Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy.

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation.

The immunologically "cold" microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

Programmed pH-responsive core-shell nanoparticles for precisely targeted therapy of ulcerative colitis.

pH-Responsive nanotherapeutics were recently developed for the treatment of ulcerative colitis (UC). However, they target the entire colon rather than the UC site, which leads to insufficient accumulation in inflamed colon lesions and causes side effects. Core-shell nanoparticles exhibit unique advantages in improving the precision of targeted delivery. In this study, Eudragit® EPO and L100, two pH-sensitive materials, were coated on nano-sized curcumin to fabricate core-shell nanoparticles. The developed CNs@EPO@L100 exhibited programmed pH-responsive drug release behavior, improved in vitro anti-inflammatory ability, and enhanced accumulation at the site of inflammation in the colon. Furthermore, after oral administration, CNs@EPO@L100 significantly ameliorated the inflammatory symptoms in mice. Taken together, this study provides insights into programmed release through the rational application of pH-sensitive materials and offers strategies for a precisely targeted therapy of UC using core-shell nanoparticles.

Hybrid chalcogen bonds in prodrug nanoassemblies provides dual redox-responsivity in the tumor microenvironment.

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.

Metal complex-based liposomes: Applications and prospects in cancer diagnostics and therapeutics.

Metal complexes are of increasing interest as pharmaceutical agents in cancer diagnostics and therapeutics, while some of them suffer from issues such as limited water solubility and severe systemic toxicity. These drawbacks severely hampered their efficacy and clinical applications. Liposomes hold promise as delivery vehicles for constructing metal complex-based liposomes to maximize the therapeutic efficacy and minimize the side effects of metal complexes. This review provides an overview on the latest advances of metal complex-based liposomal delivery systems. First, the development of metal complex-mediated liposomal encapsulation is briefly introduced. Next, applications of metal complex-based liposomes in a variety of fields are overviewed, where drug delivery, cancer imaging (single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI)), and cancer therapy (chemotherapy, phototherapy, and radiotherapy) were involved. Moreover, the potential toxicity, action of toxic mechanisms, immunological effects of metal complexes as well as the advantages of metal complex-liposomes in this content are also discussed. In the end, the future expectations and challenges of metal complex-based liposomes in clinical cancer therapy are tentatively proposed.

Emerging systemic delivery strategies of oncolytic viruses: A key step toward cancer immunotherapy.

Oncolytic virotherapy (OVT) is a novel type of immunotherapy that induces anti-tumor responses through selective self-replication within cancer cells and oncolytic virus (OV)-mediated immunostimulation. Notably, talimogene laherparepvec (T-Vec) developed by the Amgen company in 2015, is the first FDA-approved OV product to be administered via intratumoral injection and has been the most successful OVT treatment. However, the systemic administration of OVs still faces huge challenges, including in vivo pre-existing neutralizing antibodies and poor targeting delivery efficacy. Recently, state-of-the-art progress has been made in the development of systemic delivery of OVs, which demonstrates a promising step toward broadening the scope of cancer immunotherapy and improving the clinical efficacy of OV delivery. Herein, this review describes the general characteristics of OVs, focusing on the action mechanisms of OVs as well as the advantages and disadvantages of OVT. The emerging multiple systemic administration approaches of OVs are summarized in the past five years. In addition, the combination treatments between OVT and traditional therapies (chemotherapy, thermotherapy, immunotherapy, and radiotherapy, etc.) are highlighted. Last but not least, the future prospects and challenges of OVT are also discussed, with the aim of facilitating medical researchers to extensively apply the OVT in the cancer therapy.

Probing the new strategy for the oral formulations of taxanes: changing the method with the situation.

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.

Small-Molecule Prodrug Nanoassemblies: An Emerging Nanoplatform for Anticancer Drug Delivery.

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.

Low dose shikonin and anthracyclines coloaded liposomes induce robust immunogenetic cell death for synergistic chemo-immunotherapy.

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.

Emerging nanotaxanes for cancer therapy.

The clinical application of taxane (including paclitaxel, docetaxel, and cabazitaxel)-based formulations is significantly impeded by their off-target distribution, unsatisfactory release, and acquired resistance/metastasis. Recent decades have witnessed a dramatic progress in the development of high-efficiency, low-toxicity nanotaxanes via the use of novel biomaterials and nanoparticulate drug delivery systems (nano-DDSs). Thus, in this review, the achievements of nanotaxanes-targeted delivery and stimuli-responsive nano-DDSs-in preclinical or clinical trials have been outlined. Then, emerging nanotherapeutics against tumor resistance and metastasis have been overviewed, with a particular emphasis on synergistic therapy strategies (e.g., combination with surgery, chemotherapy, radiotherapy, biotherapy, immunotherapy, gas therapy, phototherapy, and multitherapy). Finally, the latest oral nanotaxanes have been briefly discussed.

Erythrocyte membrane-camouflaged carrier-free nanoassembly of FRET photosensitizer pairs with high therapeutic efficiency and high security for programmed cancer synergistic phototherapy.

Phototherapy has been intensively investigated as a non-invasive cancer treatment option. However, its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity. To achieve high therapeutic efficiency and high security, a nanoassembly of Forster Resonance Energy Transfer (FRET) photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy. For proof-of-concept, an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6 (Ce6, FRET donor) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, FRET acceptor) is investigated for breast cancer treatment. Notably, Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy (PDT) only when DiR is photobleached by 808-nm laser. As a result, Ce6-caused phototoxicity could be well controlled. Under cascaded laser irradiation (808-660 nm), tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs, relieves tumor hypoxia, and promotes the PDT efficacy of Ce6. Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.

Unique flower-like Cur-metal complexes loaded liposomes for primary and metastatic breast cancer therapy.

Mounting researches continue to support a favorable role for the drug metal complex against cancer progress and metastasis. However, pharmaceutical barriers were encountered when drug metal complexes needed further pre-clinical and clinical evaluations due to their poor aqueous solubility. In this research, liposomes loaded metal ion as nano-scaled reaction vehicles were used to carry out a synthesis reaction between metal ion and curcumin (Cur) to prepare Cur-metal drug liposomal formulations. The unique flower-like conformation of Cur-M liposomes was observed for the first time and dominated in the Cur-M liposomal formulations system by the cryo-transmission electron microscopy. Different metal ions behaved significant differences in formulations' appearance, release profile, cytotoxic effect against various cell lines, pharmacokinetic profiles, biodistribution and antitumor efficiency. Cur-M liposomes presented enhanced cellular uptake and ROS generation effects, thus augmenting the cytotoxicity of Cur. Superior performances of Cur-copper complexes liposomes were observed in improving Cur stability, promoting apoptosis, inhibiting the proliferation and angiogenesis, therefore enhancing therapeutic effect for primary and metastatic breast cancer. Overall, the current work highlights the potentially significant development value of Cur-M liposomes as an injectable agent for cancer treatment, even superior to the commercial agent Doxil.

Remote loading paclitaxel-doxorubicin prodrug into liposomes for cancer combination therapy.

The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX-S-DOX (PSD). The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu2+) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+ gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.

Ratiometric delivery of doxorubicin and berberine by liposome enables superior therapeutic index than DoxilⓇ.

Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine (BER) and doxorubicin (DOX), which was called LipoBeDo. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, LipoBeDo, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The LipoBeDo significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil (P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.

Extraction optimization of accelerated solvent extraction for eight active compounds from Yaobitong capsule using response surface methodology: Comparison with ultrasonic and reflux extraction.

This work described the development of a novel method for simultaneous extraction of eight active compounds (including catechin, albiflorin, paeoniflorin, ferulic acid, ginsenoside Rg1, tetrahydropalmatine, ginsenoside Rb1 and osthole) from Yaobitong capsule by accelerated solvent extraction (ASE). Response surface methodology (RSM) with desirability functions was employed to optimize the extraction conditions yielding the optimal conditions of ASE (extraction time 8 min, extraction temperature 80 °C, extraction solvent 70% methanol and flushing volume 100%). A high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD) method was developed and validated for simultaneous quantification of the eight compounds in Yaobitong capsule. The values of correlation coefficient (R) were satisfactory between 0.9992 and 0.9999 over the linear concentration range of 0.5-1000 µg mL-1. It was found that the limits of detection (LODs) and the limits of quantification (LOQs) for the eight active compounds were 0.10-2.90 µg•mL-1 and 0.30-9.40 µg•mL-1, respectively. The recoveries of the eight main active compounds in Yaobitong capsule were in the range of 93.31%-106.22%. And the contents of the analytes extracted by ASE under the optimal conditions were compared to traditional solvent extraction methods, such as ultrasonic and reflux extraction. The results indicated that the ASE method proved to be more suitable for the extract of active compounds in Yaobitong capsule, which could obtain higher extraction efficiency. At last, the proposed method was applied to analyze ten batches of actual samples, which provided high extraction efficiency and had wide potential application in the analysis of traditional Chinese medicines.

Ferroptosis-driven nanotherapeutics for cancer treatment.

The clinical efficacy of existing cancer therapies is still far from satisfactory. There is an urgent need to integrate the emerging biomedical discovery and technological innovation with traditional therapies. Ferroptosis, a non-apoptotic programmed cell death modality, has attracted remarkable attention as an emerging therapeutic target for cancer treatment, especially with the burgeoning bionanotechnology. Given the rapid progression in ferroptosis-driven cancer nanotherapeutics, we intend to outline the latest advances in this field at the intersection of ferroptosis and bionanotechnology. First, the research background of ferroptosis and nanotherapeutics is briefly introduced to illustrate the feasibility of ferroptosis-driven nanotherapeutics for cancer therapy. Second, the emerging nanotherapeutics developed to facilitate ferroptosis of tumor cells are overviewed, including promotion of the Fenton reaction, inhibition of cellular glutathione peroxidase 4 (GPX-4), and exogenous regulation of lipid peroxidation. Moreover, ferroptosis-based combination therapeutics are discussed, including the emerging nanotherapeutics combining ferroptosis with tumor imaging, phototherapy, chemotherapy and immunomodulation. Finally, the future expectations and challenges of ferroptosis-driven nanotherapeutics in clinical cancer therapy are spotlighted.

Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy.

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.

Self-Assembly of a Pure Photosensitizer as a Versatile Theragnostic Nanoplatform for Imaging-Guided Antitumor Photothermal Therapy.

Imaging-guided diagnosis and phototherapy has been emerging as promising theragnostic strategies for detection and treatment of cancer. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) has been widely investigated for in vivo imaging and photothermal therapy (PTT). However, the tumor-homing ability and PTT efficiency of DiR is greatly limited by its extremely low water solubility and nonspecific distribution in off-target tissues. Herein, a facile nanoassembly of pure DiR is reported as a theragnostic nanocarrier platform for imaging-guided antitumor phototherapy. Self-assembly of DiR has almost no effect on its in vitro photothermal efficacy when compared with DiR solution. Interestingly, the PEGylated nanoassemblies of DiR showed distinct advantages over DiR solution and non-PEGylated nanoassemblies in terms of systemic circulation and tumor-homing capability in vivo. As a result, PEGylated DiR nanoassemblies demonstrate potent photothermal tumor therapy in BALB/c mice bearing 4T1 xenograft tumors. Such a pure photosensitizer-based nanoassembly holds great potential as a versatile platform for efficient imaging-guided cancer therapy.

Reduction-sensitive Paclitaxel Prodrug Self-assembled Nanoparticles with Tetrandrine Effectively Promote Synergistic Therapy Against Drug-sensitive and Multidrug-resistant Breast Cancer.

Codelivery of multiple drugs with complementary anticancer mechanisms by nanocarriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE coloaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells. TPNPs were facilitated to release PTX and TET under a highly reductive environment in tumor cells through the in vitro simulative release study. Cell apoptosis study and Western blotting analysis exhibited TPNPs could significantly increase cell apoptosis via modulating the levels of Bcl-2 protein and Caspase-3, which might be triggered by excess cellular reactive oxygen species (ROS) production through an intracellular ROS detection test. Cellular uptake study showed that TET could increase PTX accumulation in MCF-7/Adr cells but not in MCF-7 cells, which explained stronger synergetic efficacy of TPNPs on MCF-7/Adr cells. Overall, encapsulation of hydrophobic drugs, such as TET, in reduction-sensitive PTX-SS-VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumor cells in a synergistic manner. Such a uniquely small molecular weight prodrug-nanocarrier opens up new perspectives for the development of nanomedicines.