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1.
Innovation (Camb) ; 5(1): 100547, 2024 Jan 08.
Article in English | MEDLINE | ID: mdl-38170012

ABSTRACT

Cognitive decline has been linked to periodontitis through an undetermined pathophysiological mechanism. This study aimed to explore the mechanism underlying periodontitis-related cognitive decline and identify therapeutic strategies for this condition. Using single-nucleus RNA sequencing we found that changes in astrocyte number, gene expression, and cell‒cell communication were associated with cognitive decline in mice with periodontitis. In addition, activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome was observed to decrease the phagocytic capability of macrophages and reprogram macrophages to a more proinflammatory state in the gingiva, thus aggravating periodontitis. To further investigate this finding, lipid-based nanoparticles carrying NLRP3 siRNA (NPsiNLRP3) were used to inhibit overactivation of the NLRP3 inflammasome in gingival macrophages, restoring the oral microbiome and reducing periodontal inflammation. Furthermore, gingival injection of NPsiNLRP3 reduced the number of Serpina3nhigh astrocytes in the hippocampus and prevented cognitive decline. This study provides a functional basis for the mechanism by which the destruction of periodontal tissues can worsen cognitive decline and identifies nanoparticle-mediated restoration of gingival macrophage function as a novel treatment for periodontitis-related cognitive decline.

2.
Sci Bull (Beijing) ; 69(3): 354-366, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38072706

ABSTRACT

Engineered T cells expressing chimeric antigen receptor (CAR) exhibit high response rates in B-cell malignancy treatments and possess therapeutic potentials against various diseases. However, the complicated ex vivo production process of CAR-T cells limits their application. Herein, we use virus-mimetic fusogenic nanovesicles (FuNVs) to produce CAR-T cells in vivo via membrane fusion-mediated CAR protein delivery. Briefly, the FuNVs are modified using T-cell fusogen, adapted from measles virus or reovirus fusogens via displaying anti-CD3 single-chain variable fragment. The FuNVs can efficiently fuse with the T-cell membrane in vivo, thereby delivering the loaded anti-CD19 (αCD19) CAR protein onto T-cells to produce αCD19 CAR-T cells. These αCD19 CAR-T cells alone or in combination with anti-OX40 antibodies can treat B-cell lymphoma without inducing cytokine release syndrome. Thus, our strategy provides a novel method for engineering T cells into CAR-T cells in vivo and can further be employed to deliver other therapeutic membrane proteins.


Subject(s)
Lymphoma, B-Cell , Receptors, Chimeric Antigen , Humans , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes , Receptors, Chimeric Antigen/genetics , Antigens, CD19
3.
Biomater Sci ; 11(22): 7445-7457, 2023 Nov 07.
Article in English | MEDLINE | ID: mdl-37819252

ABSTRACT

The topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin (SN38), has demonstrated potent anticancer activity. However, its clinical application is hindered by its low solubility and high crystallization propensity, which further complicates its encapsulation into nanoparticles for systemic delivery. Herein, we explore the utilization of lipid-assisted poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) nanoparticles to achieve ultrahigh loading capability for SN38. Through the introduction of cationic, anionic, or neutral lipids, the SN38 loading efficiency and loading capacity is elevated to >90% and >10% respectively. These lipids efficiently attenuate the intermolecular π-π stacking of SN38, thereby disrupting its crystalline structure. Moreover, we assess the therapeutic activity of SN38-loaded formulations in various tumor models and identify an anionic lipid 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) sodium salt (DOPG)-assisted formulation that exhibits the highest anticancer activity and has favorable biosafety. Overall, our findings present a simple and robust strategy to achieve ultrahigh loading efficiency of SN38 using commonly employed PEG-b-PLA nanoparticles, opening up a new avenue for the systemic delivery of SN38.


Subject(s)
Nanoparticles , Neoplasms , Humans , Polyethylene Glycols/chemistry , Nanoparticles/chemistry , Fatty Alcohols , Polyesters , Cell Line, Tumor
4.
Med Rev (2021) ; 3(2): 152-179, 2023 Apr.
Article in English | MEDLINE | ID: mdl-37724086

ABSTRACT

Immune cells are indispensable defenders of the human body, clearing exogenous pathogens and toxicities or endogenous malignant and aging cells. Immune cell dysfunction can cause an inability to recognize, react, and remove these hazards, resulting in cancers, inflammatory diseases, autoimmune diseases, and infections. Immune cells regulation has shown great promise in treating disease, and immune agonists are usually used to treat cancers and infections caused by immune suppression. In contrast, immunosuppressants are used to treat inflammatory and autoimmune diseases. However, the key to maintaining health is to restore balance to the immune system, as excessive activation or inhibition of immune cells is a common complication of immunotherapy. Nanoparticles are efficient drug delivery systems widely used to deliver small molecule inhibitors, nucleic acid, and proteins. Using nanoparticles for the targeted delivery of drugs to immune cells provides opportunities to regulate immune cell function. In this review, we summarize the current progress of nanoparticle-based strategies for regulating immune function and discuss the prospects of future nanoparticle design to improve immunotherapy.

5.
Nat Commun ; 14(1): 1993, 2023 04 08.
Article in English | MEDLINE | ID: mdl-37031188

ABSTRACT

PD-1/PD-L1 blockade therapy that eliminates T-cell inhibition signals is successful, but poor benefits are often observed. Increasing T-cell infiltration and quantity of PD-1/PD-L1 inhibitors in tumor can improve efficacy but remains challenging. Here, we devise tumor-specific gene nanomedicines to mobilize tumor cells to secrete CXCL9 (T-cell chemokine) and anti-PD-L1 scFv (αPD-L1, PD-L1 blocking agent) for enhanced immunotherapy. The tyrosinase promoter-driven NPTyr-C9AP can specifically co-express CXCL9 and αPD-L1 in melanoma cells, thereby forming a CXCL9 gradient for T-cell recruitment and high intratumoral αPD-L1 concentration for enhancing T-cell activation. As a result, NPTyr-C9AP shows strong antimelanoma effects. Moreover, specific co-expression of CXCL9 and αPD-L1 in various tumor cells is achieved by replacing the tyrosinase promoter of NPTyr-C9AP with a survivin promoter, which increases T-cell infiltration and activation and therapeutic efficacy in multiple tumors in female mice. This study provides a strategy to maximize the immunotherapeutic outcome regardless of the heterogeneous tumor microenvironment.


Subject(s)
Neoplasms , T-Lymphocytes , Female , Mice , Animals , Programmed Cell Death 1 Receptor , Monophenol Monooxygenase , Nanomedicine , Immunotherapy , B7-H1 Antigen/genetics , Tumor Microenvironment , Cell Line, Tumor
6.
Pharm Res ; 40(1): 145-156, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36002611

ABSTRACT

PURPOSE: Hepatitis B virus (HBV) infection is such a global health problem that hundreds of millions of people are HBV carriers. Current anti-viral agents can inhibit HBV replication, but can hardly eradicate HBV. Cytosine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODNs) are an adjuvant that can activate plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs) to induce therapeutic immunity for HBV eradication. However, efficient delivery of CpG ODNs into pDCs and cDCs remains a challenge. In this study, we constructed a series of cationic lipid-assisted nanoparticles (CLANs) using different cationic lipids to screen an optimal nanoparticle for delivering CpG ODNs into pDCs and cDCs. METHODS: We constructed different CLANCpG using six cationic lipids and analyzed the cellular uptake of different CLANCpG by pDCs and cDCs in vitro and in vivo, and further analyzed the efficiency of different CLANCpG for activating pDCs and cDCs in both wild type mice and HBV-carrier mice. RESULTS: We found that CLAN fabricated with 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP) showed the highest efficiency for delivering CpG ODNs into pDCs and cDCs, resulting in strong therapeutic immunity in HBV-carrier mice. By using CLANCpG as an immune adjuvant in combination with the injection of recombinant hepatitis B surface antigen (rHBsAg), HBV was successfully eradicated and the chronic liver inflammation in HBV-carrier mice was reduced. CONCLUSION: We screened an optimized CLAN fabricated with DOTAP for efficient delivery of CpG ODNs to pDCs and cDCs, which can act as a therapeutic vaccine adjuvant for treating HBV infection.


Subject(s)
Hepatitis B , Nanoparticles , Mice , Animals , Hepatitis B virus , Oligodeoxyribonucleotides/pharmacology , Phosphates , Cytosine , Guanosine , Hepatitis B/drug therapy , Fatty Acids, Monounsaturated , Adjuvants, Immunologic/therapeutic use , Dendritic Cells
7.
Mol Ther Nucleic Acids ; 30: 270-271, 2022 Dec 13.
Article in English | MEDLINE | ID: mdl-36320321
8.
ACS Nano ; 16(9): 15226-15236, 2022 09 27.
Article in English | MEDLINE | ID: mdl-36018240

ABSTRACT

In situ cancer vaccines consisting of antigens and adjuvants are a promising cancer treatment modality; however, the convenient manufacture of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remains a major challenge. Herein, we outline a facile approach to simultaneously achieve the in situ programming of vaccines via two synergetic nanomedicines, Tu-NPFN and Ln-NPR848. Tu-NPFN (∼100 nm) generated a large number of antigens under an alternating magnetic field, and Ln-NPR848 (∼35 nm) encapsulating adjuvant R848 captured a portion of generated antigens for the manufacture of nanovaccines in situ and LN-targeted delivery, which significantly promoted the uptake and maturation of dendritic cells to initiate potent anticancer immune responses. Notably, combined with an anti-CTLA4 antibody (aCTLA-4), this therapy completely eradicated distant tumors in some mice and exerted a long-term immune memory effect on tumor metastasis. This study provides a generalizable strategy for in situ cancer vaccination.


Subject(s)
Cancer Vaccines , Neoplasms , Adjuvants, Immunologic , Animals , Antigens , Immunotherapy , Lymph Nodes , Mice , Neoplasms/pathology
9.
ACS Nano ; 16(9): 13821-13833, 2022 09 27.
Article in English | MEDLINE | ID: mdl-35993350

ABSTRACT

To address the low response rate to immune checkpoint blockade (ICB) therapy, we propose a specific promoter-driven CRISPR/Cas9 system, F-PC/pHCP, that achieves permanent genomic disruption of PD-L1 and elicits a multifaceted anticancer immune response to potentiate immunotherapy. This system consists of a chlorin e6-encapsulated fluorinated dendrimer and HSP70-promoter-driven CRISPR/Cas9. F-PC/pHCP under 660 nm laser activated the HSP70 promoter and enabled the specific expression of the Cas9 protein to disrupt the PD-L1 gene, preventing immune escape. Moreover, F-PC/pHCP also induced immunogenic cell death (ICD) of tumor cells and reprogrammed the immunosuppressive tumor microenvironment. Overall, this specific promoter-driven CRISPR/Cas9 system showed great anticancer efficacy and, more importantly, stimulated an immune memory response to inhibit distant tumor growth and lung metastasis. This CRISPR/Cas9 system represents an alternative strategy for ICB therapy as well as enhanced cancer immunotherapy.


Subject(s)
B7-H1 Antigen , Dendrimers , B7-H1 Antigen/genetics , CRISPR-Associated Protein 9/genetics , CRISPR-Cas Systems/genetics , Cell Line, Tumor , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Immunity , Immunologic Factors , Immunotherapy , Reactive Oxygen Species/metabolism , Tumor Microenvironment/genetics
10.
J Control Release ; 345: 494-511, 2022 05.
Article in English | MEDLINE | ID: mdl-35337940

ABSTRACT

Abnormal immune cell functions are commonly related to various diseases, including cancer, autoimmune diseases, and infectious diseases. Messenger RNA (mRNA)-based therapy can regulate the functions of immune cells or assign new functions to immune cells, thereby generating therapeutic immune responses to treat these diseases. However, mRNA is unstable in physiological environments and can hardly enter the cytoplasm of target cells; thus, effective mRNA delivery systems are critical for developing mRNA therapy. The two mRNA vaccines of Pfizer-BioNTech and Moderna have demonstrated that lipid nanoparticles (LNPs) can deliver mRNA into dendritic cells (DCs) to induce immunization against severe acute respiratory syndrome coronavirus 2, which opened the floodgates to the development of mRNA therapy. Apart from DCs, other immune cells are promising targets for mRNA therapy. This review summarized the barriers to mRNA delivery and advances in mRNA delivery for regulating the functions of different immune cells.


Subject(s)
COVID-19 , Nanoparticles , COVID-19/therapy , COVID-19 Vaccines , Humans , Liposomes , RNA, Messenger/genetics , SARS-CoV-2/genetics
11.
ACS Appl Mater Interfaces ; 13(25): 29424-29438, 2021 Jun 30.
Article in English | MEDLINE | ID: mdl-34129318

ABSTRACT

Efficient capture and presentation of tumor antigens by antigen-presenting cells (APCs), especially dendritic cells (DCs), are crucial for activating the anti-tumor immunity. However, APCs are immunosuppressed in the tumor microenvironment, which hinders the tumor elimination. To reprogram APCs for inducing strong anti-tumor immunity, we report here a co-delivery immunotherapeutic strategy targeting the phagocytosis checkpoint (signal regulatory protein α, SIRPα) and stimulator of interferon genes (STING) of APCs to jointly enhance their ability of capturing and presenting tumor antigens. In brief, a small interfering RNA targeting SIRPα (siSIRPα) and a STING agonist (cGAMP) were co-delivered into APCs by the encapsulation into poly(ethylene glycol)-b-poly(lactide-co-glycolide)-based polymeric nanoparticles (NPsiSIRPα/cGAMP). siSIRPα-mediated SIRPα silence promoted APCs to actively capture tumor antigens by engulfing tumor cells. The cGAMP-stimulated STING signaling pathway further enhanced the functions of APCs, thereby increased the activation and expansion of CD8+ T cells. Using ovalbumin (OVA)-expressing melanoma as a model, we demonstrated that NPsiSIRPα/cGAMP stimulated the activation of OVA-specific CD8+ T cells and induced holistic anti-tumor immune responses by reversing the immunosuppressive phenotype of APCs. Collectively, this co-delivery strategy synergistically enhanced the functions of APCs and can be extended to the treatment of tumors with poor immunogenicity.


Subject(s)
Antineoplastic Agents , Immunotherapy/methods , Membrane Proteins , Receptors, Immunologic/metabolism , Animals , Antigens, Neoplasm/metabolism , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cells, Cultured , Male , Membrane Proteins/agonists , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Neoplasms, Experimental , Nucleotides, Cyclic , Phagocytosis/drug effects , Signal Transduction/drug effects
12.
Adv Healthc Mater ; 10(11): e2002139, 2021 06.
Article in English | MEDLINE | ID: mdl-33870637

ABSTRACT

Considerable breakthroughs in the treatment of malignant tumors using antibody drugs, especially immunomodulating monoclonal antibodies (mAbs), have been made in the past decade. Despite technological advancements in antibody design and manufacture, multiple challenges face antibody-mediated cancer therapy, such as instability in vivo, poor tumor penetration, limited response rate, and undesirable off-target cytotoxicity. In recent years, an increasing number of biomaterials-based delivery systems have been reported to enhance the antitumor efficacy of antibody drugs. This review summarizes the advances and breakthroughs in integrating biomaterials with therapeutic antibodies for enhanced cancer therapy. A brief introduction to the principal mechanism of antibody-based cancer therapy is first established, and then various antibody immobilization strategies are provided. Finally, the current state-of-the-art in biomaterials-based antibody delivery systems and their applications in cancer treatment are summarized, highlighting how the delivery systems augment the therapeutic efficacy of antibody drugs. The outlook and perspective on biomaterials-based delivery of antitumor antibodies are also discussed.


Subject(s)
Antineoplastic Agents, Immunological , Neoplasms , Antibodies, Monoclonal/therapeutic use , Biocompatible Materials/therapeutic use , Humans , Immunotherapy , Neoplasms/drug therapy
13.
Nat Commun ; 12(1): 1359, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33649336

ABSTRACT

Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.


Subject(s)
Antibodies, Monoclonal/metabolism , Immunomodulation , Immunotherapy , Nanoparticles/chemistry , Neoplasms/immunology , Neoplasms/therapy , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cytotoxicity, Immunologic , Female , Immobilized Proteins/metabolism , Immunity , Killer Cells, Natural/immunology , Male , Mice, Inbred C57BL , Nanoparticles/ultrastructure , T-Lymphocytes/immunology
14.
Adv Drug Deliv Rev ; 168: 3-29, 2021 01.
Article in English | MEDLINE | ID: mdl-31759123

ABSTRACT

The CRISPR-Cas system initiated a revolution in genome editing when it was, for the first time, demonstrated success in the mammalian cells. Today, scientists are able to readily edit genomes, regulate gene transcription, engineer posttranscriptional events, and image nucleic acids using CRISPR-Cas-based tools. However, to efficiently transport CRISPR-Cas into target tissues/cells remains challenging due to many extra- and intra-cellular barriers, therefore largely limiting the applications of CRISPR-based therapeutics in vivo. In this review, we summarize the features of plasmid-, RNA- and ribonucleoprotein (RNP)-based CRISPR-Cas therapeutics. Then, we survey the current in vivo delivery systems. We specify the requirements for efficient in vivo delivery in clinical settings, and highlight both efficiency and safety for different CRISPR-Cas tools.


Subject(s)
CRISPR-Cas Systems/genetics , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Gene Editing/methods , Drug Delivery Systems , Epigenome/genetics , Exosomes/metabolism , Gene Regulatory Networks/physiology , Genetic Vectors/metabolism , Lipids/chemistry , Nanoparticles/chemistry , RNA/metabolism , Transcription, Genetic/physiology
15.
ACS Appl Mater Interfaces ; 12(43): 48259-48271, 2020 Oct 28.
Article in English | MEDLINE | ID: mdl-33070614

ABSTRACT

Nanotechnology has shown great promise in treating diverse diseases. However, developing nanomedicines that can cure autoimmune diseases without causing systemic immunosuppression is still quite challenging. Herein, we propose an all-in-one nanomedicine comprising an autoantigen peptide and CRISPR-Cas9 to restore specific immune tolerance by engineering dendritic cells (DCs) into a tolerogenic phenotype, which can expand autoantigen-specific regulatory T (Treg) cells. In brief, we utilized cationic lipid-assisted poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles to simultaneously encapsulate an autoimmune diabetes-relevant peptide (2.5mi), a CRISPR-Cas9 plasmid (pCas9), and three guide RNAs (gRNAs) targeting costimulatory molecules (CD80, CD86, and CD40). We demonstrated that the all-in-one nanomedicine was able to effectively codeliver these components into DCs, followed by simultaneous disruption of the three costimulatory molecules and presentation of the 2.5mi peptide on the genome-edited DCs. The resulting tolerogenic DCs triggered the generation and expansion of autoantigen-specific Treg cells by presenting the 2.5mi peptide to CD4+ T cells in the absence of costimulatory signals. Using autoimmune type 1 diabetes (T1D) as a typical disease model, we demonstrated that our nanomedicine prevented autoimmunity to islet components and inhibited T1D development. Our all-in-one nanomedicine achieved codelivery of CRISPR-Cas9 and the peptide to DCs and could be easily applied to other autoimmune diseases by substitution of different autoantigen peptides.


Subject(s)
Autoantigens/immunology , CRISPR-Cas Systems/immunology , Nanomedicine , Peptides/immunology , Animals , Cell Engineering , Cells, Cultured , Dendritic Cells , Humans , Immune Tolerance , Mice , Mice, Inbred NOD , Particle Size , Surface Properties
16.
Biomater Sci ; 8(23): 6683-6694, 2020 Dec 07.
Article in English | MEDLINE | ID: mdl-33089844

ABSTRACT

Studies have shown that the simultaneous regulation of tumor cell proliferation and the suppressive tumor immune microenvironment (TIME) could achieve better therapeutic effects. However, the targets of the proliferation and the TIME are different, which greatly limits the development of cancer therapy. A recent study found CD155, a highly expressed poliovirus receptor in melanoma cells and melanoma-infiltrating macrophages, functions as both an oncogene and immune checkpoint. Thus, it is supposed that targeting CD155 could bring dual therapeutic effects. Herein, we propose silencing the CD155 of melanoma cells and melanoma-infiltrating macrophages by a nanoparticle-delivered small interference RNA (siRNA) targeting CD155 (siCD155). We encapsulated siCD155 into cationic lipid-assisted nanoparticles (CLANsiCD155) and demonstrated that the intravenous injection of CLANsiCD155 could efficiently deliver siCD155 into melanoma cells and melanoma-infiltrating macrophages. The downregulation of CD155 in melanoma cells directly inhibited their proliferation, and meanwhile, the downregulation of CD155 in melanoma-infiltrating macrophages increased the activation of NK cells and T cells. Owing to this dual effect, CLANsiCD155 significantly inhibited the growth of B16-F10 melanoma. Our study suggests that nanoparticle-delivered siCD155 may be a simple but effective strategy for inhibiting tumor proliferation and reprogramming TIME.


Subject(s)
Melanoma , Nanoparticles , RNA, Small Interfering , Receptors, Virus , Skin Neoplasms , Animals , Cell Proliferation , Melanoma/therapy , RNA, Small Interfering/genetics , Skin Neoplasms/therapy , Tumor Microenvironment
18.
Angew Chem Int Ed Engl ; 59(18): 7168-7172, 2020 04 27.
Article in English | MEDLINE | ID: mdl-32003112

ABSTRACT

Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH-responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor-specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Polymers/pharmacology , Prodrugs/pharmacology , Tetrazoles/pharmacology , Theranostic Nanomedicine , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/diagnostic imaging , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Click Chemistry , Drug Screening Assays, Antitumor , Female , Hydrogen-Ion Concentration , Mammary Neoplasms, Experimental/diagnostic imaging , Mammary Neoplasms, Experimental/drug therapy , Mice , Mice, Inbred BALB C , Mice, Nude , Micelles , Molecular Structure , Nanoparticles/chemistry , Optical Imaging , Polymers/chemical synthesis , Polymers/chemistry , Prodrugs/chemical synthesis , Prodrugs/chemistry , Tetrazoles/chemistry , Tumor Microenvironment/drug effects
19.
Biomater Sci ; 7(11): 4698-4707, 2019 Nov 01.
Article in English | MEDLINE | ID: mdl-31495833

ABSTRACT

Rheumatoid arthritis (RA) is a systemic autoimmune disease that can cause irreversible joint deformity. There is still no cure for RA, and current therapeutics, including methotrexate and adalimumab, cause serious off-target effects and systemic immunosuppression, which in turn increases the risk of infection. Bruton's tyrosine kinase (BTK) in macrophages and B cells has been demonstrated to be a promising therapeutic target for RA. However, high doses of BTK inhibitors are required for efficient BTK suppression, which limits their clinical use. Small interfering RNA (siRNA) is promising for the silencing of specific genes and has been used for the treatment of multiple diseases. To deliver siRNA into macrophages and B cells for BTK gene silencing, we employed cationic lipid-assisted PEG-b-PLGA nanoparticles (CLANs) to encapsulate siRNA. We demonstrated that macrophages and B cells were able to efficiently ingest the CLANs both in vitro and in vivo. Thereafter, we encapsulated siRNA targeting BTK (siBTK) into the CLANs, denoted as CLANsiBTK, and demonstrated that CLANsiBTK significantly inhibited BTK expression in macrophages and B cells. In a collagen-induced mouse arthritis model, CLANsiBTK treatment dramatically reduced joint inflammation and other RA symptoms but showed no toxicity, proving that using CLANsiBTK is a promising approach for RA therapy.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , Arthritis, Rheumatoid/drug therapy , Nanoparticles/chemistry , Protein Kinase Inhibitors/pharmacology , RNA, Small Interfering/pharmacology , Animals , Arthritis, Rheumatoid/metabolism , Mice
20.
ACS Nano ; 13(8): 8648-8658, 2019 08 27.
Article in English | MEDLINE | ID: mdl-31328920

ABSTRACT

Lymph nodes (LNs) are normally the primary site of tumor metastasis, and effective delivery of chemotherapeutics into LNs through systemic administration is critical for metastatic cancer treatment. Here, we uncovered that improved perfusion in a primary tumor facilitates nanoparticle translocation to LNs for inhibiting tumor metastasis. On the basis of our finding that an iCluster platform, which undergoes size reduction from ∼100 nm to ∼5 nm at the tumor site, markedly improved particle perfusion in the interstitium of the primary tumor, we further revealed in the current study that such tumor-specific size transition promoted particle intravasation into tumor lymphatics and migration into LNs. Quantitative analysis indicated that the drug deposition in LNs after iCluster treatment was significantly higher in the presence of a primary tumor in comparison with that after primary tumor resection. Early intervention of metastatic 4T1 tumors with iCluster chemotherapy and subsequent surgical resection of the primary tumor resulted in significantly extending animal survival, with 4 out of the 10 mice remaining completely tumor-free for 110 days. Additionally, in the more clinical relevant late metastatic model, iCluster inhibited the metastatic colonies to the lungs and extended animal survival time. This finding provides insights into the design of more effective nanomedicines for treating metastatic cancer.


Subject(s)
Lymphatic Metastasis/therapy , Nanoparticles/therapeutic use , Neoplasms/therapy , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Heterografts , Humans , Lymphatic Metastasis/pathology , Mice , Neoplasm Invasiveness/pathology , Neoplasms/pathology
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