based on calcium crosslinked polyaspartic acid conjugated to either a toll-like receptor (TLR)7/8 agonist or a photosensitizer is reported. Intratumoral administration of the nanocomplex followed by laser irradiation induces cell killing and hence generation of a pool of tumor-associated antigens, with concomitant promotion of DCs maturation and expansion of T cells in tumor-draining lymph nodes. Suppression of tumor growth is observed both at the primary site and at the distal site, thereby hinting at successful induction of an adaptive anti-tumor response. This strategy holds promise for therapeutic application in a pre-operative and post-operative setting to leverage to mutanome of the patient's own tumor to mount immunological memory to clear residual tumor cells and metastasis.


Assuntos
Vacinas Anticâncer , Neoplasias , Receptor 7 Toll-Like , Receptor 8 Toll-Like , Adjuvantes Imunológicos/uso terapêutico , Animais , Antígenos de Neoplasias , Cálcio , Vacinas Anticâncer/administração & dosagem , Células Dendríticas , Sistemas de Liberação de Medicamentos , Imunidade , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Vacinação
7.
Adv Healthc Mater ; 11(12): e2102739, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35306756

RESUMO

Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.


Assuntos
Nanopartículas , Neoplasias , Adjuvantes Imunológicos , Linhagem Celular Tumoral , Ácido Fólico , Humanos , Morte Celular Imunogênica , Imunoterapia , Manose , Neoplasias/tratamento farmacológico , Oxaliplatina/farmacologia , Polímeros , Receptor 7 Toll-Like/agonistas , Microambiente Tumoral
8.
Asian J Pharm Sci ; 15(5): 576-590, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33193861

RESUMO

Vaccines therapeutics manipulate host's immune system and have broad potential for cancer prevention and treatment. However, due to poor immunogenicity and limited safety, fewer cancer vaccines have been successful in clinical trials. Over the past decades, nanotechnology has been exploited to deliver cancer vaccines, eliciting long-lasting and effective immune responses. Compared to traditional vaccines, cancer vaccines delivered by nanomaterials can be tuned towards desired immune profiles by (1) optimizing the physicochemical properties of the nanomaterial carriers, (2) modifying the nanomaterials with targeting molecules, or (3) co-encapsulating with immunostimulators. In order to develop vaccines with desired immunogenicity, a thorough understanding of parameters that affect immune responses is required. Herein, we discussed the effects of physicochemical properties on antigen presentation and immune response, including but not limited to size, particle rigidity, intrinsic immunogenicity. Furthermore, we provided a detailed overview of recent preclinical and clinical advances in nanotechnology for cancer vaccines, and considerations for future directions in advancing the vaccine platform to widespread anti-cancer applications.

9.
AAPS PharmSciTech ; 21(5): 193, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661922

RESUMO

Pemetrexed disodium (PMX) stands out in the treatment of non-small cell lung cancer (NSCLC), but with short half-life and toxic side effects. This study was to design cationic liposomes for targeting delivery PMX to the lungs. The PMX cationic liposome was prepared by thin-film hydration using stearylamine (SA) as the positive component of charge-regulating charge. Then, the PMX cationic liposome (SA-PMX-Lips) was characterized by particle size, morphology, entrapment efficiency (EE), and drug loading (DL). Finally, the drug release behavior in vitro, the pharmacokinetic study, and tissue distribution of SA-PMX-Lips were evaluated separately, with PMX solution (PMX-Sol) and PMX liposome (PMX-Lips) as the control. According to results, SA-PMX-Lips were spherical and the particle size was 219.7 ± 4.97 nm with a narrow polydispersity index (PDI) (0.231 ± 0.024) and a positive zeta potential 22.2 ± 0.52 mV. Its EE was 92.39 ± 1.94% and DL was 9.15 ± 0.07%. The results of in vitro and in vivo experiments showed that SA-PMX-Lips released slowly, prolonged retention time and increased the value of AUC. More notably, SA-PMX-Lips could improve the accumulation of drugs in the lungs and the relative uptake rate (Re) was 2.35 in the lungs, which indicated its lung targeting. In summary, SA-PMX-Lips showed the potential for the effective delivery of PMX and the treatment of NSCLC.


Assuntos
Aminas/química , Pemetrexede/administração & dosagem , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Liberação Controlada de Fármacos , Humanos , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Tamanho da Partícula , Pemetrexede/farmacocinética , Pemetrexede/uso terapêutico , Distribuição Tecidual
10.
ACS Biomater Sci Eng ; 6(9): 4993-5000, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-33455292

RESUMO

Strategies that can reduce the harmful side effects of potent immunomodulatory drugs are in high demand to facilitate clinical translation of the newest generation of immunotherapy. Indeed, uncontrolled triggering of the immune system can lead to life-threatening cascade reactions, such as e.g. cytokine storm. In particular, drug formulations that combine simplicity and degradability are of formidable relevance. Imidazoquinolines are an excellent example of such small molecule immunomodulatory drugs that exhibit in unformulated form a highly undesirable pharmacokinetic profile. Imidazoquinolines are potent inducers of type I interferons that are of great interest in the context of anticancer and antiviral therapy through triggering of Toll like receptors 7 and 8. In this work we aimed to alter the pharmacokinetic profile of imidazoquinolines using a simple, yet efficient, strategy that holds high potential for clinical translation. Hereto, we conjugated an imidazoquinoline to the backbone of poly(aspartate) and further formulated this into a degradable coacervate through complex coacervation with a nontoxic degradable polycation. The intrinsic TLR activity of the imidazoquinoline was well preserved and our formulation strategy offered spatial control over its biological activity in vivo.


Assuntos
Imunoterapia , Neoplasias , Humanos , Fatores Imunológicos , Neoplasias/tratamento farmacológico
11.
AAPS PharmSciTech ; 20(3): 133, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30820689

RESUMO

Irinotecan (IRT), the pro-drug of SN-38, has exhibited potent cytotoxicity against various tumors. In order to enhance the anti-tumor effect of IRT, we prepared IRT-loaded PLGA nanoparticles (IRT-PLGA-NPs) by emulsion-solvent evaporation method. Firstly, IRT-PLGA-NPs were characterized through drug loading (DL), entrapment efficiency (EE), particle size, zeta potential, transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). We next studied the in vitro release characteristics of IRT-PLGA-NPs. Finally, the pharmacokinetics and pharmacodynamics profiles of IRT-PLGA-NPs were investigated. The results revealed that IRT-PLGA-NPs were spherical with an average size of (169.97 ± 6.29) nm and its EE and DL were (52.22 ± 2.41)% and (4.75 ± 0.22)%, respectively. IRT-PLGA-NPs could continuously release drug for 14 days in vitro. In pharmacokinetics studies, for pro-drug IRT, the t1/2ß of IRT-PLGA-NPs was extended from 0.483 to 3.327 h compared with irinotecan solution (IRT-Sol), and for its active metabolite SN-38, the t1/2ß was extended from 1.889 to 4.811 h, which indicated that IRT-PLGA-NPs could prolong the retention times of both IRT and SN-38. The pharmacodynamics results revealed that the tumor doubling time, growth inhibition rate, and specific growth rate of IRT-PLGA-NPs were 2.13-, 1.30-, and 0.47-fold those of IRT-Sol, respectively, which demonstrated that IRT-PLGA-NPs could significantly inhibit the growth of tumor. In summary, IRT-PLGA-NPs, which exhibited excellent therapeutic effect against tumors, might be used as a potential carrier for tumor treatment in clinic.


Assuntos
Antineoplásicos/síntese química , Irinotecano/síntese química , Nanopartículas/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/análise , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/análise , Materiais Biocompatíveis/síntese química , Varredura Diferencial de Calorimetria/métodos , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/análise , Portadores de Fármacos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Irinotecano/administração & dosagem , Irinotecano/análise , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/análise , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/análise , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/análise , Inibidores da Topoisomerase I/síntese química , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia
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