Ferrocene-Conjugated Paclitaxel Prodrug for Combined Chemo-Ferroptosis Therapy of Cancer.

Herein, we developed a paclitaxel prodrug (PSFc) through the conjugation of paclitaxel (PTX) and ferrocene via a redox-responsive disulfide bond. PSFc displays acid-enhanced catalytic activity of Fenton reaction and is capable of forming stable nanoparticles (PSFc NPs) through the assembly with distearoyl phosphoethanolamine-PEG2000. After being endocytosed, PSFc NPs could release PTX to promote cell apoptosis in response to overexpressed redox-active species of tumor cells. Meanwhile, the ferrocene-mediated Fenton reaction promotes intracellular accumulation of hydroxyl radicals and depletion of glutathione, thus leading to ferroptosis. Compared with the clinically used Taxol, PSFc NPs exhibited more potent in vivo antitumor outcomes through the combined effect of chemotherapy and ferroptosis. This study may offer insight into a facile design of a prodrug integrating different tumor treatment methods for combating malignant tumors.

Self-assembled nanoformulations of paclitaxel for enhanced cancer theranostics.

Chemotherapy has occupied the critical position in cancer therapy, especially towards the post-operative, advanced, recurrent, and metastatic tumors. Paclitaxel (PTX)-based formulations have been widely used in clinical practice, while the therapeutic effect is far from satisfied due to off-target toxicity and drug resistance. The caseless multi-components make the preparation technology complicated and aggravate the concerns with the excipients-associated toxicity. The self-assembled PTX nanoparticles possess a high drug content and could incorporate various functional molecules for enhancing the therapeutic index. In this work, we summarize the self-assembly strategy for diverse nanodrugs of PTX. Then, the advancement of nanodrugs for tumor therapy, especially emphasis on mono-chemotherapy, combinational therapy, and theranostics, have been outlined. Finally, the challenges and potential improvements have been briefly spotlighted.

Porphyrin Cholesterol Conjugates for Enhanced Photodynamic Immunotherapy toward Lung Cancer.

Lung cancer is the major cause of cancer death worldwide. Immune checkpoint inhibitors (ICIs) of PD-1/PD-L1 have improved the survival rate in some patients with lung cancer. However, the efficacy of ICIs is limited by the inhibitory tumor immune microenvironment. Herein, we designed porphyrin cholesterol conjugates (TPPC) for synergistic photodynamic therapy (PDT)-immunotherapy for lung cancer. Porphyrin derivatives with great reactive oxygen species (ROS) production efficiency have been applied as photosensitizers in clinics, and cholesterol is one of the main components of the cell membrane. Porphyrin cholesterol conjugates could assemble into nanoparticles (NPs) in the absence of surfactants or amphiphilic polymers. On the other hand, TPPC NP-mediated PDT could accumulate at the tumor site and induce immunogenic cell death to stimulate and recruit antigen-presenting cells to mature and activate T cells, rendering cancer cells more sensitive to ICIs. Importantly, the combination strategy reshapes the tumor immune microenvironment to enhance the antitumor immune response and significantly suppresses the tumor growth and eliminates metastasis. This study offers theoretical guidance for the combination of PDT and ICIs as a potential therapeutic option in lung cancer.

A Paclitaxel Prodrug with Copper Depletion for Combined Therapy toward Triple-Negative Breast Cancer.

Tuning the content of copper is of great significance for the treatment of cancer and neurodegenerative diseases. Herein, we synthesized a redox-responsive paclitaxel (PTX) prodrug by conjugating PTX with a copper chelator through a disulfide bond. The as-fabricated prodrug (PSPA) showed specific chelation toward copper ions and could assemble with distearoyl phosphoethanolamine-PEG2000 to form stable nanoparticles (PSPA NPs) in aqueous media. Upon being internalized by tumor cells, PSPA NPs could respond to high levels of redox-active species inside cells and efficiently release PTX. The copper chelator could increase oxidative stress- and abnormal metabolism-induced cell death through intracellular copper depletion. The combination of chemotherapy and copper depletion therapy generated an enhanced therapeutic outcome toward triple-negative breast cancer with an ignorable systemic toxicity. Our work may provide insight into the combination of metabolic regulation and chemotherapy for combating malignant tumors.

Carboxylated paclitaxel prodrug nanofibers for enhanced chemotherapy.

The facile availability of nanoformulations with enhanced antitumor performance remains a big challenge. Herein, we synthesize paclitaxel prodrugs with amphiphilic structures and robust assembling ability. Carboxylated paclitaxel prodrugs (PSCB) containing disulfide bonds prefer to form exquisite nanofibers, while phenylcarbinol end capped paclitaxel prodrugs (PSP) assemble into spherical nanoparticles. The transformation of morphology from nanofibers to nanorods can be realized via tuning the content of paclitaxel. Hydrophilic domains of PSCB nanofibers accelerate the cleavage of disulfide bond for rapid drug release in tumor cells, thus exhibiting the enhanced cytotoxicity and antitumor activity. This study provides a crucial insight into the functional design of hydrophobic drugs to improve chemotherapy.

Hypoxia-Activated PEGylated Paclitaxel Prodrug Nanoparticles for Potentiated Chemotherapy.

Developing controlled drug-release systems is imperative and valuable for increasing the therapeutic index. Herein, we synthesized hypoxia-responsive PEGylated (PEG = poly(ethylene glycol)) paclitaxel prodrugs by utilizing azobenzene (Azo) as a cleavable linker. The as-fabricated prodrugs could self-assemble into stable nanoparticles (PAP NPs) with high drug content ranging from 26 to 44 wt %. The Azo group in PAP NPs could be cleaved at the tumorous hypoxia microenvironment and promoted the release of paclitaxel for exerting cytotoxicity toward cancer cells. In addition, comparative researches revealed that the PAP NPs with the shorter methoxy-PEG chain (molecular weight = 750) possessed enhanced tumor suppression efficacy and alleviated off-target toxicity. Our work demonstrates a promising tactic to develop smart and simple nanomaterials for disease treatment.

Indocyanine green potentiated paclitaxel nanoprodrugs for imaging and chemotherapy.

Self-assembled prodrug nanoparticles with tumor-responsive capacity have great potential in tumor visualization and treatment. However, the nanoparticle formulas usually contain multiple components, especially polymeric materials, which result in various potential issues. Herein, we report an indocyanine green (ICG)-driven assembly of paclitaxel prodrugs integrating near-infrared fluorescence imaging and tumor-specific chemotherapy. By feat of the hydrophilic merit of ICG, paclitaxel dimer could form more uniformly monodispersed nanoparticles. This two-in-one strategy reinforces the complementary advantages, resulting in superior assembly behavior, robust colloidal stability, enhanced tumor accumulation as well as desirable near-infrared imaging and in vivo feedback of chemotherapy. The in vivo experiments validated the prodrug activation at tumor sites as evidenced by enhanced fluorescence intensity, potent tumor growth suppression, and reduced systemic toxicity compared with commercial Taxol. The universality of ICG potentiated strategy toward photosensitizers and fluorescence dyes was confirmed. This presentation provides deep insight into the feasibility of constructing clinical-close alternatives for improving antitumor efficacy.

Fluorinated paclitaxel prodrugs for potentiated stability and chemotherapy.

Robust colloidal stability is an essential prerequisite for effective drug delivery. Herein, a series of fluorinated paclitaxel prodrugs bridged with redox-responsive linkages were synthesized, and the effect of fluorination on the assembly behavior and physiological stability was investigated. The 17-fluorinated ethanol-modified paclitaxel prodrug could self-assemble into stable nanoparticles without the addition of any surfactants. Fluorinated paclitaxel prodrug nanoparticles possessed potent cytotoxicity toward cancer cells and superior antitumor activity. This study offers a universal fluorination approach to improve drug delivery efficacy by enhancing the self-assembly capability and improving the colloidal stability of prodrugs for potentiating chemotherapy.

Combination of starvation therapy and Pt-NP based chemotherapy for synergistic cancer treatment.

Platinum nanoparticles (Pt-NPs) have been developed for enhanced toxicity against tumor cells. However, the therapeutic effect of Pt-NPs was severely limited by the lack of cellular uptake of Pt-NPs and an oxidative environment. The combination of starvation therapy with Pt-NP based chemotherapy in a well-designed nano-system is expected to eliminate tumors. Therefore, GOx and Pt-NPs were coated with PLGA to obtain a functional nano-system (GOx-Pt-NS), which increased the cellular uptake of Pt-NPs. The accumulation of GOx-Pt-NS in tumors increased significantly via the enhanced permeability and retention (EPR) effect of nanoparticles. In addition, protection of the GOx-Pt-NS overcame several drawbacks of GOx such as poor stability, short in vivo half-life, immunogenicity, and systemic toxicity. Glucose oxidase (GOx) elevated the gluconic acid ROS levels in tumor cells, resulting in an acidic and oxidative environment. The acidic and oxidative environment enhanced the conversion of Pt2+via Pt NPs as well as DNA-binding ability. Finally, combining GOx based starvation therapy with Pt-NP based chemotherapy was expected to eliminate tumors more efficiently through a synergistic strategy.