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1.
Biomaterials ; 290: 121815, 2022 11.
Article in English | MEDLINE | ID: mdl-36201947

ABSTRACT

Photothermal therapy (PTT) has been known as an effective weapon against cancer. However, the necrosis induced by hyperthermia post PTT can trigger excessive inflammation response and arouse tumor self-protection resulting in tumor immunosuppression, metastasis and recurrence. To settle this issue, we here reported a multifunctional light-activatable nanocomplex (MILAN) to avoid hyperthermia and achieve temperate-heat PTT for extensive apoptosis, but not necrosis, and further antitumor immune response augmentation to inhibit metastasis and recurrence. Upon NIR irradiation, MILAN would controllably maintain around 43 °C, thus evoking the temperature-triggered phase transformation for the controllable drug release. Then, the released gambogic acid broke the thermoresistance of tumor cells, realizing enhanced apoptosis. Thereafter, the generated tumor-associated antigen accompanied with MILAN could facilitate dendritic cells (DCs) maturation for improved antigen presentation. Furthermore, MILAN promoted the tumor perfusion of DCs and T lymphocytes in triple-negative breast cancer (TNBC) models. Simultaneously, the immunosuppressive microenvironment was relieved and a strong systemic immune response was elicited against tumor progress through MILAN. Consequently, systemic immunity and persistent immune memory effect were fortified for pronounced cancer metastasis and recurrence inhibition. This work tactfully avoids the side effects of hyperthermia and brought a novel insight into cancer immunotherapy against TNBC.


Subject(s)
Hyperthermia, Induced , Nanoparticles , Triple Negative Breast Neoplasms , Humans , Phototherapy/methods , Hyperthermia, Induced/methods , Photothermal Therapy , Hot Temperature , Immunotherapy/methods , Inflammation/therapy , Cell Line, Tumor , Tumor Microenvironment
2.
Biomaterials ; 272: 120795, 2021 05.
Article in English | MEDLINE | ID: mdl-33836292

ABSTRACT

Since the 5-year survival rate of pancreatic cancer is only 10.0%, new therapies are urgently needed. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically on tumor cells, nevertheless its clinical application was seriously restricted by resistance and short in vivo half-life. Herein, a novel multifunctional R6ST protein equipped with cell penetrating peptides R6, intrinsic apoptosis inducing tetrapeptide AVPI and soluble TRAIL was designed and constructed. Then, it was recruited to prepare self-sustained nanoplatform (SSN) to reverse TRAIL-resistance of pancreatic cancer through simultaneously promoting extrinsic and intrinsic apoptotic pathway, as well to elongate circulation time. Once administrated, high tumor accumulation and cellular uptake of SSN were achieved through prolonged circulation time, targeting ability of soluble TRAIL to death receptors and positive-charged R6, and further enhanced through reversed upregulation of death receptors on TRAIL-resistant tumor cells by the cumulated artesunate released in cytoplasm as a positive feedback loop. Furthermore, this loop simultaneously promoted extrinsic apoptosis of TRAIL fragment via the upregulated death receptors on TRAIL-resistant pancreatic cancer cells and intrinsic apoptosis of AVPI tetrapeptide via the efficient accumulation and uptake of R6ST on SSN. Hence, SSN exhibited synergistic antitumor effect and provided a new strategy for TRAIL-resistant pancreatic cancer therapy.


Subject(s)
Drug Resistance, Neoplasm , Pancreatic Neoplasms , Apoptosis , Cell Line, Tumor , Humans , Pancreatic Neoplasms/drug therapy , Receptors, TNF-Related Apoptosis-Inducing Ligand , TNF-Related Apoptosis-Inducing Ligand
3.
Int J Pharm ; 552(1-2): 16-26, 2018 Dec 01.
Article in English | MEDLINE | ID: mdl-30253209

ABSTRACT

In the present study, we have developed the robust nanoparticles (MGC-GNP/PTX), which are TAMs and tumor cells-dual recognizable, for targeting cancer therapy. Of great importance, the developed nano-platforms are glutathione (GSH)-activable, which means it remains structure intact under normal physiological condition and can be disrupted when exposed to certain concentration of GSH. As demonstrated by the drug release assay in vitro, MGC-GNP/PTX exhibited an excellent structure stability under the normal condition with only 10% of cumulative drug release at 72 h. However, after increasing the concentration of GSH to 1 mM or 10 mM, the release of PTX from the nanoparticles was significantly accelerated and approximately 35% or 95% of drugs was released. Cellular experiments and in vivo tumor targeting assay displayed that the developed nanoparticles have a super capacity of tumor cells and TAMs-dual targeting drug delivery, which resulted in much stronger cytotoxicity when compared to the unmodified ones. Finally, the pharmacodynamic evaluation indicated that the mice treated with MGC-GNP/PTX displayed the strongest tumor suppression ability versus other groups. More importantly, the treatment of MGC-GNP/PTX did not significantly influence the body weight and pathological of the mice, indicated that the prepared nanoparticle system had a satisfactory bio-safety for targeting tumor drug delivery.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Glutathione/administration & dosage , Lung Neoplasms/drug therapy , Nanoparticles/administration & dosage , Paclitaxel/administration & dosage , Tumor Microenvironment/drug effects , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacokinetics , Cell Line , Drug Liberation , Glutathione/chemistry , Glutathione/pharmacokinetics , Humans , Lung Neoplasms/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/chemistry , Paclitaxel/chemistry , Paclitaxel/pharmacokinetics
4.
J Biomed Nanotechnol ; 14(2): 267-280, 2018 Feb 01.
Article in English | MEDLINE | ID: mdl-31352923

ABSTRACT

7-Ethyl-10-hydroxy-camptothecin (SN-38), an efficient topoisomerase inhibitor, is the biological metabolite of irinotecan used as the first-line chemotherapy drug for colon cancer. However, the hydrophobicity and instability of SN-38 limit its further clinical application. In this study, to improve water dispersity and the anti-tumor efficiency of SN-38, a prodrug, SN-38-BOC, that could efficiently transform to active SN-38 in the acidic tumor microenvironment was synthesized and encapsulated into MPEG-P(CL-ran-TMC) micelles (SN-38-BOC micelles). SN-38-BOC micelles could accumulate in tumors due to the EPR effect and exhibit a sustained release behavior, which was rapidly transformed to active SN-38 by the acidic environment of tumor tissues (pH 5.5-6.8), thus achieving efficient anti-tumor activity. Compared with the free SN-38-BOC group, enhanced cytotoxicity and apoptotic induction were obtained from the SN-38-BOC micelle-treated group in both HCT116 and CT26 cells. In addition, SN-38-BOC micelles showed more effective anti-angiogenesis than free SN-38-BOC in a transgenic zebrafish model. Furthermore, SN-38-BOC micelles exhibited stronger inhibition of tumor growth in both HCT116 and CT26 subcutaneous xenograft tumor models. Histological analysis revealed that SN-38-BOC micelles showed a more effective anti-tumor activity than the free drug by inducing more apoptosis, inhibiting angiogenesis, and suppressing proliferation. Thus, the pH-activatable SN-38-BOC micelle could serve as a promising candidate in colorectal tumor therapy.


Subject(s)
Micelles , Antineoplastic Agents , Camptothecin , Cell Line, Tumor , Humans , Hydrogen-Ion Concentration , Irinotecan , Prodrugs
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