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1.
Nano Lett ; 24(33): 10114-10123, 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39109634

RESUMEN

Personalized cancer vaccines targeting specific neoantigens have been envisioned as one of the most promising approaches in cancer immunotherapy. However, the physicochemical variability of the identified neoantigens limits their efficacy as well as vaccine manufacturing in a uniform format. Herein, we developed a uniform nanovaccine platform based on poly(2-oxazoline)s (POx) to chemically conjugate neoantigen peptides, regardless of their physicochemical properties. This vaccine system could self-assemble into nanoparticles with uniform size (around 50 nm) and improve antigen accumulation as well as infiltration in the lymph node to increase antigen presentation. In vivo vaccination using this system conjugated with three predicted peptide neoantigen peptides from the MC38 tumor cell line induced 100% robust CD8+ T cell responses and superior tumor clearance compared to free peptides. This POx-based vaccine carrier represents a generalizable approach to increase the availability and efficacy of screened neoantigen peptides for a personalized cancer vaccine.


Asunto(s)
Antígenos de Neoplasias , Vacunas contra el Cáncer , Nanopartículas , Péptidos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/química , Péptidos/química , Péptidos/inmunología , Animales , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/química , Ratones , Nanopartículas/química , Humanos , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Oxazoles/química , Polímeros/química , Inmunoterapia/métodos , Nanovacunas
2.
Nano Lett ; 21(16): 6781-6791, 2021 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-34382807

RESUMEN

Gut bacteria and their metabolites influence the immune microenvironment of liver through the gut-liver axis, thus representing emerging therapeutic targets for liver cancer therapy. However, directly manipulating gut microbiota or their metabolites is not practical in clinic since the safety concerns and the complicated mechanism of action. Considering the dysregulated bile acid profiles associated with liver cancer, here we propose a strategy that directly manipulates the primary and secondary bile acid receptors through nanoapproach as an alternative and more precise way for liver cancer therapy. We show that nanodelivery of bile acid receptor modulators elicited robust antitumor immune responses and significantly changed the immune microenvironment in the murine hepatic tumor. In addition, ex vivo stimulation on both murine and patient hepatic tumor tissues suggests the observation here may be meaningful for clinical practice. This study elucidates a novel and precise strategy for liver cancer immunotherapy.


Asunto(s)
Microbioma Gastrointestinal , Neoplasias Hepáticas , Animales , Ácidos y Sales Biliares , Humanos , Inmunoterapia , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Microambiente Tumoral
3.
Nano Lett ; 20(4): 2514-2521, 2020 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-32109068

RESUMEN

The crosstalk between tumor and stroma cells is a central scenario in the tumor microenvironment (TME). While the predominant effect of tumor cells on immune cells is establishing an immunosuppressive context, tumor cell death at certain conditions will boost antitumor immunity. Herein, we report a rationally designed tumor specific enhanced oxidative stress polymer conjugate (TSEOP) for boosting antitumor immunity. The TSEOP is prepared by Passerini reaction between cinnamaldehyde (CA), 4-formylbenzeneboronic acid pinacol ester, and 5-isocyanopent-1-yne, followed by azide-alkyne click reaction with poly(l-glutamic acid)-graft-poly(ethylene glycol) monomethyl ether (PLG-g-mPEG). Under tumor stimuli condition, CA and quinone methide (QM) are quickly generated, which cooperatively induce strong oxidative stress, immunogenic tumor cell death (ICD), and activation of antigen presenting cells. In vivo studies show that the TSEOP treatment boosts tumor-specific antitumor immunity and eradicates both murine colorectal and breast tumors. This study should be inspirational for designing polymers as immunotherapeutics in cancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Inmunidad/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Polímeros/farmacología , Acroleína/análogos & derivados , Acroleína/química , Acroleína/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Inmunoterapia , Ratones , Neoplasias/inmunología , Neoplasias/metabolismo , Polietilenglicoles/química , Polietilenglicoles/farmacología , Ácido Poliglutámico/análogos & derivados , Ácido Poliglutámico/farmacología , Polímeros/química , Microambiente Tumoral/efectos de los fármacos
4.
Small ; 15(9): e1805182, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30690891

RESUMEN

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, no targeted treatment is available for TNBC, and the most common clinical therapy is tumor resection, which often promotes metastasis risks. Strong evidence suggests that the lymphatic metastasis is mediated by the C-C chemokine receptor type 7 (CCR7)/C-C motif chemokine ligand 21 crosstalk between tumor cells and the lymphatic system. It is hypothesized that CCR7 is a key immune modulator in the tumor microenvironment and the local blockade of CCR7 could effectively inhibit TNBC lymphatic metastasis. Accordingly, a plasmid encoding an antagonistic CCR7 affinity protein-CCR7 trap is delivered by tumor targeting nanoparticles in a highly metastatic 4T1 TNBC mouse model. Results show that CCR7 traps are transiently expressed, locally disrupt the signaling pathways in the tumor site, and efficiently inhibit TNBC lymphatic metastasis, without inducing immunosuppression as observed in systemic therapies using CCR7 monoclonal antibody. Significantly, upon applying CCR7 trap therapy prior to tumor resection, a 4T1 TNBC mouse model shows good prognosis without any further metastasis and relapse. In addition, CCR7 trap therapy efficiently inhibits the lymphatic metastasis in a B16F10 melanoma mouse model, indicating its great potential for various metastatic diseases treatment.


Asunto(s)
Nanopartículas/química , Receptores CCR7/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Línea Celular Tumoral , Femenino , Humanos , Metástasis Linfática/genética , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores CCR7/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología
5.
Small ; 13(12)2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28079981

RESUMEN

Nanomedicine (NM) cannot penetrate deeply into solid tumors, which is partly attributed to the heterogeneous microenvironment and high interstitial fluid pressure of solid tumors. To improve NM efficacy, there has been tremendous effort developing tumor-penetrating NMs by miniaturizing NM sizes or controlling NM surface properties. But progress along the direction of developing tumor penetrating nanoparticle has been slow and improvement of the overall antitumor efficacy has been limited. Herein, a novel strategy of inhibiting solid tumor with high efficiency by dual-functional, nontumor-penetrating NM is demonstrated. The intended NM contains 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular-disrupting agent, and doxorubicin (DOX), a cytotoxic drug. Upon arriving at the target tumor site, sustained release of DMXAA from NMs results in disruption of tumor vessel functions, greatly inhibiting the interior tumor cells by cutting off nutritional supply. Meanwhile, the released DOX kills the residual cells at the tumor exterior regions. The in vivo studies demonstrate that this dual-functional, nontumor penetrating NM exhibits superior anticancer activity, revealing an alternative strategy of effective tumor growth inhibition.


Asunto(s)
Nanomedicina , Neoplasias/patología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Dispersión Dinámica de Luz , Femenino , Humanos , Hidrodinámica , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células 3T3 NIH , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Polímeros/síntesis química , Polímeros/química , Distribución Tisular/efectos de los fármacos
6.
Nanomedicine ; 12(2): 377-86, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26711966

RESUMEN

Disulfiram (DSF) showed great potential in an in vitro tumor therapy study; however, those results could not be applied to an in vivo study due to the extreme instability of DSF in blood. Here, we describe a system of methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide)/poly(ε-caprolactone) (mPEG-PLGA/PCL) mixed nanoparticles (NPs) for DSF loading and delivery. By adjusting the mPEG-PLGA/PCL content ratios, the DSF loading capacity increased to 7.8%, while the hydrodynamic radii of the NPs were around 50-100nm. The DSF-loaded NPs showed high stability in distilled water and 10% serum-containing phosphate buffered saline. The NPs efficiently protected DSF from degradation while maintaining its anti-tumor properties. Furthermore, a pharmacokinetics study demonstrated that NP delivery system enhanced the DSF concentration in the blood after tail vein injection. Finally, DSF delivery using this model effectively slowed the growth of a 4T1 murine xenograft tumor. FROM THE CLINICAL EDITOR: The anti-tumor efficacy of the anti-alcoholic drug disulfiram has been known for some time. However, its use in the clinical setting is limited due to the underlying instability of the drug. In this study, the authors utilized a nanocarrier system of mPEG-PLGA/PCL for the delivery of this drug. The promising results may allow encapsulation of other drugs.


Asunto(s)
Disuasivos de Alcohol/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Disulfiram/uso terapéutico , Portadores de Fármacos/química , Nanopartículas/química , Poliésteres/química , Polietilenglicoles/química , Inhibidores del Acetaldehído Deshidrogenasa/administración & dosificación , Inhibidores del Acetaldehído Deshidrogenasa/sangre , Inhibidores del Acetaldehído Deshidrogenasa/uso terapéutico , Disuasivos de Alcohol/administración & dosificación , Disuasivos de Alcohol/sangre , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Mama/efectos de los fármacos , Mama/patología , Neoplasias de la Mama/patología , Disulfiram/administración & dosificación , Disulfiram/sangre , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Ratas Sprague-Dawley
7.
Small ; 11(31): 3755-61, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25919954

RESUMEN

A strategy for enhancing the treatment efficacy of nanomedicines within the central region of solid tumors is developed by combining nanomedicines and free small-molecule vascular disrupting agents (VDAs). The nanomedicines (cis-diamminedichloroplatinum-loaded nanoparticles) primarily target cells at the tumor periphery whereas the free small-molecule VDA (combretastatin A4 disodium phosphate) efficiently kills the cancer cells within the central regions of the tumor.


Asunto(s)
Inhibidores de la Angiogénesis/química , Nanomedicina/métodos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Acústica , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Antineoplásicos/química , Línea Celular Tumoral , Cisplatino/química , Quimioterapia Combinada , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/administración & dosificación , Estilbenos/química
8.
Mol Pharm ; 11(5): 1562-74, 2014 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-24606535

RESUMEN

A tumor-acidity-activated charge-conversional polyionic complex nanoparticle system was developed by simply mixing a pair of oppositely charged block copolymers: anionic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine) (mPEG-b-P(Glu-co-Phe)) and cationic methoxy poly(ethy1ene glycol)-b-poly(l-lysine-co-l-phenylalanine) (mPEG-b-P(Lys-co-Phe)). The nanoparticles could stay negatively charged under normal physiological pH value and reverse the surface charge to positive at the tumor extracellular environment. Doxorubicin (DOX) was encapsulated into the nanoparticles fabricated by a self-assembly process, and the DOX-loaded polyionic complex nanoparticles (DOX-NPs) retained the charge-conversional property. In vitro DOX release study demonstrated that DOX release was promoted by the significantly increased acidity in endosomes and lysosomes (pH ≈ 5-6). Cellular uptake studies confirmed that the DOX-NPs could be more effectively internalized by cells at the tumor extracellular pH value. In vitro cytotoxicity assays demonstrated that the polyionic complex nanoparticles had good biocompatibility, and DOX-NPs showed efficient cell proliferation inhibition to HeLa and A549 tumor cells. Maximum tolerated dose (MTD) studies revealed that DOX-NPs had a significantly higher MTD (more than 25 mg of DOX/kg) in mice compared to that for free DOX (5 mg of DOX/kg). Furthermore, DOX-NPs showed superior antitumor activity and reduced side toxicity compared to free DOX in A549 tumor bearing nude mice.


Asunto(s)
Antineoplásicos/química , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Péptidos/química , Polietilenglicoles/química , Polímeros/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Células HeLa , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Adv Drug Deliv Rev ; 211: 115345, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38834140

RESUMEN

Emerging evidence reveal that tumor-associated bacteria (TAB) can facilitate the initiation and progression of multiple types of cancer. Recent work has emphasized the significant role of intestinal microbiota, particularly bacteria, plays in affecting responses to chemo- and immuno-therapies. Hence, it seems feasible to improve cancer treatment outcomes by targeting intestinal bacteria. While considering variable richness of the intestinal microbiota and diverse components among individuals, direct manipulating the gut microbiota is complicated in clinic. Tumor initiation and progression requires the gut microbiota-derived metabolites to contact and reprogram neoplastic cells. Hence, directly targeting tumor-associated bacteria metabolites may have the potential to provide alternative and innovative strategies to bypass the gut microbiota for cancer therapy. As such, there are great opportunities to explore holistic approaches that incorporates TAB-derived metabolites and related metabolic signals modulation for cancer therapy. In this review, we will focus on key opportunistic areas by targeting TAB-derived metabolites and related metabolic signals, but not bacteria itself, for cancer treatment, and elucidate future challenges that need to be addressed in this emerging field.


Asunto(s)
Microbioma Gastrointestinal , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/microbiología , Microbioma Gastrointestinal/fisiología , Animales , Bacterias/metabolismo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología
10.
Biomater Sci ; 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39225616

RESUMEN

Virus-like nanoparticle vaccines can efficiently activate the humoral immune response by cross-linking B cell receptors with their surface multivalent antigen arrays. This structurally dependent mechanism makes it crucial to regulate and optimize structural parameters to enhance the efficacy of nanoparticle vaccines. In this study, we prepared nanoparticle vaccines with different aspect ratios by chemically modifying antigen proteins onto the surfaces of poly(amino acid) nanoparticles of various shapes (spherical, ellipsoidal, and rod-like). This allowed us to investigate the impact of structural anisotropy on the humoral immune activation efficacy of nanoparticle vaccines. Furthermore, the end-group molecules of poly(amino acid) materials possess aggregation-induced emission (AIE) properties, which facilitate monitoring the dynamics of nano-assemblies within the body. Results showed that rod-like nanoparticle vaccines (RLNVax) with a higher aspect ratio (AR = 5) exhibited greater lymph node draining efficiency and could elicit more effective B cell activation compared to conventional isotropic spherical nanoparticle vaccines. In a murine subcutaneous immunization model using ovalbumin (OVA) as a model antigen, RLNVax elicited antigen-specific antibody titers that were about 64 times and 4.6 times higher than those induced by free antigen proteins and spherical nanoparticle vaccines, respectively. Additionally, when combined with an aluminum adjuvant, antibody titers elicited by RLNVax were further enhanced by 4-fold. These findings indicate that the anisotropic rod-like structure is advantageous for improving the humoral immune activation efficacy of nanoparticle vaccines, providing significant insights for the design and optimization of next-generation nanoparticle vaccines.

11.
J Mater Chem B ; 12(24): 5848-5860, 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38775048

RESUMEN

Nanoparticles have been regarded as a promising vaccine adjuvant due to their innate immune potentiation and enhanced antigen transport. However, the inefficient infiltration into the lymph node (LN) paracortex of nanoparticles caused by subcapsular sinus (SCS) obstruction is the main challenge in further improvement of nanovaccine immune efficacy. Herein, we propose to overcome paracortex penetration by using nanovaccine to spontaneously and continuously release antigens after retention in the SCS. In detail, we utilized a spontaneous retro-Diels-Alder (r-D-A) reaction linker to connect poly{(2-methyl-2-oxazoline)80-co-[(2-butyl-2-oxazoline)15-r-(2-thioethyl-2-oxazoline)8]} (PMBOxSH) and peptides for the peptide nanovaccine construction. The r-D-A reaction linker can spontaneously break over time, allowing the nanovaccine to release free antigens and adjuvants upon reaching the LN, thereby facilitating the entry of released antigens and adjuvants into the interior of the LNs. We showed that the efficacy of the peptide nanovaccine constructed using this dynamic linker could be significantly improved, thus greatly enhancing the tumor inhibition efficacy in the B16-OVA model. This dynamic-covalent-chemistry-based vaccine strategy may inspire designing more efficient therapeutic vaccines, especially those that require eliciting high-amount T cell responses.


Asunto(s)
Inmunidad Celular , Ganglios Linfáticos , Nanopartículas , Péptidos , Animales , Ratones , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Nanopartículas/química , Péptidos/química , Péptidos/farmacología , Inmunidad Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Reacción de Cicloadición , Femenino , Tamaño de la Partícula , Nanovacunas
12.
J Control Release ; 370: 528-542, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38705520

RESUMEN

Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.


Asunto(s)
Aspirina , Neoplasias Colorrectales , Dextranos , Microbioma Gastrointestinal , Homeostasis , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Homeostasis/efectos de los fármacos , Administración Oral , Dextranos/administración & dosificación , Dextranos/química , Nanomedicina , Ratones Endogámicos BALB C , Inflamación/tratamiento farmacológico , Masculino , Ratones , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Nanopartículas/administración & dosificación , Línea Celular Tumoral , Femenino
13.
Adv Sci (Weinh) ; : e2405935, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39116306

RESUMEN

Local immunotherapy represents a promising solution for preventing tumor recurrence and metastasis post tumor surgical resection by eliminating residue tumor cells as well as eliciting tumor-specific immune responses. Minimally invasive surgery has become a mainstream surgical method worldwide due to its advantages of aesthetics and rapid postoperative recovery. Unfortunately, the currently reported local immunotherapy strategies are mostly designed to be used after open laparotomy, which go against the current surgical philosophy of minimally invasive therapy and is not suitable for clinical translation. Aiming at this problem, a minimally invasive injectable gel (MIGel) is herein reported loaded with immunotherapeutic agents for gastric and liver cancer postoperative treatment. The MIGel is formed by crosslinking between oxidized dextran (ODEX) and 4-arm polyethylene glycol hydroxylamine (4-arm PEG-ONH2) through oxime bonds, which can be injected through a clinic-used minimally invasive drainage tube and adhered tightly to the tissue. The loaded oxaliplatin (OxP) and resiquimod (R848) can be released constantly over two weeks and resulted in over 75% cure rate in orthotopic mouse gastric and liver cancer model. Collectively, a concept of minimally invasive local immunotherapy is proposed and MIGel is designed for local intraperitoneal cancer immunotherapy through minimally invasive surgery, with good clinical translation potential.

14.
Natl Sci Rev ; 11(3): nwad310, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38312378

RESUMEN

Virus-like particle (VLP) vaccines had shown great potential during the COVID-19 pandemic, and was thought to be the next generation of antiviral vaccine technology due to viromimetic structures. However, the time-consuming and complicated processes in establishing a current recombinant-protein-based VLP vaccine has limited its quick launch to the out-bursting pandemic. To simplify and optimize VLP vaccine design, we herein report a kind of viromimetic polymer nanoparticle vaccine (VPNVax), with subunit receptor-binding domain (RBD) proteins conjugated to the surface of polyethylene glycol-b-polylactic acid (PEG-b-PLA) nanoparticles for vaccination against SARS-CoV-2. The preparation of VPNVax based on synthetic polymer particle and chemical post-conjugation makes it possible to rapidly replace the antigens and construct matched vaccines at the emergence of different viruses. Using this modular preparation system, we identified that VPNVax with surface protein coverage of 20%-25% had the best immunostimulatory activity, which could keep high levels of specific antibody titers over 5 months and induce virus neutralizing activity when combined with an aluminum adjuvant. Moreover, the polymer nano-vectors could be armed with more immune-adjuvant functions by loading immunostimulant agents or chemical chirality design. This VPNVax platform provides a novel kind of rapidly producing and efficient vaccine against different variants of SARS-CoV-2 as well as other viral pandemics.

15.
ACS Nano ; 18(4): 3087-3100, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38235966

RESUMEN

Breast cancer is the most commonly diagnosed cancer, and surgical resection is the first choice for its treatment. With the development of operation techniques, surgical treatment for breast cancer is evolving toward minimally invasive and breast-conserving approaches. However, breast-conserving surgery is prone to an increased risk of cancer recurrence and is becoming a key challenge that needs to be solved. In this study, we introduce a one-shot injectable nano-in-gel vaccine (NIGel-Vax) for postoperative breast cancer therapy. The NIGel-Vax was constructed by mixing protein antigens with PEI-4BImi-Man adjuvant and then encapsulated in a hydrogel made with oxidized dextran (ODEX) and 4-arm PEG-ONH2. Using 4T1 tumor-extracted proteins as antigen, the NIGel-Vax achieved a 92% tumor suppression rate and a 33% cure rate as a postoperative therapy in the 4T1 tumor model. Using the tumor-associated antigen trophoblast cell-surface antigen 2 (TROP2) protein as the antigen, NIGel-Vax achieved a 96% tumor suppression rate and a 50% cure rate in triple-negative breast cancer (TNBC) models. This design provides an encouraging approach for breast cancer postoperative management.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Vacunas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Nanovacunas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Mastectomía Segmentaria , Hidrogeles/uso terapéutico , Línea Celular Tumoral
16.
Sci Bull (Beijing) ; 69(7): 922-932, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38331707

RESUMEN

Neoantigen cancer vaccines have been envisioned as one of the most promising means for cancer therapies. However, identifying neoantigens for tumor types with low tumor mutation burdens continues to limit the effectiveness of neoantigen vaccines. Herein, we proposed a "hit-and-run" vaccine strategy which primes T cells to attack tumor cells decorated with exogenous "neo-antigens". This vaccine strategy utilizes a peptide nanovaccine to elicit antigen-specific T cell responses after tumor-specific decoration with a nanocarrier containing the same peptide antigens. We demonstrated that a poly(2-oxazoline)s (POx) conjugated with OVA257-264 peptide through a matrix metalloprotease 2 (MMP-2) sensitive linker could efficiently and selectively decorate tumor cells with OVA peptides in vivo. Then, a POx-based nanovaccine containing OVA257-264 peptides to elicit OVA-specific T cell responses was designed. In combination with this hit-and-run vaccine system, an effective vaccine therapy was demonstrated across tumor types even without OVA antigen expression. This approach provides a promising and uniform vaccine strategy against tumors with a low tumor mutation burden.


Asunto(s)
Vacunas contra el Cáncer , Neoplasias , Humanos , Epítopos , Antígenos de Neoplasias , Neoplasias/terapia , Péptidos
17.
Mater Horiz ; 11(11): 2739-2748, 2024 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-38516806

RESUMEN

A qualified delivery system is crucial for the successful application of messenger RNA (mRNA) technology. While lipid nanoparticles (LNPs) are currently the predominant platform for mRNA delivery, they encounter challenges such as high inflammation and difficulties in targeting non-liver tissues. Polymers offer a promising delivery solution, albeit with limitations including low transfection efficiency and potential high toxicity. Herein, we present a poly(L-glutamic acid)-based phosphatidyl polymeric carrier (PLG-PPs) for mRNA delivery that combines the dual advantages of phospholipids and polymers. The PLGs grafted with epoxy groups were firstly modified with different amines and then with alkylated dioxaphospholane oxides, which provided a library of PLG polymers grafted with various phosphatidyl groups. In vitro studies proved that PLG-PPs/mRNA polyplexes exhibited a significant increase in mRNA expression, peaking 14 716 times compared to their non-phosphatidyl parent polymer. Impressively, the subset PA8-PL3 not only facilitated efficient mRNA transfection but also selectively delivered mRNA to the spleen instead of the liver (resulting in 69.73% protein expression in the spleen) once intravenously administered. This type of phosphatidyl PLG polymer library provides a novel approach to the construction of mRNA delivery systems especially for spleen-targeted mRNA therapeutic delivery.


Asunto(s)
ARN Mensajero , Bazo , Bazo/metabolismo , Animales , ARN Mensajero/administración & dosificación , Polímeros/química , Ratones , Humanos , Transfección/métodos , Ácido Poliglutámico/análogos & derivados , Ácido Poliglutámico/química , Nanopartículas , Fosfolípidos/química , Técnicas de Transferencia de Gen
18.
Adv Healthc Mater ; : e2400886, 2024 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-38824421

RESUMEN

Vaccine is the most important way for fighting against infection diseases. However, multiple injections and unsatisfied immune responses are the main obstacles for current vaccine application. Herein, a dynamic covalent hydrogel (DCH) is used as a single-dose vaccine adjuvant for eliciting robust and sustained humoral immunity. By adjusting the mass ratio of the DCH gel, 10-30 d constant release of the loaded recombinant protein antigens is successfully realized, and it is proved that sustained release of antigens can significantly improve the vaccine efficacy. When loading SARS-CoV-2 RBD (Wuhan and Omicron BA.1 strains) antigens into this DCH gel, an over 32 000 times and 8000 times improvement is observed in antigen-specific antibody titers compared to conventional Aluminum adjuvanted vaccines. The universality of this DCH gel adjuvant is confirmed in a Nipah G antigen test as well as a H1N1 influenza virus antigen test, with much improved protection of C57BL/6 mice against H1N1 virus infection than conventional Aluminum adjuvanted vaccines. This sustainably released, single-dose DCH gel adjuvant provides a new promising option for designing next-generation infection vaccines.

19.
Biomater Sci ; 11(8): 2620-2638, 2023 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-36661319

RESUMEN

Sialic acid is a kind of monosaccharide expressed on the non-reducing end of glycoproteins or glycolipids. It acts as a signal molecule combining with its natural receptors such as selectins and siglecs (sialic acid-binding immunoglobulin-like lectins) in intercellular interactions like immunological surveillance and leukocyte infiltration. The last few decades have witnessed the exploration of the roles that sialic acid plays in different physiological and pathological processes and the use of sialic acid-modified materials as therapeutics for related diseases like immune dysregulation and virus infection. In this review, we will briefly introduce the biomedical function of sialic acids in organisms and the utilization of multivalent sialic acid materials for targeted drug delivery as well as therapeutic applications including anti-inflammation and anti-virus.


Asunto(s)
Ácido N-Acetilneuramínico , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Ácidos Siálicos , Glicoproteínas , Leucocitos
20.
ACS Biomater Sci Eng ; 9(7): 4108-4116, 2023 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-35653749

RESUMEN

OX40 (CD134, TNFRSF4) is a member of the tumor necrosis factor receptor superfamily that can be activated by its cognate ligand OX40L (CD252, TNFSF4) and functions as a pair of T cell costimulatory molecules. The interaction between OX40 and OX40L (OX40/OX40L) plays a critical role in regulating antitumor immunity, including promoting effector T cells expansion and survival, blocking natural regulatory T cells (Treg) activity, and antagonizing inducible Treg generation. However, current OX40 agonists including anti-OX40 monoclonal antibodies (aOX40) have serious side effects after systemic administration, which limits their clinical success and application. Herein, we propose a strategy to reprogram tumor cells into OX40L-expressing "artificial" antigen-presenting cells (APCs) by OX40L plasmid-loaded nanoparticles for boosting antitumor immunity in situ. A novel gene transfection carrier was prepared by a modular hierarchical assembly method, which could efficiently transfect various tumor cells and express OX40L proteins on their surface. These surface-decorated OX40L proteins were proved to stimulate T cell proliferation in vitro while stimulating strong antitumor immune responses in vivo. Importantly, this in situ reprogramming strategy did not induce any toxicity as observed in aOX40 treatment, thus providing a novel method for immune checkpoint stimulator application.


Asunto(s)
Neoplasias , Ligando OX40 , Humanos , Ligando OX40/genética , Ligando OX40/metabolismo , Linfocitos T Reguladores/metabolismo , Activación de Linfocitos , Neoplasias/tratamiento farmacológico
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