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1.
Biomaterials ; 306: 122477, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38309054

RESUMO

Camptothesome is a sphingomyelin-conjugated camptothecin (SM-CSS-CPT) nanovesicle that fortified the therapeutic delivery of CPT in diverse cancer types. To mitigate the Camptothesome-induced IDO1 negative feedback mechanism, we had co-encapsulated, indoximod (IND, IDO1 inhibitor) into Camptothesome using doxorubicin-derived IND (DOX-IND). To maximize the therapeutic potential of DOX-IND/Camptothesome, herein, we first dissected the synergistic drug ratio (DOX-IND/SM-CSS-CPT) via systematical in vitro screening. DOX-IND/Camptothesome with optimal drug ratio synchronized in vivo drug delivery with significantly higher tumor uptake compared to free drugs. This optimum DOX-IND/Camptothesome outperformed the combination of Camptothesome, Doxil and IND or other IDO1 inhibitors (BMS-986205 or epacadostat) in treating mice bearing late-stage MC38 tumors, and combination with immune checkpoint blockade (ICB) enabled it to eradicate 60 % of large tumors. Further, this optimized co-delivery Camptothesome beat Folfox and Folfiri, two first-line combination chemotherapies for colorectal cancer in antitumor efficacy and exhibited no side effects as compared to the severe systemic toxicities associated with Folfox and Folfiri. Finally, we demonstrated that the synergistic DOX-IND/Camptothesome was superior to the combined use of Onivyde + Doxil + IND in curbing the advanced orthotopic CT26-Luc tumors and eliminated 40 % tumors with complete metastasis remission when cooperated with ICB, eliciting stronger anti-CRC immune responses and greater reversal of immunosuppression. These results corroborated that with precise optimal synergistic drug ratio, the therapeutic potential of DOX-IND/Camptothesome can be fully unleased, which warrants further clinical investigation to benefit the cancer patients.


Assuntos
Neoplasias Colorretais , Doxorrubicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Animais , Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis , Neoplasias Colorretais/tratamento farmacológico , Linhagem Celular Tumoral
2.
Nat Commun ; 15(1): 2073, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453918

RESUMO

Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the physiological environment, Chol is rapidly extracted from the lipid bilayer by biomembranes, which jeopardizes membrane stability and results in premature leakage for delivered payloads, yielding suboptimal clinic efficacy. Herein, we report a Chol-modified sphingomyelin (SM) lipid bilayer via covalently conjugating Chol to SM (SM-Chol), which retains membrane condensing ability of Chol. Systemic structure activity relationship screening demonstrates that SM-Chol with a disulfide bond and longer linker outperforms other counterparts and conventional phospholipids/Chol mixture systems on blocking Chol transfer and payload leakage, increases maximum tolerated dose of vincristine while reducing systemic toxicities, improves pharmacokinetics and tumor delivery efficiency, and enhances antitumor efficacy in SU-DHL-4 diffuse large B-cell lymphoma xenograft model in female mice. Furthermore, SM-Chol improves therapeutic delivery of structurally diversified therapeutic agents (irinotecan, doxorubicin, dexamethasone) or siRNA targeting multi-drug resistant gene (p-glycoprotein) in late-stage metastatic orthotopic KPC-Luc pancreas cancer, 4T1-Luc2 triple negative breast cancer, lung inflammation, and CT26 colorectal cancer animal models in female mice compared to respective FDA-approved nanotherapeutics or lipid compositions. Thus, SM-Chol represents a promising platform for universal and improved drug delivery.


Assuntos
Bicamadas Lipídicas , Esfingomielinas , Humanos , Feminino , Camundongos , Animais , Bicamadas Lipídicas/química , Esfingomielinas/química , Lipossomos/química , Fosfolipídeos/química , Colesterol/química
3.
Int J Pharm ; 634: 122655, 2023 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-36720448

RESUMO

Tumor immunotherapy has revolutionized the field of oncology treatments in recent years. As one of the promising strategies of cancer immunotherapy, tumor immunogenic cell death (ICD) has shown significant potential for tumor therapy. Nanoparticles are widely used for drug delivery due to their versatile characteristics, such as stability, slow blood elimination, and tumor-targeting ability. To increase the specificity of ICD inducers and improve the efficiency of ICD induction, functionally specific nanoparticles, such as liposomes, nanostructured lipid carriers, micelles, nanodiscs, biomembrane-coated nanoparticles and inorganic nanoparticles have been widely reported as the vehicles to deliver ICD inducers in vivo. In this review, we summarized the strategies of different nanoparticles for ICD-induced cancer immunotherapy, and systematically discussed their advantages and disadvantages as well as provided feasible strategies for solving these problems. We believe that this review will offer some insights into the design of effective nanoparticulate systems for the therapeutic delivery of ICD inducers, thus, promoting the development of ICD-mediated cancer immunotherapy.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Morte Celular Imunogênica , Neoplasias/tratamento farmacológico , Imunoterapia , Nanotecnologia , Nanopartículas/uso terapêutico
4.
Pharmaceutics ; 16(1)2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38258045

RESUMO

Over the past several decades, liposomes have been extensively developed and used for various clinical applications such as in pharmaceutical, cosmetic, and dietetic fields, due to its versatility, biocompatibility, and biodegradability, as well as the ability to enhance the therapeutic index of free drugs. However, some challenges remain unsolved, including liposome premature leakage, manufacturing irreproducibility, and limited translation success. This article reviews various aspects of liposomes, including its advantages, major compositions, and common preparation techniques, and discusses present U.S. FDA-approved, clinical, and preclinical liposomal nanotherapeutics for treating and preventing a variety of human diseases. In addition, we summarize the significance of and challenges in liposome-enabled nanotherapeutic development and hope it provides the fundamental knowledge and concepts about liposomes and their applications and contributions in contemporary pharmaceutical advancement.

5.
Talanta ; 260: 124589, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37126925

RESUMO

In this work, 2,4,6-tris(4-aminophenyl)-1,3,5-triazine (TAPT) and 1,3,5-tris(4-formylphenyl)benzene (TFPB) were used as monomers to construct a triazine-containing imine-linked covalent organic framework (COF), which was then bonded onto the surface of aldehydized silica (SiO2-CHO), and finally a COF@silica composite material (TAPT-TFPB COF@SiO2) was successfully prepared. The chromatographic separation performance of SiO2-CHO, TAPT-TFPB COF@SiO2 and TAPT-TFPB COF@SiO2/SiO2-CHO (80/20, mass ratio) was evaluated and compared. It was found that separation efficiency was obviously enhanced by adding an appropriate amount of SiO2-CHO into TAPT-TFPB COF@SiO2. The obtained TAPT-TFPB COF@SiO2/SiO2-CHO showed more favorable separation ability than SiO2-CHO and TAPT-TFPB COF@SiO2. Various aromatic compounds including alkylbenzenes, polycyclic aromatic hydrocarbons, environmental endocrine disruptors, foodborne stimulants and phenyl ketones were effectively separated on the TAPT-TFPB COF@SiO2/SiO2-CHO column in reversed phase chromatography mode. The silica microspheres surface-modified with triazine-containing imine-linked COFs proved to be a new type of promising chromatographic packing materials.

6.
Nat Commun ; 14(1): 7235, 2023 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-37945606

RESUMO

Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.


Assuntos
Melanoma Experimental , Esfingomielinas , Feminino , Camundongos , Animais , Receptor de Morte Celular Programada 1 , Melanoma Experimental/tratamento farmacológico , Oximas , Ativação Linfocitária , Imunoterapia
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