Cabazitaxel (CTX) is a potent chemotherapeutic agent, but its clinical application is limited by serious side effects, poor tumor selectivity and rapid systemic clearance. Inspired by the clinical success of albumin-bound paclitaxel (Abraxane^®) and the high affinity of CTX for human serum albumin (HSA), we aimed to develop a stable and tumor-responsive albumin-based delivery system for CTX using disulfide bond reorganization strategy. Intramolecular disulfide bonds in HSA were briefly broken by various reducing agent to promote CTX loading, followed by the recombination of intermolecular disulfide bonds to form albumin nanoparticles. Compared with nanoparticles prepared using the traditional Nab^TM method (Nab@HSA NPs), which was employed in the preparation of Abraxane^®, those prepared via the L-cysteine-based disulfide bond reorganization strategy (L-Cys@HSA NPs) showed improved stability and reduction-responsive drug release. In vivo studies confirmed that L-Cys@HSA NPs significantly enhanced the pharmacokinetic profile and tumor accumulation of CTX. Consequently, L-Cys@HSA NPs demonstrated the strongest antitumor efficacy while maintaining high level of safety. Overall, this disulfide bond reorganization strategy provides a robust platform for the design of albumin-based nanomedicine and enables the efficient delivery of chemotherapeutics.

Photodynamic therapy (PDT) employs lasers to activate photosensitizers, generating reactive oxygen species (ROS) for tumor cell destruction. However, the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency. Recent studies have shown that lysosome-targeted PDT can directly disrupt the “explosive depot” of tumor cells by triggering the release of abundant hydrolases from lysosomes. Nevertheless, existing lysosome-targeted strategies rely predominantly on a single protonation mechanism, resulting in low targeted efficiency. To enhance lysosome-targeted bursting, this study adopted a dual-mode recognition strategy, combining “hydrophobic interaction-aided fusion” with “charge-directed anchoring”. Specifically, pyropheophorbide-a (PPa) was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths (C1, C4, C8, and C12), yielding lysosome-targeted bursting photosensitizers (PPa1, PPa4, PPa8, and PPa12). Self-assembled nanoparticles (LPPa NPs) were then prepared to facilitate tumor delivery. The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency, lysosomal targeted capability, and assembly stability of LPPa NPs. Notably, PPa4 NPs demonstrated superior cellular uptake, enhanced ROS generation, and effective lysosome-targeted bursting, thereby markedly improving antitumor efficacy. In summary, the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.

Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines. These prodrugs typically consist of drug modules, response modules, and modification modules. The general role of modification modules is to modulate the self-assembly ability of the prodrugs. How to optimize the structure of modification modules for balanced efficacy and safety of high-toxicity chemotherapeutic drugs deserves to be further investigated. In this study, a modification strategy of aliphatic alcohols with various chain lengths (SC₄, SC₈, SC₁₂, SC₁₆ and SC₂₀) was carried out to design five cabazitaxel (CBZ) prodrugs. Among them, CBZ-SC NPs with shorter chain length (SC₄ and SC₈) showed poor self-assembly stability. CBZ-SC₁₂ NPs also failed to remain stable while the other two CBZ-SC NPs exhibited good stability. In turn, the drug release rate was hindered by the increasing chain length. CBZ-SC₁₂ NPs caused kidney damage due to their high redox-sensitivity and rapid release rate during circulation. By contrast, CBZ-SC NPs with longer chain length (SC₁₆ and SC₂₀) not only demonstrated superior stability with improved pharmacokinetic behavior, but also might solve the dilemma of dose-related toxicity caused by CBZ. Overall, these findings emphasized the importance of chain length in modification module to modulate the efficacy and safety of CBZ prodrug nanoassemblies.

Dimeric prodrug nanoassemblies (DPNAs) offer great potential in improving the efficacy of chemotherapy. Previously, we developed tetrasulfide bonds as a novel response module and the obtained γ-4S-2CTX NPs demonstrated superlative self-assembly stability and enhanced anti-tumor efficacy. However, current DPNAs mainly rely on simple PEGylation for surface modification to improve blood circulation, which lacks tumor-selective functionality and limits their further application. To address these limitations, we introduced a new surface modification strategy using RM-1 tumor cell membranes (CMs) to enhance biofunctionality. The initial attempt to use CMs as a single surface modification failed because the affinity of nanocores-CMs remains a problem, which affected the stability of membrane-coated DPNAs. To address this, we used 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethyleneglycol)-2000] (DSPE-PEG_2k) as an adhesive bridge to improve the affinity between CMs and DPNAs, resulting in a dual-modified formulation termed CM-pDPNAs. This dual modification strategy enhanced CMs binding to DPNAs, enabling precise tumor recognition and internalization, thereby improving tumor elimination efficacy. Furthermore, this approach addressed key challenges associated with current CM-coated nanoparticles (CM-NPs), including complex preparation procedures and poor drug-carrier compatibility. This work elucidates the application of CMs as surface modification modules, paving the way for the next generation of biomimetic prodrug nanoassemblies with superior stability and tumor specificity.

The clinical utility of irinotecan is restricted by individual variability in carboxylesterase expression. Direct administration of its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN38), presents an appealing alternative due to its potent anti-tumor efficacy. However, the undesirable properties of SN38, such as poor water solubility and non-target toxicity, present significant hurdles to its clinical development. Prodrug nanoassemblies based on modular design strategy show promise in overcoming these challenges by enhancing drug delivery and selective activation. In modular design, the modification module plays a crucial role in improving the self-assembly capability of prodrugs. While current studies mainly focus on using straight aliphatic chains for prodrug design, branched aliphatic chains emerge as superior alternatives warranting further investigation. In this study, we selected 2-heptylundecanol (BAlc₁₈) as modification module to construct an SN38 prodrug. Through exquisite design, SN38-SS-BAlc₁₈ NPs integrated prominent properties in self-assembly capability, specific activation and biocompatibility, resolving the challenges of irinotecan and SN38, ultimately demonstrating excellent anti-tumor efficacy. This exploration enriched the design theory of prodrug nanoassemblies that can effectively balance safety and colorectal anti-tumor efficacy.

Albumin nanoparticles (ANPs) offer unique advantages for antitumor drug delivery system, including non-immunogenicity and inherent tumor-targeting capacity. At present, only a few products, such as ABRAXANE® and FYARRO™, have been approved for clinical applications. The poor affinity of doxorubicin (DOX) for albumin, coupled with its numerous severe adverse reactions, poses challenges in the fabrication of desirable albumin nanoparticles loaded with DOX. In this study, we developed prodrugs by conjugating fatty acids of varying lengths with DOX. Our aim was to investigate the balance between efficacy and safety through the selection of appropriate modules. We synthesized five pH-sensitive doxorubicin-fatty acid prodrugs. Compared to free DOX, all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 nm. Additionally, DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor cells. Significantly, the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids, impacting their in vivo pharmacokinetics, antitumor effectiveness and tumor accumulation. This research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs, and it builds a good platform for creating ANPs which prioritize high drug loading, high efficiency, and minimal side effects.

Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems. However, in the case of camptothecins-based prodrug nanoassemblies, linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies, which are highly unfavorable for sterilization through filtration, and may cause capillary blockage upon intravenous injection. The rational design of camptothecins-based prodrug nanoassemblies remains a challenge. Herein, we propose that branched aliphatic alcohol (BAA) functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies. Correspondingly, four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin (SN38) with BAAs of varying lengths via a tumor redox-responsive disulfide bond, which self-assemble into uniform spherical nanoparticles. The length of BAA was found to significant impact the multiple drug delivery process, including colloidal stability, drug release profiles and pharmacokinetics. Overall, SN38-C21 NPs (SN38-11-heneicosanol nanoparticles), featuring the longest BAA, showcased multiple therapeutic advantages, ultimately culminating the optimal antitumor efficacy and tolerance. The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies, and provide valuable insights for developing translational camptothecins-based nanomedicines.

Prodrug-based nanoassembly emerges as a hopeful way for the efficient delivery of antitumor drugs, with carrier-free structure and ultra-high drug loading. Carbon chains are widely used to design self-assembling prodrugs. The impacts of the length of carbon chains on the self-assembly stability, drug delivery efficiency and antitumor effect of prodrugs have not been fully elucidated. Here, three paclitaxel prodrugs were synthesized by conjugating paclitaxel with octanol (C₈), decanol (C₁₀) or dodecanol (C₁₂) through disulfide bond. The three prodrugs could form homogeneous nanoparticles, with over 50% drug loading and redox dual-responsivity. Interestingly, the length extension of carbon chains ameliorates the self-assembly and the colloidal stability of prodrugs, thus improving the drug delivery efficiency. The optimal paclitaxel-dodecanol prodrug nanoassemblies exhibit better antitumor efficacy than Taxol and Abraxane. These findings are meaningful for the rational design of advanced nanomedicines in cancer therapy.