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Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by

Macrophages have a leading position in the tumor microenvironment (TME) which paves the way to carcinogenesis. Initially, monocytes and macrophages are recruited to the sites where the tumor develops. Under the guidance of different microenvironmental signals, macrophages would polarize into two functional phenotypes, named as classically activated macrophages (M1) and alternatively activated macrophages (M2). Contrary to the anti-tumor effect of M1, M2 exerts anti-inflammatory and tumorigenic characters. In progressive tumor, M2 tumor-associated macrophages (TAMs) are in the majority, being vital regulators reacting upon TME. This review elaborates on the role of TAMs in tumor progression. Furthermore, prospective macrophage-focused therapeutic strategies, including drugs not only in clinical trials but also at primary research stages, are summarized followed by a discussion about their clinical application values. Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article., Graphical abstract Tumor-associated macrophages (TAMs) as a major part in the tumor environment (TME) are associated with the progression of tumor. This review summarizes the roles TAMs play and some TAM targeting strategies. Also, this review provides some perspectives about drug targets for TAMs and some potential combination therapies.Image 1

On account of the biological significance of self-assembling peptides in blocking the cellular mass exchange as well as impeding the formation for actin filaments resulting in program cell death, stimuli-responsive polypeptide nanoparticles have attracted more and more attention. In this work, we successfully fabricated doxorubicin-loaded polyethylene glycol-block-peptide (FFKY)-block-tetraphenylethylene (PEG-Pep-TPE/DOX) nanoparticles, where the aggregation-induced emission luminogens (AIEgen, TPE-CHO) can become a fluorescence resonance energy transfer (FRET) pair with the entrapped antitumor drug DOX to detect the release of drugs dynamically. This is the first successful attempt to detect and quantify the change of FRET signals in A549 cells via three methods to monitor the cellular uptake of nanoprobes and intracellular drug molecule release intuitively. As we proposed here, the combination of free DOX and the self-assembling peptide could achieve the synergistic anticancer efficacy. The multifunctional PEG-Pep-TPE/DOX nanoparticles may provide a new opportunity for combination cancer therapy and real-time detection of the drug release from stimuli-responsive nanomedicine.

Additional file 1. Concludes the results of the characterization of multifunctional nanoliposomes and DOX-CB and the results of cellular distribution and the cell viability of DOX-CB. The results of additional animal experiments such as evaluation of the GL261-orthotopicglioma in the C57BL/6 mouse model and HE staining of different organs.

Glioblastoma is the most common brain primary malignant tumor with the highest mortality. Boron neutron capture therapy (BNCT) can efficiently kill cancer cells on the cellular scale, with high accuracy, short course and low side-effects, which is regarded as the most promising therapy for malignant brain tumors like glioma. As the keypoint of BNCT, all boron delivery agents currently in clinical use are beset by insufficient tumor uptake, especially in the tumor nucleus, which limits the clinical application of BNCT. In this study, nuclear targeting of boron is achieved by DOX-CB, consisting of doxorubicin (DOX) and carborane (CB) utilizing the nuclear translocation property of DOX. The nucleus of GL261 cells takes up almost three times the concentration of boron required for BNCT. To further kill glioma and inhibit recurrence, a new multifunctional nanoliposome delivery system DOX-CB@lipo-pDNA-iRGD is constructed. It combines DOX-CB with immunotherapy strategy of blocking macrophage immune checkpoint pathway CD47-SIRPα by CRISPR-Cas9 system, coupling BNCT with immunotherapy simultaneously. Compared with clinical drug Borocaptate Sodium (BSH), DOX-CB@lipo-pDNA-iRGD significantly enhances the survival rate of tumor-bearing mice, reduces tumor stemness, and improves the prognosis. The excellent curative effect of this nanoliposome delivery system provides an insight into the combined treatment of BNCT. Graphical Abstract

Purpose Boron neutron capture therapy (BNCT) is an emerging binary radiotherapy, which is limited for application due to the challenge of targeted delivery into tumor nowadays. Here, we propose the use of iRGD-modified polymeric nanoparticles for active targeted delivery of boron and doxorubicin (DOX) in BNCT. Methods 10B-enriched BSH was covalently grafted to PEG-PCCL to prepare 10B-polymer, then surface-modified with iRGD. And, DOX was physically incorporated into polymers afterwards. Characterization of prepared polymers and in vitro release profile of DOX from polymers were determined by several methods. Cellular uptake of DOX was observed by confocal microscope. Accumulation of boron in cells and tissues was analyzed by ICP-MS. Biodistribution of DOX was studied by ex vivo fluorescence imaging and quantitative measurement. Tumor vascular normalization of Endostar for promoting delivery efficiency of boron on refractory B16F10 tumor was also studied. Results The polymers were monodisperse and spheroidal in water with an average diameter of 24.97 nm, which were relatively stable at physiological pH and showed a sustained release of DOX, especially at endolysosomal pH. Enhanced cellular delivery of DOX was found in iRGD-modified polymer group. Cellular boron uptake of iRGD-modified polymers in A549 cells was remarkably raised fivefold (209.83 ng 10B/106 cells) compared with BSH. The polymers represented prolonged blood circulation, enhanced tumor accumulation of 10B against BSH, and favorable tumor:normal tissue boron concentration ratios (tumor:blood = 14.11, tumor:muscle = 19.49) in A549 tumor-bearing mice 24 hrs after injection. Both fluorescence imaging and quantitative measurement showed the highest tumor accumulation of DOX at 24 hrs after injecting of iRGD-modified polymers. Improvement of vascular integrity and reduction of vascular mimicries were found after Endostar injection, and raised tumor accumulation of boron as well. Conclusion The developed nanoparticle is an inspiring candidate for the safe clinical application for BNCT.

Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor.Significance: Chemotherapy is one of the main tr...

Metastasis is the primary cause of death for most cancer patients, in which tumor-associated macrophages (TAMs) are involved through several mechanisms. While hitherto there is still a lack of study on exclusive elimination of TAMs to inhibit metastasis due to the difficulties in specific targeting of TAMs, we construct an extra- and intracellular stepwise-responsive delivery system p-(aminomethyl)benzoic acid (PAMB)/doxorubicin (DOX) to achieve specific TAM depletion for the first time, thereby preventing tumor metastasis. Once accumulated into the tumor, PAMB/DOX would stepwise responsively (hypoxia and reactive oxygen species (ROS) responsively) disintegrate to expose the TAM-targeting ligand and release DOX sequentially, which depletes TAMs effectively in vivo. Owing to the inhibition of extracellular matrix (ECM) degradation, neovascularization, and tumor invasion contributed by TAM depletion, lung metastasis was successfully inhibited. Furthermore, PAMB/DOX showed efficient inhibition against tumor growth as well as spontaneous metastasis formation when combined with additional chemotherapy, representing a safe and efficient nanoplatform to modulate the adverse tumor microenvironment via TAM elimination.

Nitrogen mustard (NM) is among the earliest drugs used to treat malignant tumors and it kills tumor cells by cross-linking DNA. Unfortunately, because of the short half-life and unfavorable selectivity, NM causes significant damage to normal tissues. As NM can increase the levels of reactive oxygen species (ROS) in tumor cells, a ROS-activated nitrogen mustard prodrug (NM-Pro) was synthesized and mixed with NM at a specific ratio to obtain an "NM-ROS-NM-Pro-NM" positive feedback system, which ultimately achieves a specific lethal effect on hematological neoplasms. The further encapsulation of NM/NM-Pro in liposomes allows the sustained release of the drug and prolongs the residence time in vivo. Here, we prepared stable liposomes with a uniform particle size of 170.6 ± 2.2 nm. The optimal ratio of NM to NM-Pro in this study was 2:1. The active drug NM in the NM/NM-Pro system continuously stimulated ROS production by the cells, which in turn further activated the NM-Pro to continuously generate NM. The positive feedback pathway between the NM and NM-Pro resulted in the specific death of tumor cells. Furthermore, the K562 hematological neoplasm model was utilized to evaluate the therapeutic effect of NM/NM-Pro liposomes in vivo. After encapsulation in liposomes, the targeting of tumor cells was increased approximately two times compared with that of normal cells, and NM/NM-Pro liposomes exhibited reduced toxicity, without an increase in drug activity compared to the NM/NM-Pro combination. The NM/NM-Pro delivery system exerts a positive feedback effect on ROS production in tumor cells and displays good potential for the specific killing of hematoma cells.

Self-assembled peptide nanofibers have been widely studied in cancer nanotherapeutics with their excellent biocompatibility and low toxicity of degradation products, showing the significant potential in inhibiting tumor progression. However, poor solubility prevents direct intravenous administration of nanofibers. Although water-soluble peptide precursors have been formed via the method of phosphorylation for intravenous administration, their opportunities for broad in vivo application are limited by the weak capacity of encapsulating drugs. Herein, we designed a novel restructured reduced glutathione (GSH)-responsive drug delivery system encapsulating doxorubicin for systemic administration, which achieved the intracellular restructuration from three-dimensional micelles into one-dimensional nanofibers. After a long blood circulation, micelles endocytosed by tumor cells could degrade in response to high GSH levels, achieving more release and accumulation of doxorubicin at desired sites. Further, the synergistic chemotherapy effects of self-assembled nanofibers were confirmed in both in vitro and in vivo experiments.

Breast cancer is the leading cause of cancer-related death for women, and multidrug resistance (MDR) is the major obstacle faced by chemotherapy for breast cancer. We have previously synthesized a doxorubicin (DOX) derivative by conjugating DOX with triphenylphosphonium (TPP) to achieve mitochondrial delivery, which induced higher cytotoxicity in drug-resistant breast cancer cells than DOX itself. Due to its amphiphilicity, TPP-DOX is difficult to physically entrap in nanocarriers. Thus, we linked it to hyaluronic acid (HA) by a novel ionic bond utilizing the specific bromide ion of TPP to form supra-molecular self-assembled structures (HA-ionic-TPP-DOX). The product was analyzed uisng (1)H-NMR, (13)C-NMR and mass spectrometry. The HA nanocarriers (HA-ionic-TPP-DOX) were shown to self-assemble into spherical nanoparticles, and sensitive to acidic pH in terms of morphology and drug release. Compared with free DOX, HA-ionic-TPP-DOX produced much greater intracellular DOX accumulation and mitochondrial localization, leading to increased ROS production, slightly decreased mitochondrial membrane potential, increased cytotoxicity in MCF-7/ADR cells and enhanced tumor targeting in vivo. In xenotransplant zebrafish model with the MCF-7/ADR cell line, both TPP-DOX and HA-ionic-TPP-DOX inhibited tumor cell proliferation without inducing significant side effects compared with free DOX. In addition, we observed a better anti-tumor effect of HA-ionic-TPP-DOX on MCF-7/ADR cells in zebrafish than that of TPP-DOX treatment. Furthermore, HA-ionic-DOX-TPP exhibited favorable biocompatibility and anti-tumor effects in MCF-7/ADR tumor-bearing nude mice in comparison with the effects of TPP-DOX and DOX, suggesting the potential of HA-ionic-TPP-DOX for the targeted delivery and controlled release of TPP-DOX, which can lead to the sensitization of resistant breast tumors.

Although existing nanomedicines have focused on the tumor microenvironment with the goal of improving the effectiveness of conventional chemotherapy, the penetration of a tumor’s core still represents a formidable barrier for existing drug delivery systems. Therefore, a novel multifunctional hypoxia-induced size-shrinkable nanoparticle has been designed to increase the penetration of drugs, nucleic acids, or probes into tumors. This cooperative strategy relies on three aspects: (i) the responsiveness of nanoparticles to hypoxia, which shrink when triggered by low oxygen concentrations; (ii) the core of a nanoparticle involves an internal cavity and strong positive charges on the surface to deliver both doxorubicin and siRNA; and (iii) a reactive oxygen species (ROS) probe is incorporated in the nanoparticle to monitor its preliminary therapeutic response in real time, which is expected to realize the enhanced efficacy together with the ability to self-monitor the anticancer activity. A more effective inhibition of tumor growth was observed in tumor-bearing zebrafish, demonstrating the feasibility of this cooperative strategy for in vivo applications. This research highlights a promising value in delivering drugs, nucleic acids, or probes to a tumor’s core for cancer imaging and treatment. Statement of Significance Hypoxia-induced chemoresistance of tumor cells still represents a formidable barrier, as it is difficult for existing drug delivery systems to penetrate the tumor hypoxia core. This study involves the hypoxia-responsive size-shrinkable nanoparticle co-delivery of DOX and siRNA to enhance the penetration of DOX deep within tumors and subsequently disturb crucial pathways of cancer development induced by hypoxia and to improve sensitization to DOX chemotherapy. Furthermore, the nanopreparation can combine the ROS probe as a self-reporting nanopreparation to realize the function of real-time feedback efficacy, which has a good application prospect in the diagnosis and treatment of cancer.

Multidrug resistance (MDR) is the major obstacle for chemotherapy. In a previous study, we have successfully synthesized a novel doxorubicin (DOX) derivative modified by triphenylphosphonium (TPP) to realize mitochondrial delivery of DOX and showed the potential of this compound to overcome DOX resistance in MDA-MB-435/DOX cells. (1) To introduce specificity for DOX-TPP to cancer cells, here we report on the conjugation of DOX-TPP to hyaluronic acid (HA) by hydrazone bond with adipic acid dihydrazide (ADH) as the acid-responsive linker, producing HA- hydra-DOX-TPP nanoparticles. Hyaluronic acid (HA) is a natural water-soluble linear glycosaminoglycan, which was hypothesized to increase the accumulation of nanoparticles containing DOX-TPP in the mitochondria of tumor cells upon systemic administration, overcoming DOX resistance, in vivo. Our results showed HA- hydra-DOX-TPP to self-assemble to core/shell nanoparticles of good dispersibility and effective release of DOX-TPP from the HA- hydra-DOX-TPP conjugate in cancer cells, which was followed by enhanced DOX mitochondria accumulation. The HA- hydra-DOX-TPP nanoparticles also showed improved anticancer effects, better tumor cell apoptosis, and better safety profile compared to free DOX in MCF-7/ADR bearing mice.

Jiejian Chen,1,2 Qiyao Yang,1,2 Minchen Liu,3 Mengting Lin,2 Tiantian Wang,2 Zhentao Zhang,2 Xincheng Zhong,2 Ningning Guo,2 Yiying Lu,2 Jing Xu,1 Changsheng Wang,4 Min Han,2 Qichun Wei1 1Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of China; 2Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China; 3Engineering Research Center of Modern Preparation Technology of TCM, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 4Department of Spinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People’s Republic of ChinaCorrespondence: Qichun WeiDepartment of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of ChinaTel +86 571 8778 3521Fax +86 571 8721 4404Email qichun_wei@zju.edu.cnChangsheng WangDepartment of Spinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People’s Republic of ChinaEmail wangcs15@163.comPurpose: Boron neutron capture therapy (BNCT) is an emerging binary radiotherapy, which is limited for application due to the challenge of targeted delivery into tumor nowadays. Here, we propose the use of iRGD-modified polymeric nanoparticles for active targeted delivery of boron and doxorubicin (DOX) in BNCT.Methods: 10B-enriched BSH was covalently grafted to PEG-PCCL to prepare 10B-polymer, then surface-modified with iRGD. And, DOX was physically incorporated into polymers afterwards. Characterization of prepared polymers and in vitro release profile of DOX from polymers were determined by several methods. Cellular uptake of DOX was observed by confocal microscope. Accumulation of boron in cells and tissues was analyzed by ICP-MS. Biodistribution of DOX was studied by ex vivo fluorescence imaging and quantitative measurement. Tumor vascular normalization of Endostar for promoting delivery efficiency of boron on refractory B16F10 tumor was also studied.Results: The polymers were monodisperse and spheroidal in water with an average diameter of 24.97 nm, which were relatively stable at physiological pH and showed a sustained release of DOX, especially at endolysosomal pH. Enhanced cellular delivery of DOX was found in iRGD-modified polymer group. Cellular boron uptake of iRGD-modified polymers in A549 cells was remarkably raised fivefold (209.83 ng10B/106cells)compared with BSH. The polymers represented prolonged blood circulation, enhanced tumor accumulation of 10B against BSH, and favorable tumor:normal tissue boron concentration ratios (tumor:blood = 14.11, tumor:muscle = 19.49) in A549 tumor-bearing mice 24 hrs after injection. Both fluorescence imaging and quantitative measurement showed the highest tumor accumulation of DOX at 24 hrs after injecting of iRGD-modified polymers. Improvement of vascular integrity and reduction of vascular mimicries were found after Endostar injection, and raised tumor accumulation of boron as well.Conclusion: The developed nanoparticle is an inspiring candidate for the safe clinical application for BNCT.Keywords: BNCT, drug delivery, polymer–drug conjugate, BSH, doxorubicin

Currently, the limited penetration of nanoparticles remains a major challenge for antitumor nanomedicine to penetrate into the tumor tissues. Herein, we propose a size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to our knowledge, which was formed by conjugating the terminal glucose of hyaluronic acid (HA) to the superficial amidogen of poly(amidoamine) (PAMAM), using a matrix metalloproteinase-2 (MMP-2)-cleavable peptide (PLGLAG) via click reaction. These nanoparticles had an initial size of ∼200 nm, but once deposited in the presence of MMP-2, they experienced a dramatic and fast size change and dissociated into their dendrimer building blocks (∼10 nm in diameter) because of cleavage of PLGLAG. This rapid size-shrinking characteristic not only promoted nanoparticle extravasation and accumulation in tumors benefited from the enhanced permeability and retention effect but also achieved faster nanoparticle diffusion and penetration. We have further conducted comparative studies of MMP-2-sensitive macromolecules (HA-pep-PAMAM) and MMP-2-insensitive macromolecules (HA-PAMAM) synthesized with a similar particle size, surface charge, and chemical composition and evaluated in both monolayer cells and multicellular spheroids. The results confirmed that the enzyme-responsive size shrink is an implementable strategy to enhance drug penetration and to improve therapeutic efficacy. Meanwhile, macromolecule-based nanoparticles with size-variable characteristics not only promote drug penetration, but they can also be used as gene delivery systems, suggesting great potential as nano-delivery systems.