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Small molecule prodrugs self-assembled nano-delivery systems with tumor responsive linkages are emerging as an effective platform. However, the heterogeneity of tumor microenvironment may limit the anti-tumor effect of prodrug nanomedicines with a single response module. Here, we chose disulfide bond as the response module and branched chain alcohol as the self-assembly modification module to construct a single-responsive prodrug. We also constructed a double-responsive paclitaxel prodrug combining triglyceride and disulfide bond, taking into account of the highly expressed lipase and glutathione levels in tumor cells. The results showed that the anti-tumor effect of single-responsive branched chain alcohol modified prodrug nanoparticles was inferior to triglyceride prodrug nanoparticles with dual response modules. The triglyceride structure can not only serve as a self-assembly modification module, but also serve as a response module for intelligent drug release in tumor. Such dual roles will facilitate the efficient delivery of small molecule self-assembled prodrugs to tumor sites.
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In the prodrug-based self-assembled nanoassemblies, prodrugs usually consist of drug modules, response modules, and modification modules. Modification modules play a critical role in regulating the nano-assembly ability of the prodrugs. Herein, we carried out a "fatty alcoholization" strategy and chose various lengths of aliphatic alcohol chains (AC) as modification modules to construct disulfide bond bridged paclitaxel (PTX) prodrug nanoassemblies. The PTX-AC prodrugs would self-assemble into nanoassemblies (PTX-AC PNs) with higher drug loading, stability, and tumor selectivity than commercial preparations. After comprehensive exploration, we found the chain length (AC12, AC16, AC20, AC24) of modification modules affected the assembly of PTX-AC PNs, further leading to disparate in vivo fate and antitumor efficacy. With the increase of the chain length of the modification modules (from AC12 to AC20), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC24, the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC20 PNs with proper chain length may solve the paradox of efficacy and tolerance in 4 T1 breast tumor owing to their optimal nano-assembly stability and modest redox-sensitivity. In short, this work highlighted the importance of screening optimal modification modules in developing prodrug nanoassemblies.
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Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.
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HYPOTHESIS: Hydrophilic cationic drugs such as mitoxantrone hydrochloride (MTO) pose a significant delivery challenge to the development of nanodrug systems. Herein, we report the use of a hydrophobic ion-pairing strategy to enhance the nano-assembly of MTO. EXPERIMENTS: We employed biocompatible sodium cholesteryl sulfate (SCS) as a modification module to form stable ion pairs with MTO, which balanced the intermolecular forces and facilitated nano-assembly. PEGylated MTO-SCS nanoassemblies (pMS NAs) were prepared via nanoprecipitation. We systematically evaluated the effect of the ratio of the drug module (MTO) to the modification module (SCS) on the nanoassemblies. FINDINGS: The increased lipophilicity of MTO-SCS ion pair could significantly improve the encapsulation efficiency (â¼97 %) and cellular uptake efficiency of MTO. The pMS NAs showed prolonged blood circulation, maintained the same level of tumor antiproliferative activity, and exhibited reduced toxicity compared with the free MTO solution. It is noteworthy that the stability, cellular uptake, cytotoxicity, and in vivo pharmacokinetic behavior of the pMS NAs increased in proportion to the molar ratio of SCS to MTO. This study presents a self-assembly strategy mediated by ion pairing to overcome the challenges commonly associated with the poor assembly ability of hydrophilic cationic drugs.
Assuntos
Antineoplásicos , Ésteres do Colesterol , Interações Hidrofóbicas e Hidrofílicas , Mitoxantrona , Mitoxantrona/química , Mitoxantrona/farmacologia , Mitoxantrona/farmacocinética , Humanos , Animais , Ésteres do Colesterol/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Camundongos , Proliferação de Células/efeitos dos fármacos , Cátions/química , Sobrevivência Celular/efeitos dos fármacos , Tamanho da Partícula , Nanopartículas/química , Propriedades de Superfície , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Polietilenoglicóis/químicaRESUMO
Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a response module, and a surface functionalization module. Among these modules, surface functionalization is an essential process to enhance the biocompatibility and stability of the nanoassemblies. Here, we selected mitoxantrone (MTO) as the drug module and DSPE-PEG2K as surface functionalization module to develop MTO prodrug nanoassemblies. We systematically evaluated the effect of surface functionalization module ratios (10%, 20%, 40%, and 60% of prodrug, WDSPE-mPEG2000/Wprodrug) on the prodrug nanoassemblies. The results indicated that 40% NPs significantly improved the self-assembly stability and cellular uptake of prodrug nanoassemblies. Compared with MTO solution, 40% NPs showed better tumor specificity and pharmacokinetics, resulting in potent antitumor activity with a good safety profile. These findings highlighted the pivotal role of the surface functionalization module in regulating the performance of mitoxantrone prodrug nanoassemblies for cancer treatment.
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Antineoplásicos , Nanopartículas , Pró-Fármacos , Mitoxantrona , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodosRESUMO
The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.
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Dimeric prodrug nanoassemblies (DPNAs) stand out as promising strategies for improving the efficiency and safety of chemotherapeutic drugs. The success of trisulfide bonds (-SSS-) in DPNAs makes polysulfide bonds a worthwhile focus. Here, we explore the comprehensive role of tetrasulfide bonds (-SSSS-) in constructing superior DPNAs. Compared to trisulfide and disulfide bonds, tetrasulfide bonds endow DPNAs with superlative self-assembly stability, prolonged blood circulation, and high tumor accumulation. Notably, the ultra-high reduction responsivity of tetrasulfide bonds make DPNAs a highly selective "tumor bomb" that can be ignited by endogenous reducing agents in tumor cells. Furthermore, we present an "add fuel to the flames" strategy to intensify the reductive stress at tumor sites by replenishing exogenous reducing agents, making considerable progress in selective tumor inhibition. This work elucidates the crucial role of tetrasulfide bonds in establishing intelligent DPNAs, alongside the combination methodology, propelling DPNAs to new heights in potent cancer therapy.
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Pró-Fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Pró-Fármacos/química , Substâncias Redutoras , Linhagem Celular TumoralRESUMO
Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo-drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self-assembly stability, and site-specific activation of prodrugs. The "in series" increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (âSC(S)Sâ), with a stable "satellite-type" distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. âSC(S)Sâ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self-assembly stability of homodimeric prodrugs while maintaining the on-demand bioactivation. Furthermore, âSC(S)Sâ bond inhibits antioxidant defense system, leading to up-regulation of the cellular ROS and apoptosis of tumor cells. These improvements of âSC(S)Sâ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. âSC(S)Sâ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.
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Antineoplásicos , Nanopartículas , Pró-Fármacos , Tionas , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Polímeros , Enxofre , Nanopartículas/química , Liberação Controlada de FármacosRESUMO
The prodrug-based nanoassemblies offer an alternative to settle the deficiencies of traditional chemotherapy drugs. In this nanosystem, prodrugs typically comprise drug modules, modification modules, and response modules. The response modules are crucial for facilitating the accurate conversion of prodrugs at specific sites. In this work, we opted for differentiated disulfide bonds as response modules to construct docetaxel (DTX) prodrug nanoassemblies. Interestingly, a subtle change in response modules leads to a "U-shaped" conversion rate of DTX-prodrug nanoassemblies. Prodrug nanoassemblies with the least carbon numbers between the disulfide bond and ester bond (PDONα) offered the fastest conversion rate, resulting in powerful treatment outcomes with some unavoidable toxic effects. PDONß, with more carbon numbers, possessed a slow conversion rate and poor antitumor efficacy but good tolerance. With most carbon numbers in PDONγ, it demonstrated a moderate conversion rate and antitumor effect but induced a risk of lethality. Our study explored the function of response modules and highlighted their importance in prodrug development.
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Antineoplásicos , Nanopartículas , Pró-Fármacos , Docetaxel , Pró-Fármacos/química , Linhagem Celular Tumoral , Dissulfetos/química , Carbono , Antineoplásicos/farmacologia , Nanopartículas/químicaRESUMO
The clinical application of cabazitaxel (CTX) is restricted by severe dose-related toxicity, failing to considering therapeutic efficacy and safety together. Self-assembled prodrugs promote new drug delivery paradigms as they can self-deliver and self-formulate. However, the current studies mainly focused on the use of straight chains to construct self-assembled prodrugs, and the role of branched chains in prodrug nanoassemblies remains to be clarified. In this study, we systematically explored the structure-function relationship of prodrug nanoassemblies using four CTX prodrugs that contained branched chain aliphatic alcohols (BAs) with different alkyl lengths. Overall, CTX-SS-BA20 NPs with the proper alkyl length exhibited significant improvements in both antitumor efficacy and biosafety. Furthermore, compared with straight chain (SC) modified prodrug nanoassemblies (CTX-SS-SC20 NPs), CTX-SS-BA20 NPs still hold great therapeutic promise due to its good biosafety. These findings illustrated the significance of BAs as modified chains in designing prodrug nanoassemblies for narrowing the efficacy-to-safety gap of cancer therapy.
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Nanopartículas , Pró-Fármacos , Sistemas de Liberação de Medicamentos , Taxoides , Linhagem Celular TumoralRESUMO
The anti-PD-L1 immunotherapy has shown promise in treating cancer. However, certain patients with metastatic cancer have low response and high relapse rates. A main reason is systemic immunosuppression caused by exosomal PD-L1, which can circulate in the body and inhibit T cell functions. Here, we show that Golgi apparatus-Pd-l1-/- exosome hybrid membrane coated nanoparticles (GENPs) can significantly reduce the secretion of PD-L1. The GENPs can accumulate in tumors through homotypic targeting and effectively deliver retinoic acid, inducing disorganization of the Golgi apparatus and a sequence of intracellular events including alteration of endoplasmic reticulum (ER)-to-Golgi trafficking and subsequent ER stress, which finally disrupts the PD-L1 production and the release of exosomes. Furthermore, GENPs could mimic exosomes to access draining lymph nodes. The membrane antigen of PD-l1-/- exosome on GENPs can activate T cells through a vaccine-like effect, strongly promoting systemic immune responses. By combining GENPs with anti-PD-L1 treatment in the sprayable in situ hydrogel, we have successfully realized a low recurrence rate and substantially extended survival periods in mice models with incomplete metastatic melanoma resection.
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Exossomos , Melanoma , Animais , Camundongos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Imunoterapia , Linfócitos T , Terapia de Imunossupressão , Complexo de Golgi , Exossomos/metabolismoRESUMO
Prodrug-based nanoassemblies have been developed to solve the bottlenecks of chemotherapeutic drugs. The fabricated prodrugs usually consist of active drug modules, response modules, and modification modules. Among three modules, the response modules play a vital role in controlling the intelligent drug release at tumor sites. Herein, various locations of disulfide bond linkages were selected as response modules to construct three Docetaxel (DTX) prodrugs. Interestingly, the small structural difference caused by the length of response modules endowed corresponding prodrug nanoassemblies with unique characteristic. α-DTX-OD nanoparticles (NPs) possessed the advantages of high redox-responsiveness due to their shortest linkages. However, they were too sensitive to retain the intact structure in the blood circulation, leading to severe systematic toxicity. ß-DTX-OD NPs significantly improved the pharmacokinetics of DTX but may induce damage to the liver. In comparison, γ-DTX-OD NPs with the longest linkages greatly ameliorated the delivery efficiency of DTX as well as improved DTX's tolerance dose.
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Antineoplásicos , Nanopartículas , Pró-Fármacos , Docetaxel , Pró-Fármacos/química , Nanopartículas/química , Liberação Controlada de Fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Portadores de Fármacos/químicaRESUMO
Albumin has emerged as a versatile drug carrier. To harness albumin as a carrier for doxorubicin (DOX), we synthesized three acid-labile DOX prodrugs using stearic acid (SA), oleic acid (OA), and linoleic acid (LA) as the albumin-binding motif, respectively. Different from conventional albumin nanodrugs (such as Abraxane, with a drug loading of 10%), the DOX prodrugs assembled albumin nanoparticles (NPs) have an ultrahigh drug loading (>35%). Noteworthy, we demonstrated that the saturation of fatty acids exerted great influence on colloidal stability of prodrug NPs, thus affecting their in vivo pharmacokinetics, tumor accumulation and antitumor efficacy. Furthermore, the hydrazone bond-bridged DOX prodrugs could remain intact in the bloodstream but allow DOX to be released in the acidic tumor environment, resulting in improved antitumor efficacy and safety. Our work gives novel insights into the structure-to-efficacy relationship of albumin-bound fatty acid prodrugs and provides a simple strategy for advanced albumin-bound nanomedicines.
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Nanopartículas , Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Ácidos Graxos , Doxorrubicina/uso terapêutico , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Concentração de Íons de Hidrogênio , Albuminas/uso terapêutico , Linhagem Celular TumoralRESUMO
Homodimeric prodrug nanoassemblies (HDPNs) have been widely studied for efficient cancer therapy by virtue of their ultra-high drug loading and distinct nanostructure. However, the development of SN38 HDPNs is still a great challenge due to the rigid planar aromatic ring structure. Improving the structural flexibility of homodimeric prodrugs by increasing the linker length may be a potential strategy for constructing SN38 HDPNs. Herein, three SN38 homodimeric prodrugs with different linker lengths were synthesized. The number of carbon atoms from the disulfide bond to the adjacent ester bond is 1 (denoted as α-SN38-SS-SN38), 2 (ß-SN38-SS-SN38), and 3 (γ-SN38-SS-SN38), respectively. Interestingly, we found that α-SN38-SS-SN38 exhibited extremely low yield and poor chemical stability. Additionally, ß-SN38-SS-SN38 demonstrated suitable chemical stability but poor self-assembly stability. In comparison, γ-SN38-SS-SN38 possessed good chemical and self-assembly stability, thereby improving the tumor accumulation and antitumor efficacy of SN38. We developed the SN38 HDPNs for the first time and illustrated the underlying molecular mechanism of increasing the linker length to enhance the chemical and self-assembly stability of homodimeric prodrugs. These findings would provide new insights for the rational design of HDPNs with superior performance.
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Nanoestruturas , Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/química , Irinotecano/uso terapêutico , Solubilidade , Neoplasias/tratamento farmacológicoRESUMO
Prodrug-based nanoassemblies, which combine the merits of prodrug technology and nanocarriers, are regarded as promising platforms for cancer treatment. Notably, the chemical structure of prodrugs is closely associated with antitumor efficacy and safety, and the intrinsic relationships among them need further exploration. Herein, paclitaxel was conjugated with 2-octyldodecan-1-ol through different positions of disulfide bond to construct the prodrug nanoassemblies. Interestingly, the minor differences in chemical structure not only dominated the assembly performance and drug release of nanoassemblies, but also significantly impacted the pharmacokinetics, antitumor efficacy, and safety. It was worth noting that prodrug nanoassemblies with one carbon atom between disulfide bond and ester bond had faster drug release and better antitumor effect, while prodrug nanoassemblies with three carbon atoms between disulfide bond and ester bond possessed moderate antitumor effect and better safety. Our findings illustrated the structure-function relationships of self-assembled prodrugs and provided a promising paradigm for the precise engineering of advanced prodrug nanoplatforms. STATEMENT OF SIGNIFICANCE: 1. The major effects of minor differences in prodrug chemical structure on pharmacodynamics and safety were explored, which had important clinical reference significance and value. 2. The in-depth exploration of structure-function relationships to balance efficacy and safety had important guiding significance for the design of prodrug nanoassemblies.
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Nanopartículas , Pró-Fármacos , Pró-Fármacos/química , Linhagem Celular Tumoral , Paclitaxel/química , Liberação Controlada de Fármacos , Dissulfetos/química , Carbono , Sistemas de Liberação de Medicamentos , Nanopartículas/químicaRESUMO
Sulfur bonds, especially trisulfide bond, have been found to ameliorate the self-assembly stability of homodimeric prodrug nanoassemblies and could trigger the sensitive reduction-responsive release of active drugs. However, the antitumor efficacy of homodimeric prodrug nanoassemblies with single reduction-responsivity may be restricted due to the heterogeneous tumor redox microenvironment. Herein, we replace the middle sulfur atom of trisulfide bond with an oxidizing tellurium atom or selenium atom to construct redox dual-responsive sulfur-tellurium-sulfur and sulfur-selenium-sulfur hybrid chalcogen bonds. The hybrid chalcogen bonds, especially the sulfur-tellurium-sulfur bond, exhibit ultrahigh dual-responsivity to both oxidation and reduction conditions, which could effectively address the heterogeneous tumor microenvironment. Moreover, the hybrid sulfur-tellurium-sulfur bond promotes the self-assembly of homodimeric prodrugs by providing strong intermolecular forces and sufficient steric hindrance. The above advantages of sulfur-tellurium-sulfur bridged homodimeric prodrug nanoassemblies result in the improved antitumor efficacy of docetaxel with satisfactory safety. The exploration of hybrid chalcogen bonds in drug delivery deepened insight into the development of prodrug-based chemotherapy to address tumor redox heterogeneity, thus enriching the design theory of prodrug-based nanomedicines.
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Neoplasias , Pró-Fármacos , Selênio , Humanos , Pró-Fármacos/química , Microambiente Tumoral , Liberação Controlada de Fármacos , Telúrio , Oxirredução , Neoplasias/tratamento farmacológico , EnxofreRESUMO
Prodrug-based self-assembled nanoparticles combined with the merits of nanotechnology and prodrugs strategies have gradually become a research trending topic in the field of drug delivery. These prodrugs usually consist of parent drugs, connecting bonds, and modifying chains. The influences of the connecting bonds and modifying chains on the pharmaceutical characteristics, in vivo delivery fate, and antitumor activity of prodrug nanoassemblies remain elusive. Herein, three docetaxel (DTX) prodrugs were designed using sulfur bonds (thioether bond or disulfide bond) as connecting bonds and fatty alcohols (straight chain or branched chain) as modifying chains. Interestingly, the difference between connecting bonds and modifying chains deeply influenced the colloidal stability, redox responsive drug release, cytotoxicity, pharmacokinetic properties, tumor accumulation, and antitumor effect of prodrug nanoassemblies. DTX conjugated with branched chain fatty alcohols via disulfide bonds (HUA-SS-DTX) significantly improved the antitumor efficiency of DTX and reduced the systematic toxicity. Our study elaborates on the vital role of connecting bonds and modifying chains in the rational design of prodrug nanoassemblies.
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Pró-Fármacos , Pró-Fármacos/química , Linhagem Celular Tumoral , Docetaxel , Dissulfetos/química , Álcoois GraxosRESUMO
Cancer immunotherapies such as tumor vaccines, chimeric antigen receptor T cells and immune checkpoint blockades, have attracted tremendous attention. Among them, tumor vaccines prime immune response by delivering antigens and adjuvants to the antigen presenting cells (APCs), thus enhancing antitumor immunotherapy. Despite tumor vaccines have made considerable achievements in tumor immunotherapy, it remains challenging to efficiently deliver tumor vaccines to activate the dendritic cells (DCs) in lymph nodes (LNs). Rational design of nanovaccines on the basis of biomedical nanotechnology has emerged as one of the most promising strategies for boosting the outcomes of cancer immunotherapy. In recent years, great efforts have been made in exploiting various nanocarrier-based LNs-targeting tumor nanovaccines. In view of the rapid advances in this field, we here aim to summarize the latest progression in LNs-targeting nanovaccines for cancer immunotherapy, with special attention to various nano-vehicles developed for LNs-targeting delivery of tumor vaccines, including lipid-based nanoparticles, polymeric nanocarriers, inorganic nanocarriers and biomimetic nanosystems. Moreover, the recent trends in nanovaccines-based combination cancer immunotherapy are provided. Finally, the rationality, advantages and challenges of LNs-targeting nanovaccines for clinical translation and application are spotlighted.
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Vacinas Anticâncer , Nanopartículas , Neoplasias , Humanos , Vacinas Anticâncer/uso terapêutico , Imunoterapia , Células Apresentadoras de Antígenos , Linfonodos , Neoplasias/tratamento farmacológicoRESUMO
Photodynamic therapy (PDT) has been extensively explored as a noninvasive cancer treatment modality. However, the dilemma of tumor hypoxia and short half-life of singlet oxygen (1O2) severely restrict the therapeutic efficacy of PDT. Herein, we develop a facile three-in-one PDT nanoamplifier (AA@PPa/Hemin NPs) assembled by pyropheophorbide a (PPa), hemin, and arachidonic acid (AA). Interestingly, AA not only acts as an enabler to facilitate the assembly of PPa and hemin in the construction of ternary hybrid nanoassemblies but also acts as a lipid reactive oxygen species (ROS) amplifier for robust PDT. In tumor cells, hemin plays the role of a catalase-like catalyst that accelerates the production of oxygen (O2) from hydrogen peroxide (H2O2), significantly alleviating tumor hypoxia. Under laser irradiation, vast amounts of 1O2 generated by PPa trigger the peroxidation of AA to produce large amounts of cytotoxic lipid ROS, immensely amplifying the efficiency of PDT by promptly eliciting cellular oxidative stress. As expected, AA@PPa/Hemin NPs exert potent antitumor activity in a 4T1 breast-tumor-bearing BALB/c mice xenograft model. Such a cascade nanohybrid amplifier provides a novel codelivery platform for accurate and effective PDT of cancer.
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Nanopartículas , Fotoquimioterapia , Animais , Linhagem Celular Tumoral , Hemina , Humanos , Peróxido de Hidrogênio , Lipídeos , Camundongos , Camundongos Endogâmicos BALB C , Oxigênio , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de OxigênioRESUMO
Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer cells as possible when NPs accumulate in tumors. However, macrophages and cancer-associated fibroblasts (CAFs) that are present within tumors limit the efficiency of spatiotemporal delivery. To overcome this limitation, glutathion pulse therapy is designed to promote reduction-sensitive Larotaxel (LTX) prodrug NPs to escape the phagocytosis of macrophages and penetrate through the stromal barrier established by CAFs in the murine triple negative breast cancer model. This therapy improves the penetration of NPs in tumor tissues as well as the accumulation of LTX in cancer cells, and remodels the immunosuppressive microenvironment to synergize PD-1 blockade therapy. More importantly, a method is established that can directly observe the biodistribution of NPs between different cells in vivo to accurately quantify the target drugs accumulated in these cells, thereby advancing the spatiotemporal delivery research of NPs at the "cellular level."