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1.
Adv Healthc Mater ; : e2101407, 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34601824

RESUMO

Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.

2.
Chin J Nat Med ; 19(9): 656-665, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34561076

RESUMO

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.

3.
J Nanobiotechnology ; 19(1): 282, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544447

RESUMO

BACKGROUND: Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors. METHODS: A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo. RESULTS: The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model. CONCLUSION: Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy.

4.
Adv Healthc Mater ; : e2100950, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34541825

RESUMO

Bacterial therapy, which targets the tumor site and aims at exerting an antitumor immune response, has displayed a great potential against malignant tumors. However, failure of the phase I clinical trial of Salmonella strain VNP20009 alone demonstrates that bacterial treatment alone can unsatisfy the requirements of high efficiency and biosafety. Herein, a strategy of both-in-one hybrid bacteria is proposed, wherein the chemotherapeutic drug doxorubicin (DOX) is integrated onto the surface of glucose dehydrogenase (GDH)-overexpressed non-pathogenic Escherichia coli (E. coli) strain, to potentiate the antitumor efficacy. Nicotinamide adenine dinucleotide phosphate (NADPH), which is produced by GDH from E. coli, promotes the generation of toxic reactive oxygen species (ROS) within the tumor, and ROS is then catalyzed by the DOX-activated NADPH oxidases. Importantly, the hybrid bacteria enhance stimulated systemic antitumor immune responses, thereby leading to effective tumor eradication. When this strategy is applied in four different tumor models, the hybrid bacteria significantly inhibited tumor metastasis, postsurgical regrowth, and primary/distal tumor relapse. The both-in-one ROS-immunity-boosted hybrid bacteria strategy provides knowledge for the rational design of bacteria-based synergistic cancer therapy.

5.
J Agric Food Chem ; 69(32): 9249-9258, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34357767

RESUMO

Resveratrol (RES) suffers from poor water solubility and extensive metabolism, which lead to low bioavailability. A phospholipid complex (PC) containing RES and a UDP-glucuronosyltransferase (UGT) inhibitor was prepared to address these two limiting factors, thereby improving RES bioavailability. First, 11 natural active ingredients metabolized by similar enzyme subtypes to RES were screened in a glucuronidation assay in liver microsomes. Then, glycyrrhetinic acid (GA), the strongest inhibitor, was prepared with RES in a PC. RES-PC was prepared as a control. As expected, the water solubility and the cumulative dissolution of RES were significantly enhanced by RES-PC and RES/GA-PC. Compared with the RES group, the AUC0-10 of RES and resveratrol-3-glucuronide (R-3-G) in the RES/GA-PC group showed increases of 2.49- and 1.70-fold, respectively, with the proportion of RES absorption to total absorption increasing 1.45 times. These results demonstrated that RES/GA-PC could improve the bioavailability of RES by increasing its water solubility and inhibiting its glucuronidation.


Assuntos
Glucuronosiltransferase , Microssomos Hepáticos , Disponibilidade Biológica , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Microssomos Hepáticos/metabolismo , Resveratrol/metabolismo , Solubilidade , Água/metabolismo
6.
Small ; : e2101460, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342126

RESUMO

The antitumor efficiency and clinical translation of traditional nanomedicines is mainly restricted by low drug loading, complex preparation technology, and potential toxicity caused by the overused carrier materials. In recent decades, small-molecule prodrug nanoassemblies (SMP-NAs), which are formed by the self-assembly of prodrugs themselves, have been widely investigated with distinct advantages of ultrahigh drug-loading and negligible excipients-trigged adverse reaction. Benefited from the simple preparation process, SMP-NAs are widely used for chemotherapy, phototherapy, immunotherapy, and tumor diagnosis. In addition, combination therapy based on the accurate co-delivery behavior of SMP-NAs can effectively address the challenges of tumor heterogeneity and multidrug resistance. Recent trends in SMP-NAs are outlined, and the corresponding self-assembly mechanisms are discussed in detail. Besides, the smart stimuli-responsive SMP-NAs and the combination therapy based on SMP-NAs are summarized, with special emphasis on the structure-function relationships. Finally, the outlooks and potential challenges of SMP-NAs in cancer therapy are highlighted.

7.
Theranostics ; 11(16): 7896-7910, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335971

RESUMO

Rationale: Small-molecule prodrug nanoassembly is emerging as an efficient platform for chemotherapy. The self-assembly stability plays a vital role on the drug delivery efficiency of prodrug nanoassembly. It is reported that fluoroalkylation could improve the self-assembly stability of amphiphilic polymers by utilizing the unique fluorination effect. But the application of fluoroalkylation on small-molecule prodrug nanoassembly has never been reported. Methods: Here, fluoro-modified prodrug was developed by conjugating paclitaxel with perfluorooctanol (F8-SS-PTX), and the paclitaxel-octanol prodrug (C8-SS-PTX) was used as control. The fluoro-mediated self-assembly mechanisms were illustrated using molecular dynamics simulation. In addition, the impacts of fluoroalkylation on the pharmacy characters, in vivo fate and antitumor effect of small-molecule prodrug nanoassembly were investigated in details. Results: Fluoroalkylation significantly improved the self-assembly stability of F8-SS-PTX NPs both in vitro and in vivo, which could be attributed to the fluoro-mediated hydrophobic force and halogen bonds. The AUC0-24h and tumor accumulation of F8-SS-PTX NPs was 6-fold and 2-fold higher than that of C8-SS-PTX NPs, respectively. As a result, F8-SS-PTX NPs exhibited much better antitumor effect than C8-SS-PTX NPs and Abraxane. Conclusion: Fluoroalkylation could improve the self-assembly stability, in vivo fate, and antitumor efficacy of small-molecule prodrug nanoassemblies, which could be an effective strategy for the rational design of advanced nanomedicines.


Assuntos
Fluoretos/química , Pró-Fármacos/química , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Fluoretação/métodos , Humanos , Camundongos , Simulação de Dinâmica Molecular , Nanomedicina/métodos , Nanopartículas/química , Paclitaxel/uso terapêutico , Polietilenoglicóis/química , Polímeros/química , Pró-Fármacos/farmacologia
8.
Int J Pharm ; 607: 120971, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34363915

RESUMO

The co-amorphous (CAM) technology has attracted extensive attention in recent years because it can improve the solubility and provide a formulation strategy for fixed dose combination for poorly water-soluble drugs. Atorvastatin (ATR) is a poorly water-soluble drug and it has strong anti-hyperlipidemia activity, and it is usually used in combination with lisinopril (LNP), an anti-hypertension drug. The aim of this study is to test the feasibility to develop ATR/LNP co-amorphous formulation using a cryo-milling method. The solid-state behaviors of the CAM systems were characterized by polarizing light microscopy, differential scanning calorimetry and powder X-ray diffraction. The molecular interaction between ATR and LNP was confirmed by the analysis of glass transition temperature and Fourier transform infrared spectroscopy. Compared with crystalline ATR and neat amorphous ATR, the CAM systems showed significantly increased in vitro dissolution and intrinsic dissolution rate of ATR, because LNP enhanced the supersaturation maintenance of ATR and inhibited its solution-mediated recrystallization to a certain extent.


Assuntos
Lisinopril , Atorvastatina , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Estabilidade de Medicamentos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
9.
Int J Pharm ; 607: 121027, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34418473

RESUMO

Cancer immunotherapy often fails to result in a favorable outcome owing to poor activation of immune response, the immunosuppressive tumor microenvironment, and systemic toxicity. In this study, indocyanine green (ICG) was conjugated with doxorubicin (DOX) using a hydrazone linker (DOX-ICG). Results of our in vitro and in vivo studies indicated that DOX-ICG could trigger powerful immunogenic cell death (ICD) of tumor cells. Moreover, its use in combination with immune checkpoint inhibitors could effectively inhibit both primary and abscopal tumors growth and suppress tumor metastasis. Therefore, this simple, safe, and efficient prodrug shows great potential for use in photo-activated chemo-immunotherapy.


Assuntos
Morte Celular Imunogênica , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina , Humanos , Imunoterapia , Verde de Indocianina , Neoplasias/tratamento farmacológico , Microambiente Tumoral
10.
Int J Pharm ; 606: 120923, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34303822

RESUMO

A surge of platinum(IV) compounds are utilized or investigated in cancer treatment but their therapeutic outcomes have been greatly compromised by remaining adverse effects and limited antitumor performance, attributable to nonspecific distribution and insufficient activation in tumor site. Herein, we designed a series of disulfide bond introduced Pt(IV)-lipid prodrugs with different branch length, all of which are able to self-stabilize into nanomedicine and be activated by high intracellular glutathione (GSH) level. The impact of precise modification of these prodrugs on their assembly stability, pharmacokinetics and cytotoxicity was probed to establish a connection between chemical structure and antiproliferation efficiency. With optimal assembly manner and delivery efficacy, the longest axial branched Pt(IV) prodrug CSS18 exhibited the most impressive therapeutic outcome, providing a potential path to more efficient nanocarriers for chemotherapeutic agents by chemical modulation and, giving insights into the rational design of reduction responsive platinum delivery system.


Assuntos
Antineoplásicos , Pró-Fármacos , Linhagem Celular Tumoral , Nanomedicina , Platina
11.
Artigo em Inglês | MEDLINE | ID: mdl-34309802

RESUMO

Rational designed lipid-drug derivatives provide a favorable approach to improve the druggability of highly hydrophobic prototypes. It has been regarded as common sense that good cytotoxicity is the guarantee of superior anticancer efficacy for candidate derivatives screening. However, does it apply to lipid-drug conjugate-based self-assembled nanoparticles? Here, we established the above two derivatives and a non-correlation between the cytotoxic activity in vitro and drug efficacy in vivo was found. The IC50 of DSL NPs (DTX-S-LA nanoparticles) and DL NPs (DTX-LA nanoparticles) were 4.02 and 209.6 ng/mL (DTX equivalent concentration), respectively. However, DL NPs unexpectedly showed stronger tumor inhibition abilities than DSL NPs. To explain the non-positive correlation between cytotoxicity and anticancer efficacy, more experiments were carried out in depth. Remarkably, the drug release studies in blood and PK study both suggested that the DL NPs were more stable to remain the structural integrity in circulation, which resulted in more accumulation in tumor sites. As verified by the bio-distribution study, DL NPs performed a superior target effect than DSL NPs in tumors. Our data indicated that the biological fates of so-called smart bond inserted derivatives in vivo are complicated; thus, simple cytotoxicity is not enough for derivatives screening, and the comprehensive understanding of both in vitro and in vivo behaviors is essential.

12.
J Control Release ; 336: 169-180, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34157335

RESUMO

Idebenone (IDB) has demonstrated the potential to treat mitochondrial and neurodegenerative diseases, including Alzheimer's disease (AD). However, its therapeutic effects are compromised by poor compliance due to low bioavailability. The objective of this study is to fabricate IDB nanorods (IDBNRs) to improve oral bioavailability and increase concentrations in the brain in order to enhance therapeutic effects of IDB in the treatment of AD. IDBNRs showed desired sizes and rod-shaped morphologies. The release rate and the antioxidant activity of IDBNRs were improved relative to other delivery routes. The plasma and brain concentrations were enhanced due to rapid release into the systemic circulation. In behavioral tests, mice treated orally with IDBNRs showed amelioration of AD-induced impairment of learning and memory. Thus, because of improved efficiency of drug delivery, doses can be reduced, and the compliance and therapeutic experience of patients can be improved. IDBNRs may provide effective and convenient treatments for AD patients in the future.

13.
J Control Release ; 335: 306-319, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34081995

RESUMO

Chemo-immunotherapy based on immunogenic cell death (ICD) is a promising strategy for cancer therapy. However, the effective ICD requires a high dosage of ICD stimulus, which could be associated to a dose-dependent toxicity. Therefore, in this study, a liposome remote-loaded with shikonin (a potent ICD stimulus) was developed, with the ability to effectively induce ICD at high dosage in vivo. However, a hepatotoxic effect was observed. To circumvent this problem, shikonin was combined with the anthracycline mitoxantrone or doxorubicin to develop co-loaded liposomes inducing a synergistic ICD effect and cytotoxicity to tumor cells. Cytotoxicity and uptake experiment in vitro were performed to analyze the optimal synergistic ratio of shikonin and anthracyclines based on a "formulated strategy". Interestingly, copper mediated co-loaded liposomes resulted in a pH and GSH dual-responsive release property. More importantly, pharmacokinetics and tumor biodistribution studies revealed an outstanding capacity of ratiometric delivery of dual drugs. Thus, the dual-loaded liposome enhanced the antitumor effect by the stimulation of a robust immune response at lower doses of the drugs with a higher safety compared to single-loaded liposomes. Summarized, the current work provided a reference for a rational design and development of liposomal co-delivery system of drugs and ICD-induced chemo-immunotherapy, and established a potential clinical application of shikonin-based drug combinations as a new chemo-immunotherapeutic strategy for cancer treatment.


Assuntos
Morte Celular Imunogênica , Lipossomos , Antraciclinas , Linhagem Celular Tumoral , Doxorrubicina , Humanos , Imunogenética , Imunoterapia , Naftoquinonas , Distribuição Tecidual
14.
Nanomicro Lett ; 13(1): 37, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34138211

RESUMO

The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency. With dozens of clinical trials underway, some researchers hold the following views: "humans are nearing the first commercial live bacteria therapeutic." However, the facultative anaerobe Salmonella typhimurium VNP20009, which is particularly safe and shows anticancer effects in preclinical studies, had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects. This is almost certain to disappoint people's inflated expectations, but it is noted that recent state-of-the-art research has turned attention to bacteria-mediated synergistic cancer therapy (BMSCT). In this review, the foundation of bacteria-mediated bio-therapy is outlined. Then, we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities (chemotherapy, photothermal therapy, reactive oxygen and nitrogen species therapy, immunotherapy, or prodrug-activating therapy) in the past 5 years. Next, we discuss multiple administration routes of BMSCT, highlighting potentiated antitumor responses and avoidance of potential side effects. Finally, we envision the opportunities and challenges for BMSCT development, with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.

15.
Nanoscale ; 13(23): 10536-10543, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34100041

RESUMO

The rational design of oral paclitaxel (PTX) preparations is still a challenge. Many studies focus on developing PTX-loaded nanoemulsions (NEs) for oral administration. Unfortunately, PTX has poor affinity with the commonly used oil phases, leading to low encapsulation efficiency, poor colloidal stability, and premature drug leakage of PTX-loaded NEs. Herein, three lipophilic PTX prodrugs are synthesized by conjugating PTX with citronellol (CIT), using different lengths of disulfide bond-containing linkages. Interestingly, compared with PTX, the prodrugs exhibit higher affinity with the oil phase, effectively improving the encapsulation efficiency, colloidal stability, and sustained-release behavior of NEs. In addition, the disulfide bond-bridged prodrugs could specifically release PTX in tumor cells, reducing unnecessary systemic exposure of PTX. As a result, all three prodrug NEs exhibited improved oral bioavailability and antitumor effects compared to oral Taxol. Moreover, the length of disulfide bond-containing linkages exhibits great impacts on the oral absorption, drug release, and antitumor behaviors of NEs. It is found that the prodrug NEs with the shortest linkages show comparable antitumor effects with intravenous Taxol, but with less systemic and gastrointestinal toxicity.


Assuntos
Antineoplásicos Fitogênicos , Pró-Fármacos , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Dissulfetos , Portadores de Fármacos , Paclitaxel/farmacologia , Pró-Fármacos/farmacologia
16.
Theranostics ; 11(15): 7471-7487, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158861

RESUMO

Immunotherapy provides a new avenue for combating cancer. Current research in anticancer immunotherapy is primary based on T cell-mediated cellular immunity, which can be divided into seven steps and is named the cancer-immunity cycle. Unfortunately, clinical applications of cancer immunotherapies are restricted by inefficient drug delivery, low response rates, and unmanageable adverse reactions. In response to these challenges, the combination of nanotechnology and immunotherapy (nano-immunotherapy) has been extensively studied in recent years. Rational design of advanced nano-immunotherapies requires in-depth consideration of "which" immune step is targeted, "why" it needs to be further enhanced, and "what" nanotechnology can do for immunotherapy. However, the applications and effects of nanotechnology in the cancer-immunity cycle have not been well reviewed. Herein, we summarize the current developments in nano-immunotherapy for each stage of cancer cellular immunity, with special attention on the which, why and what. Furthermore, we summarize the advantages of nanotechnology for combination immunotherapy in two categories: enhanced efficacy and reduced toxicity. Finally, we discuss the challenges of nano-immunotherapy in detail and provide a perspective.


Assuntos
Sistemas de Liberação de Medicamentos , Imunidade Celular , Imunoterapia , Nanopartículas/uso terapêutico , Neoplasias/terapia , Animais , Humanos , Neoplasias/imunologia
17.
J Control Release ; 334: 114-126, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33887284

RESUMO

Inflammatory microenvironments (IMEs) are common pathological characteristics and drive the development of multiple chronic diseases. Thus, IME-targeted therapies exhibit potential for the treatment of inflammatory diseases. Nanoplatforms have significant advantages in improving the efficiency of anti-inflammatory treatments. Owing to their improved therapeutic effects and reduced side effects, IME-targeted nanotherapies have recently drawn interest from the research community. This review introduces IMEs and discusses the application of IME-targeted nanotherapies for inflammatory diseases. The development of rational targeting strategies tailored to IMEs in damaged tissues can help promote therapies for chronic diseases.


Assuntos
Anti-Inflamatórios
18.
J Control Release ; 334: 213-223, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33894305

RESUMO

Photodynamic therapy (PDT) destroys tumor cells mainly through singlet oxygen (1O2) generated by light-irradiated photosensitizers (PSs). However, the fleeting half-life of 1O2 greatly impairs PDT efficacy. Herein, we propose an unreported unsaturated fatty acid (UFA)-assisted PS co-assembly strategy to address this problem. Three UFAs, namely, oleic acid (OA), linoleic acid (LA) and linolenic acid (LNA), are capable of co-assembling with 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (TAPP) into uniform nanoparticles. Under irradiation, TAPP produces 1O2, which directly attacks tumor cells and simultaneously oxidizes UFAs to generate lipid hydroperoxides with sustained damage. Interestingly, the unsaturation degree of UFAs is not only related to their peroxidation rate but also has a remarkable impact on the intracellular TAPP release characteristic of the nanoparticles (NPs). The TAPP-LA NPs could release the cargo rapidly and produce the highest lipid peroxidation and reactive oxygen species levels upon irradiation. Such a unique finding sheds new light on UFA-based combination applications for enhanced photodynamic efficacy by boosting lipid peroxidation.


Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Ácidos Graxos Insaturados , Peroxidação de Lipídeos , Fármacos Fotossensibilizantes
19.
Sci Adv ; 7(16)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33863733

RESUMO

Chemotherapeutic nanomedicines can exploit the neighboring effect to increase tumor penetration. However, the neighboring effect is limited, likely by the consumption of chemotherapeutic agents and resistance of internal hypoxic tumor cells. Here, we first propose and demonstrate that apoptotic bodies (ApoBDs) could carry the remaining drugs to neighboring tumor cells after apoptosis. To enhance the ApoBD-based neighboring effect, we fabricated disulfide-linked prodrug nanoparticles consisting of camptothecin (CPT) and hypoxia-activated prodrug PR104A. CPT kills external normoxic tumor cells to produce ApoBDs, while PR104A remains inactive. The remaining drugs could be effectively delivered into internal tumor cells via ApoBDs. Although CPT exhibits low toxicity to internal hypoxic tumor cells, PR104A could be activated to exert strong cytotoxicity, which further facilitates deep penetration of the remaining drugs. Such a synergic approach could overcome the limitations of the neighboring effect to penetrate deep into solid tumors for whole tumor destruction.

20.
Colloids Surf B Biointerfaces ; 203: 111766, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33866279

RESUMO

The platinum-based drugs prevail in the therapy of malignant tumors treatment. However, their clinical outcomes have been heavily restricted by severe systemic toxicities. To ensure biosafety and efficiency, herein, we constructed a disulfide bond inserted Pt(IV) self-assembled nanoplatform that is selectively activated by rich glutathione (GSH) in tumor site. Disulfide bond was introduced into the conjugates of oxaliplatin (IV) and oleic acid (OA) which conferred cascade reduction-responsiveness to nanoassemblies. Disulfide bond cleavage and reduction of Pt(IV) center occur sequentially as a cascade process. In comparison to oxaliplatin solution, Pt(IV) nanoparticles (NPs) achieved prolonged blood circulation and higher maximum tolerated doses. Furthermore, Oxa(IV)-SS-OA prodrug NPs exhibited potent anti-tumor efficiency against 4T1 cells and low toxicities in other normal tissues, which offers a promising nano-platform for potential clinical application.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Pró-Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Contenção de Riscos Biológicos , Dissulfetos , Humanos , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico
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