RESUMEN
Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG8-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) in situ for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.
Asunto(s)
Inhibidores de la Angiogénesis , Neovascularización Patológica , Neuropilina-1 , Fotoquimioterapia , Neuropilina-1/metabolismo , Humanos , Animales , Ratones , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/química , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Femenino , Axitinib/farmacología , Axitinib/química , Axitinib/uso terapéutico , Nanomedicina , Apoptosis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Ratones Endogámicos BALB C , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Ratones DesnudosRESUMEN
Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.
Asunto(s)
Neoplasias de la Mama , Fibroblastos Asociados al Cáncer , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Matriz Extracelular/metabolismo , Inmunoterapia , Fibrosis , Microambiente TumoralRESUMEN
Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.
Asunto(s)
Ciclooxigenasa 2 , Péptidos , Fotoquimioterapia , Fotoquimioterapia/métodos , Ciclooxigenasa 2/metabolismo , Péptidos/química , Péptidos/farmacología , Animales , Humanos , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/metabolismo , Femenino , Meloxicam/farmacología , Meloxicam/uso terapéutico , Ratones , Protoporfirinas/química , Protoporfirinas/farmacología , Dinoprostona/metabolismoRESUMEN
Immunotherapy is known to be a promising strategy in the clinical treatment of malignant tumors, but it has received generally low response rates in various tumors because of the poor immunogenicity and multiple immunosuppressive microenvironments. A self-delivery photodynamic re-educator, denoted as CCXB, is synthesized through the self-assembly of chlorine e6 (Ce6) and celecoxib (CXB). As a carrier-free nanomedicine, CCXB shows a high drug loading rate, improved water stability, superior cellular uptake, and tumor accumulation capability. In comparison with free Ce6, CCXB triggers much stronger photodynamic therapy (PDT) to reduce the proliferation of breast cancer cells and activates robust immune responses via the induction of immunogenic cell death (ICD). Better yet, CXB-mediated cyclooxygenase 2 (COX-2) inhibition can decrease the level of synthesis of prostaglandin E2 (PGE2) to further improve immunosuppressive microenvironments. With the increase of cytotoxic T lymphocytes (CTLs) and decrease of regulatory T cells (Tregs) in tumor, in vivo antitumor immunity is significantly amplified to inhibit the metastasis of breast cancer. This study sheds light on developing drug codelivery systems with collaborative mechanisms for immunotherapy of metastatic tumors.
Asunto(s)
Neoplasias de la Mama , Nanopartículas , Fotoquimioterapia , Humanos , Femenino , Muerte Celular Inmunogénica , Neoplasias de la Mama/patología , Inmunoterapia , Linfocitos T Citotóxicos , Inmunosupresores/farmacología , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Microambiente TumoralRESUMEN
Inflammation activation is accompanied by tumor growth, migration, and differentiation. Photodynamic therapy (PDT) can trigger an inflammatory response to cause negative feedback of tumor inhibition. In this paper, a feedback-elevated antitumor amplifier is developed by constructing self-delivery nanomedicine for PDT and cascade anti-inflammation therapy. Based on the photosensitizer chlorin e6 (Ce6) and COX-2 inhibitor indomethacin (Indo), the nanomedicine is prepared via molecular self-assembly technology without additional drug carriers. It is exciting that the optimized nanomedicine (designated as CeIndo) possesses favorable stability and dispersibility in the aqueous phase. Moreover, the drug delivery efficiency of CeIndo is significantly improved, which could be effectively accumulated at the tumor site and internalized by tumor cells. Importantly, CeIndo not only exhibits a robust PDT efficacy on tumor cells but also drastically decreases the PDT-induced inflammatory response in vivo, resulting in feedback-elevated tumor inhibition. By virtue of the synergistic effect of PDT and cascade inflammation suppression, CeIndo tremendously reduces tumor growth and leads to a low side effect. This study presents a paradigm for the development of codelivery nanomedicine for enhanced tumor therapy through inflammation suppression.
Asunto(s)
Fotoquimioterapia , Humanos , Fotoquimioterapia/efectos adversos , Fotoquimioterapia/métodos , Nanomedicina , Retroalimentación , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Inflamación/tratamiento farmacológicoRESUMEN
Therapy-induced DNA damage is the most common strategy to inhibit tumor cell proliferation, but the therapeutic efficacy is limited by DNA repair machinery. Carrier-free nanoproteolysis targeting chimeras (PROTACs), designed as SDNpros, have been developed to enhance photodynamic therapy (PDT) by blocking the DNA damage repair pathway through BRD4 degradation. Specifically, SDNpros are constructed through noncovalent interactions between the photosensitizer of chlorine e6 (Ce6) and PROTACs of BRD4 degrader (dBET57) via self-assembly. SDNpro has favorable dispersibility and a uniform nanosize distribution without drug excipients. Upon light irradiation, SDNpro produces abundant reactive oxygen species (ROS) to induce DNA oxidative damage. Meanwhile, the DNA repair pathway would be interrupted by the concurrent degradation of BRD4, which could intensify the oxidative DNA damage and elevate PDT efficiency. Beneficially, SDNpro suppresses tumor growth and avoids systemic side effects, providing a promising strategy to promote the clinical translation of PROTACs for tumor treatment.
Asunto(s)
Nanopartículas , Fotoquimioterapia , Porfirinas , Proteínas Nucleares , Excipientes , Línea Celular Tumoral , Factores de Transcripción , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Daño del ADN , Porfirinas/uso terapéuticoRESUMEN
Paraptosis is characterized by the extensive vacuolization of endoplasmic reticulum (ER) and mitochondria, which will cause the release of damage-associated molecular patterns to promote immunogenic cell death (ICD). However, the tumor can develop an immunosuppressive microenvironment to affect the ICD activation for the purpose of immune escape. Herein, a paraptosis inducer (CMN) is constructed to amplify the ICD effect for efficient immunotherapy by inhibiting the activity of indoleamine 2,3-dioxygenase (IDO). Initially, CMN is prepared by the assembly of copper ions (Cu2+), morusin (MR), and IDO inhibitor (NLG919) through noncovalent interactions. Without the need for extra drug carriers, CMN possesses very high drug contents and exhibits a favorable GSH responsiveness for disassembly. Subsequently, the released MR can trigger paraptosis to cause extensive vacuolization of ER and mitochondria, contributing to activating ICD for immunotherapy. Moreover, NLG919 would inhibit IDO to remodel the tumor microenvironment and promote the activation of cytotoxic T cells, leading to an intensive antitumor immunity. Abundant in vivo studies indicate that CMN is superior in suppressing the proliferations of not only primary tumor but also metastatic and rechallenged tumors. Such a GSH-responsive paraptosis inducer might provide a promising strategy to trigger ICD and enhance tumor immunotherapy.
Asunto(s)
Muerte Celular Inmunogénica , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Portadores de Fármacos , Inhibidores Enzimáticos , Inmunoterapia , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Reactive oxygen species (ROS) generated during photodynamic therapy (PDT) can induce autophagy to protect tumor cell from PDT-induced apoptosis. In this work, a self-delivery autophagy regulator (designated as CeCe) is developed for autophagy promotion sensitized PDT against tumor. Briefly, CeCe is prepared by the assembly of a photosensitizer of chlorin e6 (Ce6) and autophagy promoter of celastrol. By virtue of intermolecular interactions, Ce6 and celastrol are able to self-assemble into nanomedicine with great photodynamic performance and autophagy regulation capacity. Under light irradiation, CeCe would produce ROS in tumor cells to amplify the oxidative stress and promote cell autophagy. As a result, CeCe exhibits an enhanced photo toxicity by inducing autophagic cell death. In vivo experiments indicate that CeCe can predominantly accumulate in tumor tissue for a robust PDT. Moreover, CeCe has a superior therapeutic efficiency compared to monotherapy and combined treatment of Ce6 and celastrol, suggesting a synergistic antitumor effect of PDT and autophagy promotion. This self-delivery nanomedicine may advance the development of the co-delivery nanoplatform to improve the antitumor efficacy of PDT by promoting autophagy. STATEMENT OF SIGNIFICANCE: Autophagy is a "double-edged sword" in cellular homeostasis and metabolism, which can promote tumor progression but also induce an unknown impact on tumor inhibition. In this work, a self-delivery autophagy regulator (designated as CeCe) was developed for autophagy promotion sensitized photodynamic therapy (PDT). By virtue of intermolecular interactions, Ce6 and celastrol were found to self-assemble into stable CeCe without drug excipients, which exhibited great photodynamic performance and autophagy regulation capacity. In vitro and in vivo findings demonstrated a superior tumor suppression ability of CeCe over the monotherapy as well as the combined treatment of Ce6 and celastrol, suggesting a synergistic antitumor efficacy by PDT and autophagy promotion.
Asunto(s)
Nanopartículas , Fotoquimioterapia , Porfirinas , Especies Reactivas de Oxígeno/metabolismo , Retroalimentación , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Autofagia , Porfirinas/farmacología , Nanopartículas/uso terapéuticoRESUMEN
Photodynamic therapy (PDT) can generate reactive oxygen species (ROS) to cause cell apoptosis and induce immunogenic cell death (ICD) to activate immune response, becoming a promising antitumor modality. However, the overexpressions of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1) on tumor cells would reduce cytotoxic T cells infiltration and inhibit the immune activation. In this paper, a simple but effective nanosystem is developed to solve these issues for enhanced photodynamic immunotherapy. Specifically, it has been constructed a self-delivery biomedicine (CeNB) based on photosensitizer chlorine e6 (Ce6), IDO inhibitor (NLG919), and PD1/PDL1 blocker (BMS-1) without the need for extra excipients. Of note, CeNB possesses fairly high drug content (nearly 100%), favorable stability, and uniform morphology. More importantly, CeNB-mediated IDO inhibition and PD1/PDL1 blockade greatly improve the immunosuppressive tumor microenvironments to promote immune activation. The PDT of CeNB not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. Ultimately, self-delivery CeNB tremendously suppresses the tumor growth and metastasis while leads to a minimized side effect. Such simple and effective antitumor strategy overcomes the therapeutic resistance against PDT-initiated immunotherapy, suggesting a potential for metastatic tumor treatment in clinic.
Asunto(s)
Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Línea Celular Tumoral , Inhibidores Enzimáticos , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/uso terapéutico , Microambiente TumoralRESUMEN
Tumor cells activate DNA repair pathways to combat the oxidative damage induced by reactive oxygen species (ROS), contributing to their resistance to photodynamic therapy (PDT). Herein, a self-delivery photodynamic sensitizer is developed to enhance oxidative damage by blocking the DNA repair pathway through poly(ADP-ribose) polymerase (PARP) inhibition. Specifically, the photodynamic sensitizer (CeOla) is constructed based on the self-assembly of the photosensitizer chlorine e6 (Ce6) and the PARP inhibitor olaparib (Ola). Of note is that carrier free CeOla has a high drug content and favorable water stability, which could be effectively internalized by tumor cells for robust PDT upon light irradiation. Moreover, CeOla could inhibit the activation of PARP, promote the upregulation of γ-H2AX and reduce the expression of Rad51, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. As a consequence, the self-delivery CeOla greatly promotes the tumor cell apoptosis and shows a high antitumor performance with low side effects. It serves as a novel platform for the development of self-delivery nanomedicine to overcome oxidative resistance in tumor treatment.
Asunto(s)
Antineoplásicos , Fotoquimioterapia , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Antineoplásicos/farmacología , Fármacos Fotosensibilizantes/farmacología , Daño del ADN , Poli(ADP-Ribosa) Polimerasas/metabolismo , Línea Celular TumoralRESUMEN
Lipid peroxide (LPO) is the hallmark of ferroptosis, which is a promising antitumor modality for its unique advantages. However, a cellular defense system would weaken the antitumor efficacy of ferrotherapy. Herein, a GPX4 inhibitor of ML162 and a photosensitizer of chlorine e6 (Ce6) are used to prepare the self-delivery nanomedicine (C-ML162) through hydrophobic and electrostatic interactions to enhance ferroptosis by photodynamic therapy (PDT). Specifically, carrier-free C-ML162 improves the solubility, stability, and cellular uptake of antitumor agents. Upon light irradiation, the internalized C-ML162 generates large amounts of reactive oxygen species (ROS) to oxidize cellular unsaturated lipid into LPO. More importantly, C-ML162 can directly inactivate GPX4 to enhance the accumulation of toxic LPO, inducing ferroptotic cell death. Additionally, C-ML162 is capable of accumulating at a tumor site for effective treatment. This self-delivery system to amplify lipid peroxidation via GPX4 inactivation for PDT initiated ferrotherapy might provide an appealing strategy against malignancies.
Asunto(s)
Nanomedicina , Fotoquimioterapia , Peroxidación de LípidoRESUMEN
Abnormal metabolism of cancer cells results in complex tumor microenvironments (TME), which play a dominant role in tumor metastasis. Herein, self-delivery ternary bioregulators (designated as TerBio) are constructed for photodynamic amplified immunotherapy against colorectal cancer by TME reprogramming. Specifically, carrier-free TerBio are prepared by the self-assembly of chlorine e6, SB505124 (SB), and lonidamine (Lon), which exhibit improved tumor accumulation, tumor penetration, and cellular uptake behaviors. Interestingly, TerBio-mediated photodynamic therapy (PDT) could not only inhibit the primary tumor growth but also induce immunogenic cell death of tumors to activate the cascade immune response. Furthermore, TerBio are capable of TME reprograming by SB-triggered transforming growth factor (TGF)-ß blockage and Lon-induced lactic acid efflux inhibition. As a consequence, TerBio significantly suppresses distant and metastatic tumor growth by PDT-amplified immunotherapy. This study might advance the development of self-delivery nanomedicine against malignant tumor growth and metastasis.
Asunto(s)
Nanopartículas , Fotoquimioterapia , Microambiente Tumoral , Línea Celular Tumoral , Inmunoterapia/métodos , Fotoquimioterapia/métodos , Factores Inmunológicos/farmacología , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Glutamine metabolism of tumor cells plays a crucial role in maintaining cell homeostasis and reducing oxidative damage. Herein, a valid strategy of inhibiting glutamine metabolism is proposed to amplify the oxidative damage of photodynamic therapy (PDT) to tumor cells. Specifically, the authors develop a drug co-delivery system (designated as CeV) based on chlorine e6 (Ce6) and V9302 via the self-assembly technology. In spite of the strong hydrophobicity of therapeutic agents, the assembled CeV holds a favorable dispersibility in water and an improved cellular uptake capability. Under light irradiation, the internalized CeV is capable of generating abundant reactive oxygen species (ROS) for PDT. More importantly, CeV can reduce the uptake of glutamine through V9302-mediated alanine-serine-cysteine transporter of type-2 (ASCT2) inhibition, leading to a reduced glutathione (GSH) production and an amplified oxidative stress. As a result, CeV has a robust PDT efficacy on tumor inhibition by the blockade of glutamine transport. Notably, CeV exhibits a superiority on tumor suppression over the single treatment as well as the combined administration of Ce6 and V9302, which indicates the advantage of CeV for synergistic treatment. It may serve as a novel nanoplatform for developing a drug co-delivery system to improve PDT efficiency by inhibiting cell metabolism.
Asunto(s)
Nanopartículas , Fotoquimioterapia , Porfirinas , Línea Celular Tumoral , Glutamina , Nanomedicina , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/farmacologíaRESUMEN
Tumor cells adapt to excessive oxidative stress by actuating reactive oxygen species (ROS)-defensing system, leading to a resistance to oxidation therapy. In this work, self-delivery photodynamic synergists (designated as PhotoSyn) are developed for oxidative damage amplified tumor therapy. Specifically, PhotoSyn are fabricated by the self-assembly of chlorine e6 (Ce6) and TH588 through π-π stacking and hydrophobic interactions. Without additional carriers, nanoscale PhotoSyn possess an extremely high drug loading rate (up to 100%) and they are found to be fairly stable in aqueous phase with a uniform size distribution. Intravenously injected PhotoSyn prefer to accumulate at tumor sites for effective cellular uptake. More importantly, TH588-mediated MTH1 inhibition could destroy the ROS-defensing system of tumor cells by preventing the elimination of 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dG), thereby exacerbating the oxidative DNA damage induced by the photodynamic therapy (PDT) of Ce6 under light irradiation. As a consequence, PhotoSyn exhibit enhanced photo toxicity and a significant antitumor effect. This amplified oxidative damage strategy improves the PDT efficiency with a reduced side effect by increasing the lethality of ROS without generating superabundant ROS, which would provide a new insight for developing self-delivery nanoplatforms in photodynamic tumor therapy in clinic.