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Here, we introduce a novel and effective approach utilizing a cathepsin B cleavage albumin-binding SN38 prodrug specifically designed for the treatment of metastatic breast cancer. Termed Mal-va-mac-SN38, our prodrug exhibits a unique ability to rapidly and covalently bind with endogenous albumin, resulting in the formation of HSA-va-mac-SN38. This prodrug demonstrates exceptional stability in human plasma. Importantly, HSA-va-mac-SN38 showcases an impressive enhancement in cellular uptake by 4T1 breast cancer cells, primarily facilitated through caveolin-mediated endocytosis. Intriguingly, the release of the active SN38, is triggered by the enzymatic activity of cathepsin B within the lysosomal environment. In vivo studies employing a lung metastasis 4T1 breast cancer model underscore the potency of HSA-va-mac-SN38. Histological immunohistochemical analyses further illuminate the multifaceted impact of our prodrug, showcasing elevated levels of apoptosis, downregulated expression of matrix metalloproteinases, and inhibition of angiogenesis, all critical factors contributing to the anti-metastatic effect observed. Biodistribution studies elucidate the capacity of Mal-va-mac-SN38 to augment tumor accumulation through covalent binding to serum albumin, presenting a potential avenue for targeted therapeutic interventions. Collectively, our findings propose a promising therapeutic avenue for metastatic breast cancer, through the utilization of a cathepsin B-cleavable albumin-binding prodrug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The albumin-based drug delivery system is an effective drug delivery strategy for traditional chemotherapeutic drugs that can improve their antitumour efficacies and reduce systemic toxicities. The camptothecin derivative CPTS0001 has excellent antitumour activity in vitro, but it shows toxicity and side effects in vivo. In this study, we report the synthesis and biological evaluation of the β-glucuronidase-reactive albumin-binding prodrug Mal-glu-CPTS0001 based on quaternary ammonium. After intravenous administration, the compound covalently binds to plasma albumin through Michael addition, enabling it to accumulate in tumours, where tumour-associated β-glucuronidase triggers the selective release of CPTS0001. This prodrug significantly reduced the toxicity of the parent drug, and the maximum tolerated dose was increased by 2.5 times. At the same time, this prodrug enhanced the selectivity in vivo and improved the preferential accumulation of prodrug in tumours. Notably, this prodrug exhibited excellent in vivo antitumour effects in a murine breast cancer xenograft model without visible pathological toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we designed, optimized and synthesized a new multifunctional bioreductive linker (12) containing an alkynyl group (potential click chemistry fragment); the linker is based on 2-nitroimidazole which was expected to simultaneously overcome the drawbacks of hypoxia-activated prodrugs (poor selectivity and unsatisfactory water solubility). Furthermore, a hypoxia-activated, water-soluble SN-38 prodrug was obtained, and it was stable under physiological conditions and was rapidly released as an active drug under hypoxic conditions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The physicochemical properties of camptothecin (CPT) limit its clinical application. To maximize drug efficacy, a novel intelligent prodrug delivery nanoplatform with a tumor microenvironment-cleavable core crosslinking strategy was proposed based on a phenylboronic acid (PBA) modified polyethylene glycol (PEG)-polyglutamic acid (PGlu) polymer with disulfide-bonded CPT, called PBA-PEG-P(Glu-co-GlussCPT). The fabricated nanoplatform was a spherical micelle that could withstand dilution and carry a large number of therapeutic molecules to the tumor tissues, thereby minimizing premature drug release. Moreover, the nanoplatform release 6.2 ± 0.62, 12.4 ± 1.8, 46.7 ± 0.33, and 79.2 ± 1.58% of CPT after incubation in 0.02, 1, 5, and 10 mM dithiothreitol for 24 h, respectively, exhibiting good reduction-sensitivity. Moreover, the nanoplatform exhibited significant antiproliferative activity against tumor cells. In addition, with PBA modification, the nanoplatform demonstrated enhanced endocytosis efficiency. This prodrug nanoplatform also exhibited significant in vivo antitumor efficacy on both murine and human hepatoma xenograft models, without showing significant systemic toxicity but demonstrating good biocompatibility. In other words, this novel intelligent prodrug delivery nanoplatform with tumor microenvironment-cleavable core crosslinking strategy and active targeting strategy based on prodrug polymer PBA-PEG-P(Glu-co-GlussCPT) demonstrated multiple functions and significant potential for antitumor drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Paclitaxel (PTX) is the first-line treatment drug for breast cancer. However, drug resistance after a course of treatment and low selectivity restricted its clinical utility sometimes. In this study, we successfully bound PTX and vorinostat (SAHA) to form co-prodrugs based on the synergistic anticancer effects. The PTX-SAHA co-prodrugs were conjugated by glycine (1a) and succinic acid (1b) respectively and the former has shown better activity in cytotoxicity, cell cycle arrest and western-blot experiments. Therefore, 1a was further prepared to nanomicelles with mPEG 2000 -PLA 1750 as the carrier by using thin film method. PTX-SAHA co-prodrug nanomicelles were spherical with a particle size of 20-100 nm. In vitro drug release test showed 1a nanomicelles had sustained release effect, which could reduce the resistance of PTX. In vitro cytotoxicity was evaluated by SRB assay in HCT-116 cells, MCF-7 cells and drug-resistant MCF-7/ADR cells. The results showed 1a nanomicelles had comparable or even better cytotoxicity than PTX especially in the MCF-7/ADR cells. All the results suggested that PTX-SAHA co-prodrug nanomicelles were promising treatment for PTX resistance cancer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A carrier-free and reduction-degradable Janus prodrug, termed as CPT-SS-GEM, was fabricated by redox-sensitive disulfide bond linked gemcitabine and camptothecin. This amphiphilic prodrug showed high drug loading capacity, 42.6% of CPT and 32.2% of GEM, respectively. Benefiting from its amphiphilic property, CPT-SS-GEM prodrug could self-assemble into Janus nano-prodrug in water without aid of any excipient. The morphology of the nano-prodrug was spherical particle confirmed by TEM. The rapid drug release from the nano-prodrug proceeded in a reduction-dependent manner, more than 90% of the native CPT and GEM were released in the mimic microenvironment of tumor cells (pH 6.5 PBS containing 2 mM DTT) within a period of 3 h. The concurrent and ratio-metric release of CPT and GEM endowed the Janus nano-prodrug CPT-SS-GEM with pronounced in vitro synergistic antiproliferative effect in multiple cancer cell lines when the inhibition rate of cancer cell proliferation exceeded 50%, including A549, NCI-H460, HCT116, HT-29, and MCF-7/ADR. The combination index values showed as followings, 1.04-0.4 (A549), 0.24-0.60 (NCI-H460), 0.42-0.16 (HCT116), 1.98-0.15 (HT-29), 0.36-0.19 (MCF-7/ADR). Taken together, the carrier-free, redox-sensitive Janus nano-prodrug CPT-SS-GEM is a promising candidate as synergistic combination of chemotherapeutics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N4-amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N4-amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of -33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5+cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC-3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This work is aimed at the development of a reduction-sensitive drug carrier for the delivery of the anti-cancer drug paclitaxel (PTX). N,N'-bis(acryloyl)cystamine (CBA) was reacted with ethanolamine (AEOL) via Michael addition to synthesize cationic poly(CBA-AEOL) (PCA) containing disulfide bonds. Subsequently, polycaprolactone (PCL) was grafted from PCA to form a novel reduction-sensitive copolymer (PCA-g-PCL). The PCA-g-PCL copolymer self-assembled as spherical micelles with a mean size of ca. 108nm. The disulfide bonds in the PCA-g-PCL copolymer contributed to the reduction-sensitivity of the micelles, observed as stepwise aggregation under simulated reduction conditions. To improve the stability of PCA-g-PCL micelles in aqueous media, carboxyl-terminated poly(ethylene glycol) methyl ether (mPEG-COOH) was conjugated with the PCA-g-PCL copolymer via electrostatic interaction to produce polyion complex micelles with a hydrophilic PEG surface. The in vitro release of PTX from the mPEG@PCA-g-PCL micelle showed a reduction sensitive profile, namely the rate of drug release strongly depended upon the concentration of the reducing agent. Leakage of PTX was limited to below 30% under normal conditions while almost all the drug was released in 9h under reduction conditions with 40mM DTT. In conclusion, the assembled mPEG@PCA-g-PCL micelle with reduction-sensitive controlled release shows great potential for improving the therapeutic effect of paclitaxel., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and, in its advanced stages, has a 5-year survival rate of only 3% to 5%. Despite novel mechanisms and treatments being uncovered over the past few years, effective strategies for HCC are currently limited. Previous studies have proven that aconite can suppress tumor growth and progression and prevent the recurrence and metastasis of multiple cancers, but the underlying molecular mechanisms are largely unknown. In this study, different doses of aconite were applied to mice bearing subcutaneous HCC tumors. It was found that aconite had a therapeutic effect on H22 tumor-bearing mice in a dose-dependent manner by reducing tumor volumes and prolonging survival times, which could be attributed to the immunoregulatory effect of aconite. Furthermore, results showed that high-dose administration of aconite could enhance adaptive immunity and natural killer (NK) cell-mediated immunity by regulating the secretion of interferon-γ, upregulating T cells and NK cells, and modulating the expression of the NK cytotoxicity biomarker CD107a and the inhibitory receptor TIGIT. This study revealed a novel mechanism through which aconite exerts antitumor effects, not merely through apoptosis induction pathways, providing more sound evidence that aconite has the potential to be developed into an effective anti-HCC agent. [ABSTRACT FROM AUTHOR]

Despite being highly recognized as an antitumor candidate due to its high potency in binding to DNA topoisomerase I and inhibiting of DNA relegation, full clinical application of camptothecin is unfortunately hampered by its poor solubility in aqueous medium and by the adverse effects caused by its hydrolyzed product under physiological conditions. In an attempt to increase its effective solubility, nanomicelles formed through self-assembly of copolymers by polymer-drug conjugate or by physical envelopment have recently been established to improve the efficacy of many drugs. This review provides the most up-to-date information available relating novel nanomicelles technology to the improvement and realization of the full potential of camptothecin. In particular, physicochemical and biological properties of camptothecin and its derivatives, the controlled factors of micelle formation, the techniques of drug encapsulation, and the structure-properties of nanomicelles are elucidated and discussed. Undoubtedly, polymer nanomicelle carriers can be selectively delivered to tumors via the enhanced permeability and retention effect. Moreover, micelles with smart functions such as stimulus-responsive and specific drug targeting may enhance the activity of potent bioactive compounds, facilitating their clinical applications. [ABSTRACT FROM PUBLISHER]

Gram-scale syntheses of two kinds of bleomycin disaccharides are described. l -gulose subunit 12 was accomplished with a novel and short route in six steps and 37% overall yield from 4 , which could be easily prepared from the commercially available inexpensive material d -sorbitol, while 6-deoxy- l -gulose subunit was synthesized in 11 steps in 8% yield from d -glucolactone. The disaccharides were then prepared in a previously reported glycosidation coupling of the 3- O -carbamoyl-mannosyl donor with the l -gulopyranoside acceptors. Both disaccharides were finally obtained in gram-scale and the total synthesis of disaccharide 2 was achieved the first time. [ABSTRACT FROM AUTHOR]

Our recent publication showed that VES-dFdC nanocapsules in pure water could be obtained via the self-assembling of VES-dFdC prodrug synthesized by coupling gemcitabine (dFdC) with vitamin E succinate (VES). To prepare the intravenous injection nanoformulation, we present here a novel strategy to improve the stability and drug concentration of VES-dFdC nanoformulation in PBS or isotonic solution. Particularly, d -α-tocopheryl polyethylene glycol succinate (TPGS), usually used as drug solubilizer and coincidentally contains the same VES moiety as VES-dFdC prodrug and PEG chain, is selected to co-assemble with VES-dFdC prodrug. The zeta potentials of all the TPGS/VES-dFdC co-assemblies were close to 0 mV, and their particle size measured by dynamic light scattering (DLS) decreased from 113 to 36 nm with increasing TPGS/VES-dFdC molar ratios from 0.15 to 1.5. Stable colloidal suspensions were obtained without aggregates in PBS at 4 °C in one month or isotonic solution at 37 °C in one week, and the weight concentration of VES-dFdC prodrug increased from 7 to 17 mg/mL when the molar ratios of TPGS/VES-dFdC ranged from 0.5/1 to 1.5/1. The concentration of VES-dFdC prodrug was high enough to be used as intravenous injection nanoformulation in nude mice. Interestingly, along with the increase of TPGS/VES-dFdC molar ratios from 0.3/1 to 1.5/1, the morphology of TPGS/VES-dFdC co-assemblies changed from loose nanocapsule to compact micelle revealed by transmission electron microscope (TEM). Finally, the co-assembly of TPGS/VES-dFdC (TPGS/VES-dFdC: 1/1) was selected as intravenous injection nanoformulation to evaluate the antitumor activity. Compared with native dFdC, TPGS/VES-dFdC nanoformulation with 0.2 mmol/kg of dosage showed similar low toxicity in vivo , but 4.7 times high of tumor inhibition rate in nude mice with pre-established BxPC-3 tumors. [ABSTRACT FROM AUTHOR]

In this study, a novel micellar drug carrier was fabricated from an amphiphilic diblock copolymer containing poly (ethylene glycol) monomethyl ether (mPEG) and stearic moiety (C 18 ) with a linkage of valine-citrulline (VC), which can be cleaved by cathepsin B (C B ) enriched in lysosome of tumor cell. Moreover, the self-assembled micelles were observed as ellipsoid shape with major and minor axis of ca. 169 and 103 nm, respectively. Such drug carrier was used to encapsulate anti-cancer drug doxorubicin (DOX), and hence showed a faster drug release behavior in a mimic lysosome condition containing cathepsin B. It was ascribed to the lysosome-sensitivity of the valine-citrulline linkage, which was verified by the size distribution curve shifted to greater size under the same mimic lysosome condition. Furthermore, in comparison with pristine doxorubicin, the encapsulation strategy of as-fabricated micellar carrier resulted in a predominant decrease of cytotoxicity. On the whole, a micellar drug carrier, which can be disassembled by cathepsin B, has been emerging as a potential of specific drug release in lysosome. Additionally, the controlled nanoscale together with elongated structure of such assembled ellipsoid micelles might contribute passive targeting function to tumor tissue and faster cellular uptake behavior (Zhou et al. [33] ). [ABSTRACT FROM AUTHOR]

Abstract: To develop a tumor-targeting nano-sized delivery system of cis-dichlorodiammine platinum(II) (CDDP), polymer-metal complex micelles were fabricated from folate-conjugated PEG-graft-α,β-poly [(N-amino acidyl)-aspartamide] (FA-PEG-g-PAAsp) and CDDP. The formation of polymer-metal complex micelles was confirmed by the measurements of critical aggregation concentration (CAC) and particle size, and the morphological observation. It was found that all the micelles showed spherical shapes with clear core–shell structures in narrow size distributions. The typical particle size measured by dynamic laser scattering (DLS) was ca. 105nm, suggesting their passive targeting to tumor tissue and endocytosis potential. FA-PEG-g-PAAsp-CDDP micelles showed sustained drug release profiles over 40h, and their accumulative drug release was ranked in the order of FA-PEG-g-PAsp-Ami-CDDPFA-PEG-g-PAAsp-CDDP>mPEG-g-PAAsp-CDDP, the severe toxicity of CDDP in vivo limited its use as ideal anti-tumor drug. Furthermore, FA-PEG-g-PAAsp-CDDP and mPEG-g-PAAsp-CDDP showed rather low toxicity against mice, just similar to that of PBS. It indicated the great potential utilization of the FA-PEG-g-PAAsp-CDDP micelles as the tumor-targeted drug carriers of CDDP with improved anti-tumor efficacy. [Copyright &y& Elsevier]

• This nanoplatform facilitated drug loading with high drug loading efficiency. • The nanoplatform adopted pH-dependent crosslinking strategy. • The nanoplatform exhibited enhanced and fast endocytosis against HepG2 cells. • The nanoplatform exhibited outstanding antiproliferative effect. • The nanoplatform exhibited significantly low drug efflux. A novel bioinspired nanoplatform capable of fast endocytosis, lysosomal pH-triggered drug release, and reduced drug efflux based on PBA-PEG- b -P(Glu- co -GluDA) copolymer was developed in this study. The synthesized copolymer could facilitate doxorubicin encapsulation with relatively high drug-loading content and efficiency. Inspired by mussel byssal threads, a core crosslinking strategy based on the coordination between catechol and ferric ions was introduced to improve the stability of nanomicelles and realize lysosomal pH-controlled drug release. This nanoplatform could maintain integrity even after being dissolved in a good solvent, demonstrating its the potential to withstand infinite dilution of plasma after intravenous injection. Moreover, this nanoplatform demonstrated lysosomal pH-triggered drug release, and the cumulative release amount of doxorubicin under a simulated lysosomal condition was 13 times higher than that under a simulated plasma condition. Moreover, as a result of the high binding capacity between phenylboronic acid (PBA) and sialic acid on the surface of human hepatoma cell line (HepG2), the fast and enhanced endocytosis in addition to lysosomal pH-triggered release property and significantly low efflux, this nanoplatform exhibits improved delivery efficiency of doxorubicin into the nucleus and notably outstanding antiproliferative effects compared with doxorubicin. Furthermore, the PBA modification remarkably increased the mean fluorescence intensity of this nanoplatform endocytosed by HepG2 cells to twice that of doxorubicin after one hour of incubation. The nanoplatform exhibited an inhibition rate of 70% against tumor growth. Thus, this novel nanoplatform based on PBA-PEG- b -P(Glu- co -GluDA) copolymer displayed multifunctionality and exhibited great potential as an intelligent nanoplatform for antitumor drug delivery. [ABSTRACT FROM AUTHOR]