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.

Despite great therapeutic effect of Abraxane^®, complex preparation technology and unfavorable pharmacokinetics still restricted the clinical application of albumin-based paclitaxel (PTX) nanoparticles (NPs). Herein, we reported that an albumin-binding prodrug, phenylboronic acid-conjugated PTX (P-PTX), can form the uniform NPs with the diameters around 100 nm with the help of albumin via simple one-step nano-precipitation method. The albumin-based nanomedicines were stabilized by the integration of a single boronic acid with PTX due to the increased affinity based on multiple intermolecular interactions. We found that albumin-based P-PTX NPs exhibited superior colloidal stability over albumin-based PTX NPs through one-step nano-precipitation approach, achieving longer in vivo circulation time and higher concentration in tumor than those of the marketed Abraxane^®. Furthermore, the albumin-based P-PTX NPs with great stability and enhanced intratumoral enrichment, increased the maximum tolerated dose of PTX, remarkably suppressed the growth of breast tumor and lung metastasis, and prolonged survival of melanoma tumors-bearing mice. Such a convenient and effective system gains an insight into the impact of phenylboronic acid group on the albumin-based PTX NPs, and provides potent strategy for the rational design of albumin-based antitumor nanomedicines.

Tumor sentinel lymph node (SLN) metastasis plays a vital role in tumor staging and therapeutic decision-making process. However, precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent probes. Herein, we report three novel IR820-fatty acid (FA) conjugates (IR-OA, IR-LA, and IR-PA) for precise lymphatic metastasis illumination and primary tumor diagnosis. The IR-FA conjugates are able to non-covalently bound to albumin in vivo, and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin (BSA) in vitro. Moreover, the BSA-IR-FA conjugates display large Stokes shift (> 120 nm), dramatically improving in vivo imaging resolution. Among them, IR-PA demonstrates distinct advantage over IR-OA, IR-LA, and IR-maleimide (MAL) (fluorescent probe previously reported by our group) in terms of fluorescence quantum yield, photostability, and imaging resolution. As a result, IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor location. Our findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.

Self-engineered small-molecule prodrug-nanoassemblies have emerged as promising nanomedicines for cancer treatment. Modular design of prodrug molecules is crucial to guarantee the favorable assembly stability, tumor-specific prodrug activation, and satisfactory antitumor effect. However, too much attention has been paid to the pharmacophores and chemical linkages in prodrug molecules while neglects the vital roles of nonpharmacological moieties. Herein, we found that iso-carbon fatty acids with different number, position, and cis-trans configuration of double bonds dramatically affect the nanoassembly feature and drug delivery fates of thioether-linked paclitaxel prodrug-nanoassemblies. Particularly, the number and cis-trans configuration of double bonds in fatty acid moieties not only dominate the self-assembly ability and colloidal stability of prodrugs, but also exert significant influences on the pharmacokinetics, prodrug activation, and antitumor activity of prodrug-nanoassemblies. Finally, oleic acid with one cis double bond stands out as the optimal nonpharmacological moiety for thioether-linked paclitaxel prodrug-nanoassemblies. This study elucidates the crucial roles of nonpharmacological moieties in prodrugs, and provides new insights into the modular design of prodrug-based nanomedicines for cancer therapy.

The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells. However, the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions. Supplementing with an additional reductant is a promising strategy to further boost drug release. Herein, inspired by the specific absorption mechanism of triglyceride fat, structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin (SN38) were designed to improve intestinal permeability and bypass the first-pass effect. SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract. Surprisingly, we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38, indicating an effective oral delivery. In addition, the reduction-responsive disulfide bond was used as a linker, and ascorbic acid (ASC) was coadministrated to further promote the efficient release of SN38 from the prodrug. ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety. In summary, the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.

Tumor hypoxia is one of the major factors restricting the photodynamic therapy (PDT) efficacy. To address this problem, we designed an arginine-peptide complex, namely Fluorenylmethoxycarbonyl-Leucine-Leucine-Leucine-Arginine-OH (Fmoc-L₃-Arg), which is able to co-assemble with 5,10,15,20-Tetrakis (4-hydroxyphenyl) porphyrin (THPP) into stable nanoparticles (NPs) with uniform and spherical shapes. The THPP/Fomc-L₃-Arg NPs were ultra-sensitive to tumorous acidic and oxidative conditions, and could rapidly release photosensitizers in tumor cells. Meanwhile, the co-loaded Fmoc-L₃-Arg could efficiently generate nitric oxide (NO), inhibiting mitochondrial cellular respiration and increasing oxygen in tumor cells to support the profound improvement of reactive oxygen species (ROS) yield and PDT efficacy. After intravenous injection, the THPP/Fomc-L₃-Arg NPs greatly accumulated at tumor tissue and significantly inhibited tumor growth upon irradiation. In conclusion, such an arginine-peptide complex-based nanoassembly addresses the inevitable problem of hypoxia-induced tumor resistance to PDT.

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.