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ABSTRACT: α-Lactalbumin (α-lac), a natural food-sourced protein, exhibits high biocompatibility as delivery systems for small bioactive molecules or RNA. However, their potential clinical application as a delivery system is greatly limited due to the lack of targeting to desired tissues, such as tumors. Here, a delivery system/nanocarrier of nanotube (NT) was fabricated by the self-assembly of peptides hydrolyzed from α-lac. Among the loading of anti-tumor agents of doxorubicin (Dox) and siRNA, NTs were conjugated with the tLyp-1 peptide to specifically target the neuropilin 1 receptor, which exists on the membrane of MDA-MB-231 cancer cells. The micromorphology of NTs was not affected during the processes of loading and targeting modification. Additionally, no significant changes in the size and zeta potential of the tLyp-1/NTs/Dox/siRNA nanocarrier were observed when stored in phosphate buffered saline for 7 days, indicating outstanding stability. Moreover, both the cellular uptake efficiency and tumor accumulation effects of NTs on MDA-MB-231 breast cancer cells were significantly improved after modification with tLyp-1. The relative viability of MDA-MB-231 cells was decreased by 70.1% in vitro after treatment with tLyp-1/NTs/Dox/siRNA (5 μg/mL Dox). Finally, a synergistic anticancer effect of Dox and siRNA co-loaded in tLyp-1/NTs was achieved in the anticancer treatment of MDA-MB-231 tumor-bearing mice. These findings indicate that food-sourced protein α‑lac nanocarriers could be used for the co-delivery of bioactive molecules and RNA, achieving synergistic and efficient therapeutic effects.

Optimizing the delivery and penetration of nano-sized drugs within liver cancer sites, along with remodeling the tumor microenvironment, is crucial for enhancing the efficacy of chemotherapeutic agents. For this study, a platelet (PLT)-mediated nanodrug delivery system (DASA+ATO@PLT) was developed to improve the effectiveness of chemotherapy. This system delivers nano-sized dasatinib and atovaquone specifically to liver tumor sites and facilitates intra-tumoral permeation upon release. Through JC-1, immunohistochemistry, and DNA damage analyses, the therapeutic effect of DASA+ATO@PLT was assessed. In vitro simulation and intravital imaging were carried out to determine the accumulation of dasatinib and atovaquone in liver tumor sites. The experiment demonstrated the accumulation of dasatinib and atovaquone in tumor sites, followed by deep permeation in the tumor microenvironment with the assistance of PLTs, while simultaneously revealing the ability of DASA+ATO@PLT to remodel the liver cancer microenvironment (overcoming hypoxia) and enhance chemotherapeutic efficacy. This system utilizes the natural tumor recognition ability of PLTs and enhances the chemo-immunotherapeutic effect through targeted delivery of nano-chemotherapeutic drugs to the tumor, resulting in effective accumulation and infiltration. The PLT-mediated nanodrug delivery system serves as a "Trojan horse" to carry therapeutic drugs as cargo and deliver them to target cells, leading to favorable outcomes. [ABSTRACT FROM AUTHOR]

To achieve maximum curative effects and minimize side effects in trimodal synergistic cooperative tumor therapies, we propose a strategy of photothermal (PTT)-chemodynamic (CDT)-coordinated drug chemotherapy (DT) trimodal synergistic therapy. We designed a multifunctional manganese-doped mesoporous magnetic nanodrug carrier (NH2-MMNPs), which was equipped with pullulan oxide to form Schiff base bonds upon loading doxorubicin (DOX), thus creating an oMMNPs/DOX nanoplatform. This nanoplatform exhibits excellent controlled drug release, satisfactory photothermal conversion efficiency under NIR (808 nm) irradiation, good biodegradability, and targeted drug delivery capabilities. It also produces Fenton-like Mn2+ in response to the highly expressed glutathione (GSH) in the tumor microenvironment, thereby generating chemodynamic therapy. The oMMNPs/DOX demonstrated remarkable killing efficacy in HeLa and MCF-7 cancer cell cultures and reached 84.1% tumor suppression in vivo. The in vitro and in vivo results confirm that this theranostic nanoplatform exhibits excellent biocompatibility and anticancer effects. Therefore, oMMNPs/DOX have potential utility as a magnetically targeted and pH/GSH/NIR triple-triggered drug carrier for synergistic PTT/CDT/DT therapy. [ABSTRACT FROM AUTHOR]

Optimizing the delivery and penetration of nano-sized drugs within liver cancer sites, along with remodeling the tumor microenvironment, is crucial for enhancing the efficacy of chemotherapeutic agents. For this study, a platelet (PLT)-mediated nanodrug delivery system (DASA+ATO@PLT) was developed to improve the effectiveness of chemotherapy. This system delivers nano-sized dasatinib and atovaquone specifically to liver tumor sites and facilitates intra-tumoral permeation upon release. Through JC-1, immunohistochemistry, and DNA damage analyses, the therapeutic effect of DASA+ATO@PLT was assessed. In vitro simulation and intravital imaging were carried out to determine the accumulation of dasatinib and atovaquone in liver tumor sites. The experiment demonstrated the accumulation of dasatinib and atovaquone in tumor sites, followed by deep permeation in the tumor microenvironment with the assistance of PLTs, while simultaneously revealing the ability of DASA+ATO@PLT to remodel the liver cancer microenvironment (overcoming hypoxia) and enhance chemotherapeutic efficacy. This system utilizes the natural tumor recognition ability of PLTs and enhances the chemo-immunotherapeutic effect through targeted delivery of nano-chemotherapeutic drugs to the tumor, resulting in effective accumulation and infiltration. The PLT-mediated nanodrug delivery system serves as a “Trojan horse” to carry therapeutic drugs as cargo and deliver them to target cells, leading to favorable outcomes.

Oleic acid (OA) is a kind of monounsaturated omega-3 fatty acid that abounds in plants and animals which can induce apoptosis and has broad-spectrum inhibitory activity against a variety of tumor cell lines. However, OA is quite insoluble and thus inconvenient to be efficiently delivered in vivo. In this work, OA was fabricated into nanoparticles to generate OA elastic nanoparticles (OA-ENPs) with a particle size of 185.6 nm and good stability in various physiological media. OA-ENPs alone achieved a high tumor inhibition rate of 60.3% without significant side effect. More surprisingly, the resultant OA-ENPs displayed dose-dependent tumor targetability. Low dose of OA-ENPs (10 mg/kg) mainly distributed in the liver after intravenous injection, while high dose of OA-ENPs mainly distributed in tumor. At the high dose of 90 mg/kg, OA-ENPs accumulation in tumor reached nearly twice as that in the liver. Here we provide a simple but effective way to achieve excellent tumor targetability without the need of any surface modification of nanoparticles.

Tumor precision therapy and preventing tumor recurrence and metastasis are the main challenges to tumor eradication. Herein, an apoptotic body‐based vehicle with imaging navigation is developed for precise tumor delivery and photothermal‐immunotherapy by IR820‐conjugated apoptotic body loaded with R848 nanoparticles. The apoptotic body serves as ammunition stores as well as vehicle drive engines, while IR820 acts as a fluorescence imaging navigation and photothermal controlling system. The apoptotic body vehicle can deliver the ammunition to tumor and achieve deep penetration by macrophage‐hitchhiking. Fluorescence imaging navigation opens a control window for photothermal treatment, followed by photothermal triggering of in situ vaccine formation. Further, CD47 antibody loaded hydrogel strengthens innate and adaptive immunity, simultaneously the polarization of macrophages regulates the immunosuppressive microenvironment to further promote the combined antitumor immunotherapy. With breast tumor (4T1)‐bearing mice model, the apoptotic body vehicle performs excellent therapeutic efficacy for primary tumor, distant tumor, tumor metastasis, and recurrence prevention. [ABSTRACT FROM AUTHOR]

Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg phosphatidylethanolamine (PE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-disteroyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG-2000), and the mean size of the RTL was in the range of 114 to 133 nm, as measured by nanoparticle tracking analysis (NTA). The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three IV injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone. [ABSTRACT FROM AUTHOR]

In recent years, carbon monoxide (CO) has garnered increased attention as a novel green therapy for hepatocellular carcinoma (HCC) treatment. However, the CO donor is still limited in clinical application due to its lack of targeted ability and unstable release rate. Here, self-assembled amphiphilic nanomicelles glucose-polyethylene glycol (PEG)-lipoic acid (LA)-Fe 2 (CO) 6 (Glu-Fe 2 (CO) 6 ) are first designed as a CO donor and synthesized via a chemical method, combining glucose with Fe 2 (CO) 6 through PEG-LA. Some advantages of this tumor-targeted Glu-Fe 2 (CO) 6 delivery system include (I) good water-solubility, (II) the glutathione responsive CO slow release, (III) the active tumor-targeted ability of glucose as targeted ligands, and (IV) outstanding efficacy of antitumor and safety of CO therapy of HCC both in vitro and in vivo. These findings suggest that Glu-Fe 2 (CO) 6 nanomicelles hold promise for enhancing antitumor therapeutic capabilities, presenting a novel tumor-targeted delivery strategy in gas therapy for HCC treatment.

Polymeric micelles (PMs) have made significant progress in drug delivery applications. A robust core–shell structure, kinetic stability and the inherent ability to solubilize hydrophobic drugs are the highlights of PMs. This review presents the recent advances and understandings of PMs with a focus on the latest drug delivery applications. The types, methods of preparation and characterization of PMs are described along with their applications in oral, parenteral, transdermal, intranasal and other drug delivery systems. The applications of PMs for tumor-targeted delivery have been provided special attention. The safety, quality and stability of PMs in relation to drug delivery are also provided. In addition, advanced polymeric systems and special PMs are also reviewed. The in vitro and in vivo stability assessment of PMs and recent understandings in this area are provided. The patented PMs and clinical trials on PMs for drug delivery applications are considered indicators of their tremendous future applications. Overall, PMs can help overcome many unresolved issues in drug delivery. [ABSTRACT FROM AUTHOR]

A light-driven NO-generating multifunctional nanosystem (Ru-PArg-HA) could be selectively internalized by cancer cells, and exhibited efficient anticancer activity by synergistic photodynamic/gas therapy. [Display omitted] • A light-driven NO-generating multifunctional nanosystem (Ru-PArg-HA) has been developed. • The presence of HA enables Ru-PArg-HA to be selectively internalized by cancer cells. • Ru-PArg-HA exhibited targeted and efficient anticancer activity by synergistic photodynamic/gas therapy upon light irradiation. Photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment. Nevertheless, PDT alone still faces a considerable challenge in efficiently eliminating cancer cells, and combination with other therapeutic strategies can significantly improve anticancer efficacy. Herein, a multifunctional nanosystem (Ru-PArg-HA) composed of biocompatible and tumor-targeted hyaluronic acid (HA), a photosensitizer [Ru(phen) 2 (PIP-OCH 3)]2+ (termed Ru, phen = 1,10-phenanthroline, PIP-OCH 3 = 2-(4-methoxy phenyl)-1H-imidazo[4,5-f] [1,10] phenanthroline) and a NO donor poly- l -arginine (PArg), was fabricated via electrostatic interactions. Under 470 nm light irradiation, Ru-PArg-HA could not only catalyze 1,4-dihydronicotinamide adenine dinucleotide (NADH) oxidation to produce H 2 O 2 , but also could generate a large amount of reactive oxygen species (ROS, including 1O 2 and O 2 − ) for PDT therapy. The light-driven production of 1O 2 and H 2 O 2 could further convert PArg into nitric oxide (NO), enabling synergistic gas therapy. The experimental outcomes demonstrated that Ru-PArg-HA exhibited much enhanced anticancer activity compared to traditional mono-modal PDT. This finding provides new inspiration for the development of multifunctional nanosystems with efficient and targeted anticancer activity. [ABSTRACT FROM AUTHOR]

Blocking the tumor nutrient supply through angiogenic inhibitors is an effective treatment approach for malignant tumors. However, using angiogenic inhibitors alone may not be enough to achieve a significant tumor response. Therefore, we recently designed a universal drug delivery system combining chemotherapy and anti-angiogenic therapy to target tumor cells while minimizing drug-related side effects. This system (termed as PCCE) is composed of biomaterial chondroitin sulfate (CS), the anti-angiogenic peptide ES2, and paclitaxel (PTX), which collectively enhance antitumor properties. Interestingly, the PCCE system is conferred exceptional cell membrane permeability due to inherent characteristics of CS, including CD44 receptor-mediated endocytosis. The PCCE could respond to the acidic and high glutathione conditions, thereby releasing PTX and ES2. PCCE could effectively inhibit the proliferation, migration, and invasion of tumor cells and cause apoptosis, while PCCE can affect the endothelial cells tube formation and exert anti-angiogenic function. Consistently, more potent in vivo antitumor efficacy and non-toxic sides were demonstrated in B16F10 xenograft mouse models. PCCE can achieve excellent antitumor activity via modulating angiogenic and apoptosis-related factors. In summary, we have successfully developed an intelligent and responsive CS-based nanocarrier known as PCCE for delivering various antitumor drugs, offering a promising strategy for treating malignant tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Combining proteolysis targeting chimeras (PROTACs) with photodynamic therapy (PDT) is a promising strategy for cancer treatment. However, the therapeutic efficacy is impaired due to the poor water solubility or the unsatisfactory tumor distribution of drugs. Herein, we developed a Hyaluronan (HA) coating MOF-based nanoplatform (ZMCH) to achieve the combined therapy of PROTACs and PDT with tumor-specific delivery and local drug release. The PROTACs molecules and photosensitizers could be easily wrapped into the nanoparticles via the self-assembly of zinc ions and 2-methylimidazole, which is a universal encapsulation approach for the conventional PROTACs or photosensitizers. As a proof-of-concept, we demonstrated that the designed ZMCH nanoreactor effectively suppresses tumor growth in the 4T1-tumor-bearing mice model, resulting from the synergistic effect of MZ1-mediated protein degradation and the Ce6-mediated reactive oxygen species (ROS) damage. Importantly, the ZMCH-induced therapy exhibited the enhanced antitumor T-cell immunity by regulating immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor metastasis in the lungs. This work thus provides a novel approach and insights for the combination therapy of protein degradation and PDT in clinical cancer treatment. [Display omitted] • Combining PROTACs with PDT is a promising strategy for cancer treatment. • Tumor targeted delivery of PROTACs or PDT can avoid systemic toxicity. • HA coating nanocarriers exhibited the enhanced cellular uptake behavior. • The treatment trigged the amplified antitumor T-cell immune responses. [ABSTRACT FROM AUTHOR]

The conventional concept of using nanocarriers to deliver chemotherapeutic drugs has advanced to accommodate additional diagnostic capability. Nanotheranostic agents (NTA), combining both treatment and diagnostic tools, are an ideal example of engineering-health integration for cancer management. Owing to the diverse materials used to construct NTAs, their safety, effectiveness, and diagnostic accuracy could vary substantially. This systematic review consolidated current NTAs incorporating 5-fluorouracil and elucidated their toxicity, anticancer efficacy, and imaging capability. Medline and Embase databases were searched up to March 18, 2022. The search, selection, and extraction were performed by the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines to ensure completeness and reproducibility. Original research papers involving 5-fluorouracil in the preparation of nanoparticles which reported their efficacy, toxicity, and diagnostic capability in animal cancer models were recruited. The quality of included studies was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist. Nine studies were eligible for the systematic review. There was no significant toxicity reported based on animal weight and organ histology. Complete tumor remission was observed in several animal models using chemo-thermal ablation with NTAs, proving the enhancement of 5-fluorouracil efficacy. In terms of imaging performance, the time to achieve maximum tumor image intensity correlates with the presence of targeting ligand on NTAs. The NTAs, which are composed of tumor-targeting ligands, hold promises for further development. Based on the input of current NTA research on cancer, this review proposed a checklist of parameters to recommend researchers for their future NTA testing, especially in animal cancer studies. Systematic Review Registration : website, identifier registration number. [ABSTRACT FROM AUTHOR]

The conventional concept of using nanocarriers to deliver chemotherapeutic drugs has advanced to accommodate additional diagnostic capability. Nanotheranostic agents (NTA), combining both treatment and diagnostic tools, are an ideal example of engineering-health integration for cancer management. Owing to the diverse materials used to construct NTAs, their safety, effectiveness, and diagnostic accuracy could vary substantially. This systematic review consolidated current NTAs incorporating 5-fluorouracil and elucidated their toxicity, anticancer efficacy, and imaging capability. Medline and Embase databases were searched up to March 18, 2022. The search, selection, and extraction were performed by the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines to ensure completeness and reproducibility. Original research papers involving 5-fluorouracil in the preparation of nanoparticles which reported their efficacy, toxicity, and diagnostic capability in animal cancer models were recruited. The quality of included studies was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist. Nine studies were eligible for the systematic review. There was no significant toxicity reported based on animal weight and organ histology. Complete tumor remission was observed in several animal models using chemo-thermal ablation with NTAs, proving the enhancement of 5-fluorouracil efficacy. In terms of imaging performance, the time to achieve maximum tumor image intensity correlates with the presence of targeting ligand on NTAs. The NTAs, which are composed of tumor-targeting ligands, hold promises for further development. Based on the input of current NTA research on cancer, this review proposed a checklist of parameters to recommend researchers for their future NTA testing, especially in animal cancer studies.Systematic Review Registration: website, identifier registration number.

Vitamin E Poly(ethylene glycol) monoplatinum ester (TPGS) nanoparticles have attracted much attention in recent years for overcome multidrug resistance. Herein, a well-defined folic acid (FA)-conjugated and disulfide bond-linked polymer (FA-SS-TPGS) was synthesized. These polymer nanoparticles were utilized as theranostic agents for tumor-targeted magnetic resonance imaging (MRI) and chemotherapy. By loading doxorubicin (DOX) and superparamagnetic iron oxide (SPIO) particles into TPGS nanoparticles, FA-SS-TPGS@DOX/SPIO nanoparticles are obtained. In vitro drug release studies revealed that under a reducing environment in the presence of glutathione (GSH), approximately 100% of the doxorubicin (DOX) was released from the disulfide bond-linked theranostic nanoparticles within 24 h. DOX and SPIO were efficiently delivered into HepG2-ADM cells due to the folate receptor-mediated endocytosis process of the nanoparticles. Additionally, the presence of glutathione (GSH) triggered the cleaving of the disulfide bonds, further facilitating the delivery of DOX and SPIO into the cells. Furthermore, the FA-SS-TPGS @DOX-SPIO nanoparticles exhibited strong MRI contrast enhancement properties. In conclusion, FA-SS-TPGS@DOX/SPIO are potential nanoparticles for tumor-targeted MRI and chemotherapy, which can also overcome multidrug resistance.

Background: Accurate real-time tumor delineation is essential for achieving curative resection (R0 resection) during non-small cell lung cancer (NSCLC) surgery. The unique characteristics of lung tissue structure significantly challenge the use of video-assisted thoracoscopic surgery in the identification of lung nodules. This difficulty often results in an inability to discern the margins of lung nodules, necessitating either an expansion of the resection scope, or a transition to open surgery. Due to its high spatial resolution, ease of operation, and capacity for real-time observation, near-infrared fluorescence (NIRF) navigation in oncological surgery has emerged as a focal point of clinical research. Targeted NIRF probes, which accumulate preferentially in tumor tissues and are rapidly cleared from normal tissues, enhance diagnostic sensitivity and surgical outcomes. The imaging effect of the clinically approved NIRF probe indocyanine green (ICG) varies significantly from person to person. Therefore, we hope to develop a new generation of targeted NIRF probes targeting lung tumor-specific targets., Methods: First, the peptide iRGD (sequence: CRGDKGPDC) fluorescent tracer was synthesized, and characterized through mass spectrometry (MS), proton nuclear magnetic resonance ( 1 H NMR), and high-performance liquid chromatography (HPLC). Fluorescence properties were tested subsequently. Safety was performed in vitro using both human normal liver cells and human normal breast cells. Second, Metabolism and optimal imaging time were determined by tail vein injection of iRGD fluorescent tracer. Finally, Orthotopic and metastatic lung tumor models were used to evaluate the targeting properties of the iRGD fluorescent tracer., Results: We successfully synthesized an iRGD fluorescent tracer specifically designed to target NSCLC. The molecular docking analyses indicated that this tracer has receptor affinity comparable to that of iRGD for αvβ3 integrin, with a purity ≥98%. Additionally, the tracer is highly soluble in water, and its excitation and emission wavelengths are 767 and 799 nm, respectively, positioning it within the near-infrared spectrum. The cellular assays confirmed the tracer's minimal cytotoxicity, underscoring its excellent biosafety profile. In vivo studies further validated the tracer's capacity for specific NSCLC detection at the cellular level, alongside a prolonged imaging window of 6 days or more. Notably, the tracer demonstrated superior specificity in localizing very small lung nodules, which are otherwise clinically indiscernible, outperforming non-targeted ICG. Fluorescence intensity analyses across various organs revealed that the tracer is predominantly metabolized by the liver and kidneys, with excretion via bile and urine, and exhibits minimal toxicity to these organs as well as the lungs., Conclusions: The iRGD fluorescent tracer selectively accumulates in NSCLC tissues by specifically targeting αvβ3 receptors, which are overexpressed on the surface of tumor cells. This targeted approach facilitates the real-time intraoperative localization of NSCLC, presenting an improved strategy for intraoperative tumor identification with significant potential for clinical application., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-589/coif). G.X. reports the funding from the Nanjing Health Science and Technology Development Special Fund Project (No. ykk20260). D.Z. reports funding from the Scientific Research Project of Taikang Xianlin Drum Tower Hospital Affiliated Hospital of Nanjing University Medical School (No. TKKYZD20213411). Y.W. reports the funding from the Jiangsu Province Science and Technology Department (No. BE2018698), and the National Natural Science Foundation of China (No. 82127806), and the receipt of the “Jiangsu Specially-Appointed Professor” award. D.W. reports the funding from the Nanjing Health Science and Technology Development Special Fund Project (No. ykk20230). H.C. is from Nanjing Nuoyuan Medical Devices Co. Ltd., Nanjing, China. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Rotenone, a plant-based agricultural insecticide, has been shown to have anti-tumor activity through targeting mitochondrial complex I in cancer cells. However, off-target toxic side effect on nervous systems have greatly restricted the application of rotenone as anticancer drugs. Here, a folic acid-rotenol (FA-rotenol) conjugate was prepared by covalent coupling of the tumor-targeting ligand folic acid with rotenone derivative—rotenol to enhance its accumulation at tumor site. FA-rotenol conjugates present high in vitro cytotoxicties against several cell lines by inducing mitochondrial membrane potential depolarization and increasing the level of intracellular reactive oxygen species (ROS) to activate the mitochondrial pathway of apoptosis and enhance the G2/M cell cycle arrest. Because of the high affinity with over-expressed folate receptors, FA-rotenol conjugate demonstrated more effective in vivo therapeutic outcomes in 4T1 tumor-bearing mice than rotenone and rotenol. In addition, FA-rotenol conjugate can markedly inhibit the cell migration and invasion of HepG-2 cells. These studies confirm the feasibility of tumor-targeted ligand conjugated rotenone derivatives for targeted antitumor therapy; likewise, they lay the foundations for the development of other rotenol-conjugates with antitumor potential. [ABSTRACT FROM AUTHOR]

Polymeric micelles (PMs) have made significant progress in drug delivery applications. A robust core–shell structure, kinetic stability and the inherent ability to solubilize hydrophobic drugs are the highlights of PMs. This review presents the recent advances and understandings of PMs with a focus on the latest drug delivery applications. The types, methods of preparation and characterization of PMs are described along with their applications in oral, parenteral, transdermal, intranasal and other drug delivery systems. The applications of PMs for tumor-targeted delivery have been provided special attention. The safety, quality and stability of PMs in relation to drug delivery are also provided. In addition, advanced polymeric systems and special PMs are also reviewed. The in vitro and in vivo stability assessment of PMs and recent understandings in this area are provided. The patented PMs and clinical trials on PMs for drug delivery applications are considered indicators of their tremendous future applications. Overall, PMs can help overcome many unresolved issues in drug delivery.

β-cyclodextrin(βCD)-based star polymers have attracted much interest because of their unique structures and potential biomedical and biological applications. Herein, a well-defined folic acid (FA)-conjugated and disulfide bond-linked star polymer ((FA-Dex-SS)-βCD-(PCL)14) was synthesized via a couple reaction between βCD-based 14 arms poly(ε-caprolactone) (βCD-(PCL)14) and disulfide-containing α-alkyne dextran (alkyne-SS-Dex), and acted as theranostic nanoparticles for tumor-targeted MRI and chemotherapy. Theranostic nanoparticles were obtained by loading doxorubicin (DOX), and superparamagnetic iron oxide (SPIO) particles were loaded into the star polymer nanoparticles to obtain ((FA-Dex-SS)-βCD-(PCL)14@DOX-SPIO) theranostic nanoparticles. In vitro drug release studies showed that approximately 100% of the DOX was released from disulfide bond-linked theranostic nanoparticles within 24 h under a reducing environment in the presence of 10.0 mM GSH. DOX and SPIO could be delivered into HepG2 cells efficiently, owing to the folate receptor-mediated endocytosis process of the nanoparticles and glutathione (GSH), which triggered disulfide-bonds cleaving. Moreover, (FA-Dex-SS)-βCD-(PCL)14@DOX-SPIO showed strong MRI contrast enhancement properties. In conclusion, folic acid-decorated reduction-sensitive star polymeric nanoparticles are a potential theranostic nanoparticle candidate for tumor-targeted MRI and chemotherapy.

Folic acid functionalized gelatin-coated mesoporous hollow carbon nanospheres (FGMCN) were synthesized and applied to enhance the antitumor curative effect of paclitaxel (PTX) for human liver cancer cell lines (SMMC-7721). PTX was loaded in FGMCN by the adsorption method and the PTX-loaded samples (PTX-FGMCN) had a drug content of 29.8 ± 1.06%. The PTX-FGMCN with a sustained release effect was characterized by X-ray diffraction and differential scanning calorimeter in order to analyze the PTX state in FGMCN. In vitro cell experiments showed that FMHSN improves the uptake of PTX and promotes apoptosis due to the nano-targeting effect of FMHSN. An in vivo tumor bearing experiment in mice indicated that the PTX-FGMCN significantly inhibited the growth of tumors. All of these results suggested that the PTX-FGMCN may be an effective anti-hepatoma drug in the future. [ABSTRACT FROM AUTHOR]

Since the overexpression of folate receptors (FRs) in certain types of cancers, a variety of FR-targeted fluorescent probes for tumor detection have been developed. However, the reported probes almost all have the same targeting ligand of folic acid with various fluorophores and/or linkers. In the present study, a series of novel tumor-targeted near-infrared (NIR) molecular fluorescent probes were designed and synthesized based on previously reported 6-substituted pyrrolo[2,3- d ]pyrimidine antifolates. All newly synthesized probes showed specific FR binding in vitro , whereas GT-NIR-4 and GT-NIR-5 with a benzene and a thiophene ring, respectively, on the side chain of pyrrolo[2,3- d ]pyrimidine exhibited better FR binding affinity than that of GT-NIR-6 with folic acid as targeting ligand. GT-NIR-4 also showed high tumor uptake in KB tumor-bearing mice with good pharmacokinetic properties and biological safety. This work demonstrates the first attempt to replace folic acid with antifolates as targeting ligands for tumor-targeted NIR probes. We first attempted to replace folic acid with antifolates as targeting ligands to design and synthesize novel tumor-targeted Near-Infrared probes. [Display omitted] • Developed a series of novel tumor targeting near-infrared fluorescence probes mediated by folate receptors for fluorescence guided surgery. • This was the first attempt to replace folic acid with pyrrolo[2,3- d ]pyrimidine antifolates as targeting ligands for tumor-targeted NIR probes. • Both in vitro and in vivo investigations revealed that the probe GT-NIR-4 exhibited high FR binding avidity. [ABSTRACT FROM AUTHOR]

Legumain has been identified as a target for diagnosis and treatment of associated cancers. Therefore, real-time imaging of legumain activity in vivo is helpful in diagnosing and evaluating therapeutic efficacy of associated cancers. Fluorescent/photoacoustic (FL/PA) dual-modal imaging developed rapidly because of its good sensitivity and spatial resolution. As far as we know, a tumor-targeted probe for FL/PA imaging of legumain activity in vivo has not been reported. Hence, we intended to develop a tumor-targeted hemicyanine (HCy) probe ( HCy-AAN-Bio ) for FL/PA imaging of legumain in vivo. The control probe HCy-AAN does not have tumor-targeting ability. Legumain can specifically cleave HCy-AAN-Bio or HCy-AAN with the generation of FL/PA signal while more HCy-AAN-Bio could be recognized by legumain than HCy-AAN with higher sensitivity in vitro. Due to the tumor-targeting ability, HCy-AAN-Bio could image 4T1 cells with an additional 1.3-fold FL enhancement and 1.9-fold PA enhancement than HCy-AAN . In addition, HCy-AAN-Bio could image legumain activity in vivo with an additional 1.5-fold FL enhancement and 1.9-fold PA enhancement than HCy-AAN . We expected that HCy-AAN-Bio will be a powerful tool for early diagnosis of associated cancer.

In this work, a tumor-targeted and multi-stimuli responsive drug delivery system combining infrared thermal imaging of cells with thermo-chemotherapy was developed. Oxidized mesoporous carbon nanoparticles (MCNs-COOH) with high photothermal conversion ability (photothermal transduction efficiency η = 27.4%) in near-infrared (NIR) region were utilized to encapsulate doxorubicin (DOX). The outer surfaces of MCNs-COOH were capped with multifunctional carbon dots (CD HA) as simultaneous smart gatekeepers, a tumor targeting moiety and a fluorescent probe. NIR laser irradiation killed cancer cells through NIR-light induced hyperthermia, facilitated chemotherapeutic drug release and enhanced the sensitivity of tumor cells to drugs. The therapeutic efficacy in two-dimensional (2D) and three-dimensional (3D) cells demonstrated that MC-CD HA loading DOX (MC-CD HA /DOX) had good chemo-photothermal synergistic antitumor effects (combination index of CI = 0.448). The biodistribution and pharmacodynamics experiments of MC-CD HA /DOX in the 4T1 tumor model indicated that MCNs-COOH prolonged the residence time of DOX in tumor tissues and therefore actualized effective synergistic photothermal chemotherapy. By combining these excellent capabilities, the tumor-targeted and multi-stimuli responsive drug delivery system can be utilized as a visible nanoplatform for chemophotothermal synergistic therapy. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OSA) is a type of bone cancer that begins in the cells that form bones. OSA is a rare mesenchymal bone neoplasm derived from mesenchymal stem cells. Genome disorganization, chromosomal modifications, deregulation of tumor suppressor genes, and DNA repair defects are the factors most responsible for OSA development. Despite significant advances in the diagnosing and treatment of OSA, patients’ overall survival has not improved within the last twenty years. Lately, advances in modern nanotechnology have spurred development in OSA management and offered several advantages to overcome the drawbacks of conventional therapies. This technology has allowed the practical design of nanoscale devices combined with numerous functional molecules, including tumor-specific ligands, antibodies, anti-cancer drugs, and imaging probes. Thanks to their small sizes, desirable drug encapsulation efficiency, and good bioavailability, functionalized nanomaterials have found wide-spread applications for combating OSA progression. This review invokes the possible utility of engineered nanomaterials in OSA diagnosis and treatment, motivating the researchers to seek new strategies for tackling the challenges associated with it.

Graphical abstract Highlights • Fe 3 O 4 NPs conjugated with DOX, PEG, and folic acid were developed. • The amount of DOX released from the NPs was higher at pH 5.6 than pH 7.4. • The NPs showed the higher cellular uptake due to the presence of folic acid. • The NPs showed an enhanced cytotoxicity against the HeLa cells. • The transverse relaxivity (r 2 ) of the NPs was 133 mM−1S−1. Abstract Multi-functional nanocarriers based on iron oxide nanoparticles (IONPs) conjugated with doxorubicin (DOX), poly(ethylene glycol) (PEG), and folic acid (FA) (IO-MMA-DOX-PEG-OCH 3 /FA) were prepared as theranostics for cancer therapy. Using mono-methyl adipate (MMA) as a linker, the anticancer drug, DOX, was conjugated on the surface of IONPs by acid-cleavable hydrazone bond. The average size of the IO-MMA-DOX-PEG-OCH 3 /FA nanocarriers was determined as 14 and 40 nm by TEM and DLS, respectively. The saturation magnetization (Ms) and transverse relaxivity (r 2 ) value of IO-MMA-DOX-PEG-OCH 3 /FA nanocarriers were calculated as 28.62 Am2/kg and 133 mM-1s-1, respectively. The rate and amount of DOX released from the IO-MMA-DOX-PEG-OCH 3 /FA nanocarriers were higher at acidic medium (pH 5.6) than that at alkaline medium (pH 7.4) due to the presence of hydrazone bond between the DOX and IONPs. The IO-MMA-DOX-PEG-OCH 3 /FA nanocarriers showed the higher cellular uptake than FA-free nanocarriers due to the folate-receptor-mediated endocytosis, thereby presenting an enhanced cytotoxicity against folate-receptor-positive HeLa cells through apoptosis. The results confirmed that the IO-MMA-DOX-PEG-OCH 3 /FA nanocarriers could be promising for cancer therapy with the improved drug loading, tumor-targeted controlled drug release and MRI abilities. [ABSTRACT FROM AUTHOR]

Therapeutic effects of photodynamic therapy (PDT) are limited by the selectivity of photosensitizer (PS). Herein, a novel tumor-targeted drug-PS conjugate (Gan-ZnPc) which integrated with zinc phthalocyanine (ZnPc) and Ganetespib has been developed. ZnPc is a promising PS with remarkable photosensitization ability. Ganetespib is a heat shock protein 90 (Hsp90) inhibitor with preferential tumor selectivity and conjugated to ZnPc as a tumor-targeted ligand. The multifunctional small molecule conjugate, Gan-ZnPc, could be bound to extracellular Hsp90 and then selectively internalized into the tumor cells, followed by the generation of abundant intracellular reactive oxygen species (ROS) upon irradiation. Besides, Gan-ZnPc can arrest cell proliferation and induce apoptosis by the inhibition of Hsp90. Herein, with combination of the inhibition of Hsp90 and the generation of cytotoxic ROS, Gan-ZnPc implements tumor selectivity, concentrated PDT and chemotherapy in a synergistic manner, which results in highly effective anti-tumor activity in vitro and in vivo. [ABSTRACT FROM AUTHOR]

A unique pH/redox dual-sensitive cationic unimolecular nanoparticle (NP) enabling excellent endosomal/lysosomal escape and efficient siRNA decomplexation inside the target cells was developed for tumor-targeted delivery of siRNA. siRNA was complexed into the cationic core of the unimolecular NP through electrostatic interactions. The cationic core used for complexing siRNA contained reducible disulfide bonds that underwent intracellular reduction owing to the presence of high concentrations of reduced glutathione (GSH) inside the cells, thereby facilitating the decomplexation of siRNA from the unimolecular NPs. The cationic polymers were conjugated onto the hyperbranched core (H40) via a pH-sensitive bond, which further facilitated the decomplexation of siRNA from the NPs. In vitro studies on the siRNA release behaviors showed that dual stimuli (pH = 5.3, 10 mM GSH) induced the quickest release of siRNA from the NPs. In addition, the imidazole groups attached to the cationic polymer segments enhanced the endosomal/lysosomal escape of NPs via the proton sponge effect. Intracellular tracking studies revealed that siRNA delivered by unimolecular NPs was efficiently released to the cytosol. Moreover, the GE11 peptide, an anti-EGFR peptide, enhanced the cellular uptake of NPs in MDA-MB-468, an EFGR-overexpressing triple negative breast cancer (TNBC) cell line. The GE11-conjugated, GFP-siRNA-complexed NPs exhibited excellent GFP gene silencing efficiency in GFP-MDA-MB-468 TNBC cells without any significant cytotoxicity. Therefore, these studies suggest that this smart unimolecular NP could be a promising nanoplatform for targeted siRNA delivery to EFGR-overexpressing cancer cells. [ABSTRACT FROM AUTHOR]

Localized cancer treatment with combination therapy has attracted increasing attention for effective inhibition of tumor growth. In this work, we introduced diffusion molecular retention (DMR) tumor targeting effect, a new strategy that employed transferrin (Tf) modified hollow mesoporous CuS nanoparticles (HMCuS NPs) to undergo extensive diffuse through the interstitium and tumor retention after a peritumoral (PT) injection. Herein, HMCuS NPs with strong near-infrared (NIR) absorption and photothermal conversion efficiency could serve as not only a drug carrier but also a powerful contrast agent for photoacoustic imaging to guide chemo-phototherapy. The iron-dependent artesunate (AS), which possessed profound cytotoxicity against tumor cell, was used as model drug. As a result, this AS loaded Tf-HMCuS NPs (AS/Tf-HMCuS NPs) system could specially target to tumor cells and synchronously deliver AS as well as irons into tumor to achieve enhanced antitumor activity. It was found that AS/Tf-HMCuS NPs was taken up by MCF-7 cells via Tf-mediated endocytosis, and could effectively convert NIR light into heat for photothermal therapy as well as generated high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, in vivo antitumor efficacy studies showed that tumor-bearing mice treated with AS/Tf-HMCuS NPs through peritumoral (PT) injection under NIR laser irradiation displayed the strongest inhibition rate of about 74.8%, even with the reduced frequency of administration. Furthermore, to demonstrate DMR, the optical imaging, photoacoustic tomography and immunofluorescence after PT injection were adopted to track the behavior of AS/Tf-HMCuS NPs in vivo . The results exhibited that Tf-HMCuS NPs prolonged the local accumulation and retention together with slow vascular uptake and extensive interstitial diffusion, which was consistent with the biodistribution studies of AS/Tf-HMCuS NPs. Therefore, the approach of localized delivery through DMR combined with multi-mechanism therapy may be a promising method for cancer treatment. Statement of Significance In recent years, localized cancer treatment using different biomaterials has attracted increasing attention for effective inhibition of tumor growth. However, it is still challenging for this kind of system to achieve a high drug loading, overcome biological barriers from the site of injection to the site of action, and combine synergetic therapy with diagnosis without adversely affecting the formation process. This study provides a localized diffusion molecular retention (DMR) tumor targeting drug delivery system based on hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) entrapment of anticancer drug for the first time, which can achieve high drug loading, improve local drug accumulation and retention, accomplish synergistic combination of chemo-phototherapy, and finally enhance antitumor effect. In addition, HMCuS NPs also possesses the property suitable for photoacoustic imaging, which could offer us a theranostic platform. [ABSTRACT FROM AUTHOR]

To reduce the side effects and enhance the anti-tumor activities of anticancer drugs in the clinic, the use of nano mesoporous materials, with mesoporous silica (MSN) being the best-studied, has become an effective method of drug delivery. In this study, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores, and our results demonstrated that MSe could synergistically enhance the antitumor activity of DOX. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro , HSA-MSe@DOX prominently induced cancer cell toxicity by synergistically enhancing the effects of MSe and DOX. Moreover, HSA-MSe@DOX possessed tumor-targeting abilities in tumor-bearing nude mice and not only decreased the side effects associated with DOX, but also enhanced its antitumor activity. Therefore, HSA-MSe@DOX is a promising new drug that warrants further evaluation in the treatments of tumors. Statement of significance To reduce the side effects and enhance the anti-tumor activities of anticancer drugs, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro and in vivo , HSA-MSe@DOX possessed tumor-targeting abilities and not only decreased the side effects associated with DOX, but also enhanced its antitumor activity. Therefore, HSA-MSe@DOX is a promising new drug that warrants further evaluation in the treatments of tumors. [ABSTRACT FROM AUTHOR]

Recently, the therapeutic effect of chemotherapy has been obviously impaired due to premature drug release, low tumor penetration, and multidrug resistance of nanoplatforms. In this paper, a novel multiple-sensitive drug delivery system (MC-ss-CDs) was developed by gating long-wavelength emitting carbon dots (CDs) on the openings of mesoporous carbon nanoparticles (MC) through disulfide bonds. The MC with excellent photothermal transition efficiency and high drug storage capacity for doxorubicin (DOX) was used as the delivery carrier. The CDs had multiple functions, including intelligent switching to hinder unwanted release, photothermal therapy (PTT) agents to improve the heat generation effect of MCs and bioimaging trackers to monitor drug delivery. The disulfide bonds, as the linkers between MC carriers and CDs, are stable under normal physical conditions and relatively labile under high GSH concentrations in the cytoplasm of tumor cells. After arriving at the tumor microenvironment, DOX/MC-ss-CDs can rapidly break into DOX/MC and CDs under high GSH concentrations. DOX/MC could realize efficient integration of PTT and chemotherapy on the surface of the tumor by stimuli-responsive DOX release and synergetic heating of MC and CDs. The small-sized CDs with excellent penetrating ability could effectively enter the deep tumor and realize NIR-triggered photothermal ablation. The DOX/MC-ss-CDs showed a chemophotothermal effect with a combination index of 0.38 in vitro and in vivo. Therefore, the DOX/MC-ss-CDs could be employed as a trackable nanovehicle for synergistic chemotherapy and PTT at different depths. [Display omitted] • Mesoporous carbon (MC) was used as a NIR-absorbing carrier with high drug loading. • Red-emitting CDs were gated on the openings of MC by disulfide bonds. • CDs were used as photothermal agents, smart capping, and fluorescence marker. • DOX/MC-ss-CDs can realize synergistic chemotherapy and PTT at different depths. [ABSTRACT FROM AUTHOR]

In this work, a tumor-targeted and multi-stimuli responsive drug delivery system has been developed for combining photoacoustic tomography imaging with chemo-phototherapy. We utilized a kind of near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) to encapsulate doxorubicin (DOX). After that, the outer surface of HMCuS NPs was capped with multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety. Herein, HMCuS-HA could serve as a powerful contrast agent for photoacoustic tomography (PAT) to guide chemo-phototherapy by providing the identification of cancerous lesions. In vitro and in vivo studies, the nanoplatform (DOX/HMCuS-HA) pinpointed MCF-7 cells via CD44 receptor-mediated endocytosis pathway. Subsequently, intracellular enzyme-responsive controlled drug release would take place in lysosome after the HA degradation by hyaluronidase. Under near infrared (NIR) light irradiation, HMCuS NPs could not only effectively convert NIR light into heat for photothermal therapy, but also generate high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, NIR light and low pH environment could facilitate intracellular tunable drug release with spatial/temporal resolution, and thus synergistic combination of chemo-phototherapy should be simultaneously driven by an 808 nm laser irradiation, which brought out an outstanding therapeutic effect. In vivo optical imaging demonstrated that HMCuS-HA significantly enhanced targeting and accumulation capacity in tumor site. Furthermore, tumor-bearing mice treated with DOX/HMCuS-HA under NIR irradiation (808 nm, 2 W/cm 2 , 0.5 min) in vivo displayed the highest inhibition ratio of about 88.9%. Taken together, our present study of the tumor-targeted and multi-stimuli responsive drug delivery system provides new insights into multimodality theranostic applications in cancer treatment. Statement of Significance Until now, chemotherapy is still the major therapeutic approach applied in oncology. Despite their pharmacologically efficacy in cancer treatments, most chemotherapeutic agents without tumor-specific targeting ability have brought out serious toxicities to normal tissues. This study provides a promising near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) with capping of multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety to address the above problem. After the nanoplatform (DOX/HMCuS-HA) pinpointed breast cancer cells via CD44 receptor-mediated endocytosis pathway, intracellular multi-stimuli responsive controlled drug release would take place with remarkable spatial/temporal resolution. Then photoacoustic tomography (PAT) and synergistic combination of chemo-phototherapy would be simultaneously driven by the same NIR irradiation in a coordinated way, which brought out an outstanding theranostic effect. This work can arouse broad interests among researchers in the fields of nanomedicine, nanotechnology, and drug delivery system. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a serious cancer with high mortality worldwide. Gemcitabine (GEM) is easily degraded in the circulation and has no tumor-targeted effect. In our previous research, an amphiphilic GEM derivative, cyclic phosphoryl N- dodecanoyl gemcitabine (CPDG) was prepared based on the techniques of HepDirect prodrug and self-assembled drug delivery systems (SADDS), which self-assembled into the stable nanoassemblies in water. In this study, the long-circulating nanoassemblies of CPDG/CHS-PEG1500 (9:1, mol/mol) were prepared for HCC treatment. In vitro and in vivo studies of the long-circulating CPDG nanoassemblies were explored. The degradation rates of CPDG depended on the media. CPDG showed much faster degradation in the acidic environment (pH 2.0) than the weak acidic and neutral media (pH 5.0, pH 7.4). However, the degradation half-life ( t 1/2 ) of CPDG was about 43 h in the mouse plasma, longer than the t 1/2 at pH 2.0. Therefore, the long-circulating CPDG nanoassemblies could keep stable before reaching the targets in vivo . In the biodistribution study, the long-circulating CPDG nanoassemblies were bolus intravenously ( i.v. ) injected into the hepatocellular tumor-bearing mice. The distribution of CPDG in the tumors was much higher than that in the blood, indicating the tumor targeting of the long-circulating nanoassemblies. In the pharmacodynamic study, the long-circulating CPDG nanoassemblies were i.v. injected into the tumor-bearing mice with doses of (37.5, 75 μmol/kg) compared with GEM (150 μmol/kg). The mice were injected once every 3 days for totally 3 times. The long-circulating nanoassemblies nearly always showed the higher anti-cancer effects than GEM. The tumor inhibitory rates of GEM, the long circulating CPDG nanoassemblies (37.5, 75 μmol/kg) were 49.54, 42.97, 65.10%, respectively. Therefore, the long-circulating CPDG nanoassemblies had the much higher anti-cancer effect than GEM. The long-circulating CPDG nanoassemblies are promising nanomedicines to treat HCC. The combination design of tumor-targeted nanoassemblies based on HepDirect prodrug technique and SADDS theory is an effective method to modify the pharmacologically active nucleosides to treat some liver diseases. [ABSTRACT FROM AUTHOR]

Multimodal imaging has made great contribution for diagnosis and therapy of disease since it can provide more effective and complementary information in comparison to any single imaging modality. The design and fabrication of fluorescent-magnetic nanoparticles for multimodal imaging has rapidly developed over the years. Herein, we demonstrate the facile synthesis of GdS coated CdTe nanoparticles (CdTe@GdS NPs) as multimodal agents for fluorescence (FL) and T 1 -weighted magnetic resonance (MR) imaging. These nanoparticles obtain both prominent fluorescent and paramagnetic properties by coating the GdS shell on the surface of CdTe core via a simple room-temperature route in aqueous solution directly. It is shown that the as-prepared CdTe@GdS NPs have high quantum yield (QY) value of 12% and outstanding longitudinal relaxation rate ( r 1 ) of 11.25 mM s −1 , which allow them to be employed as FL/MR dual-modal imaging contrast agents. They also exhibit small particle size of 5 nm, excellent colloidal stability and low cellular toxicity for concentrations up to 750 μg mL −1 . In addition, with the conjugation of folic acid, the nanoparticles were successfully used for tumor-targeted FL/MR dual-modal imaging in vitro and in vivo . [ABSTRACT FROM AUTHOR]

In this paper, a multifunctional theranostic magnetic mesoporous silica nanoparticle (MMSN) with magnetic core was developed for magnetic-enhanced tumor-targeted MR imaging and precise therapy. The gatekeeper β-cyclodextrin (β-CD) was immobilized on the surface of mesoporous silica shell via platinum(IV) prodrug linking for reduction-triggered intracellular drug release. Then Arg-Gly-Asp (RGD) peptide ligand was further introduced onto the gatekeeper β-CD via host–guest interaction for cancer targeting purpose. After active-targeting endocytosis by cancer cells, platinum(IV) prodrug in MMSNs would be restored to active platinum(II) drug in response to the innative reducing microenvironment in cancer cells, resulting in the detachment of β-CD gatekeeper and thus simultaneously triggering the in situ release of anticancer drug doxorubicin (DOX) entrapped in the MMSNs to kill cancer cells. It was found that with the aid of an external magnetic field, drug loaded MMSNs showed high contrast in MR imaging in vivo and exhibited magnetically enhanced accumulation in the cancer site, leading to significant inhibition of cancer growth with minimal side effects. This multifunctional MMSN will find great potential as a theranostic nanoplatform for cancer treatment. [ABSTRACT FROM AUTHOR]

A new cationic polymer eprosartan-graft-PEI (ESP) containing eprosartan (ES) and polyethylenimine 1.8K was successfully developed and employed as a safe gene vector to assemble a drug (ES) and gene co-delivery complex (ESP/pDNA). Chondroitin sulfate (CS) was then used as a coating polymer to shield the surface charge of ESP/pDNA complexes, as well as a tumor targeting entity to ensure specific delivery of CS/ESP/pDNA complexes. The CS/ESP/pDNA complexes with desirable particle size and zeta potential, exhibited amidase-responsive drug release and CS-mediated endocytosis in vitro . As compared with ESP/pDNA complexes, in vivo imaging results demonstrated decreased reticuloendothelial system uptake and remarkably increased tumor accumulation of CS/ESP/pDNA complexes. All these findings indicated the potential of CS/ESP/pDNA as a promising tumor-targeted drug and gene co-delivery system. [ABSTRACT FROM AUTHOR]

The folate receptor (FR) has been widely recognized as an excellent target for the tumor-selective delivery of cytotoxic agents, and four folate–drug conjugates have entered clinical evaluations for the treatment of solid tumors to date. However, most of these conjugates required structural modification of the cytotoxic warheads in order to achieve efficient drug release from the linkers. We designed and constructed a novel folate conjugate of a highly-potent next-generation taxoid, SB-T-1214, by exploiting bioorthogonal Cu-free ‘click’ chemistry. The synthesis was highly convergent and required no HPLC purification to obtain the final folate–taxoid conjugate 1 . Conjugate 1 demonstrated highly FR-specific potency (IC 50 2.1–3.5 nM) against a panel of cancer cell lines, with a >1000-fold decrease in cytotoxicity against normal human cells (IC 50 >5000 nM). The remarkable potency and selectivity of conjugate 1 can be attributed to highly FR-specific receptor-mediated endocytosis as well as efficient release of the unmodified cytotoxic warhead using a mechanism-based self-immolative linker. [ABSTRACT FROM AUTHOR]

In our study, a silica–polymer composite nano system (MB-NSi–p53–CS ternary complexes) composed of methylene blue-encapsulated amine-terminated silica nanoparticles (MB-NSi) and chondroitin sulfate (CS) were successfully developed for tumor-targeted imaging and p53 gene therapy of lung cancer. MB was employed as a NIR probe forin vivoimaging, MB-NSi nanoparticles were served as gene vector, while CS was applied to be a coating and targeting polymer. MB-NSi–p53–CS ternary complexes displayed nanosized diameter, effective p53 condensation ability, efficient p53 protection profile, and superior bovine serum albumin stabilityin vitro. Experiments on A549 cell line further revealed low cytotoxicity, high p53 transfection, and anticancer efficacy of MB-NSi–p53–CS ternary complexes.In vivoimaging and tumor targetability assays demonstrated that MB-NSi–p53–CS ternary complexes were a preferable system with desirable imaging and tumor-targeting properties. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) have immense potential as drug-delivery carriers for cancer therapy due to their unique physicochemical properties. These particles can improve the pharmacological and therapeutic properties of the anti-cancer drugs by controlling release rates and targeted delivery process, which eliminate the limitations of conventional anti-cancer treatment methods. In recent years, chitosan-based NPs are emerging as one of the most promising delivery vehicles for cancer chemotherapy and diagnosis due to their unique characteristics such as biodegradability, biocompatibility, remarkable cell membrane penetrability, high drug-carrying capacities, pH-dependent therapeutic unloading, ability to have a multi-functionality and prolonged circulating time. This article reviews the recent developments on the preparation, properties and tumor-targeted drug-delivery applications of NPs based on chitosan and its derivatives. [ABSTRACT FROM AUTHOR]

Oleic acid (OA) is a kind of monounsaturated omega-3 fatty acid that abounds in plants and animals which can induce apoptosis and has broad-spectrum inhibitory activity against a variety of tumor cell lines. However, OA is quite insoluble and thus inconvenient to be efficiently delivered in vivo. In this work, OA was fabricated into nanoparticles to generate OA elastic nanoparticles (OA-ENPs) with a particle size of 185.6 nm and good stability in various physiological media. OA-ENPs alone achieved a high tumor inhibition rate of 60.3% without significant side effect. More surprisingly, the resultant OA-ENPs displayed dose-dependent tumor targetability. Low dose of OA-ENPs (10 mg/kg) mainly distributed in the liver after intravenous injection, while high dose of OA-ENPs mainly distributed in tumor. At the high dose of 90 mg/kg, OA-ENPs accumulation in tumor reached nearly twice as that in the liver. Here we provide a simple but effective way to achieve excellent tumor targetability without the need of any surface modification of nanoparticles.

A binary targeting vector that consists of peptide sequences of Arg-Gly-Asp (RGD) and Asn-Gly-Arg (NGR) motifs has been designed and synthesized using solid-phase peptide synthesis procedure. The vector is then coupled with Gd-DOTA to work as a targeting contrast agent ( CA1) for magnetic resonance imaging of human lung adenocarcinoma cells A549. Its longitudinal relaxivity is measured to be 7.55 mM s in aqueous solution at a magnetic field of 11.7 T, which is higher than that of Magnevist (4.25 mM s) in the same conditions. The cell experiment shows, at the same concentration, uptake quantity of CA1 by A549 is much more than Magnevist and also superior over CA2 (a single targeting contrast agent contains only RGD). The uptake can be blocked by the targetable peptide containing RGD or NGR without coupling Gd. To summarize, CA1 has very good ability to target A549 and higher relaxivity than that of Magnevist. So CA1 is promising MRI contrast agent for high-resolution MR molecular imaging of human lung adenocarcinoma A549 cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] A series of 3′-CF2H-, CF3- and CH CF2 taxoids were synthesized, which exhibit excellent activities against various human cancer cell lines. [•] Those highly potent novel 3′-Rf-taxoids (Rf=CF2H, CF3, CH CF2) serve as excellent “warheads” in the tumor-targeted drug delivery systems. [•] Novel vitamin-linker-drug conjugates have been developed, which is an excellent system to incorporate a fluorotaxoid as “warhead”. [•] Nano-scale tumor-targeted drug delivery systems, which can incorporate highly potent fluorotaxoids as “warheads” have been developed. [•] Novel drug delivery systems, bearing a18F PET tracer module as well as a 19F fluorine probe have been designed and prototype synthesized. [Copyright &y& Elsevier]

Abstract: A novel target specific small interfering RNA (siRNA) delivery system was successfully developed using hydrophobized hyaluronic acid–spermine conjugates (HHSCs), which were previously synthesized and their properties were also characterized in our published papers. Fluorescein isothiocyanate (FITC) labeled specific Silencer Select siRNAs were used as a model system suppressing the cyclooxygenase-2 (COX-2) gene expression. The polymers were able to effectively bind siRNA, self-assemble into micelles, protect siRNA from degradation by nuclease and release complexed siRNA efficiently in the presence of low concentrations of polyanionic heparin. The cytotoxicity of siRNA/HHSCs complex to SGC-7901 cells was lower than that of siRNA/PEI 25k and Lipofectamine 2000 complex according to the MTT assay. When SGC-7901 and GES-1 cells were treated with FITC labeled siRNA/HHSCs complexes, SGC-7901 cells, with a cluster determinant 44 receptor (CD44), showed higher green fluorescent intensity than GES-1 cells because of the HA receptor mediated endocytosis of the complex. In addition, the inhibitory effect on the uptake in the presence of free HA in the transfection medium revealed that siRNA/HHSC-1 complex was selectively taken up to SGC-7901 cells via HA-receptor mediated endocytosis. Based on flow cytometry and microscopy, observation revealed that siRNA/HHSC complex was taken up preferentially through caveolae-mediated endocytosis, which may be a desirable pathway for avoiding the lysosomal degradation of delivered genes. All these results demonstrated that the intracellular delivery of siRNA/HHSC complex could be facilitated by the HA-receptor mediated endocytosis. [Copyright &y& Elsevier]

In this study, folic-dextran-camptothecin (Fa-DEX-CPT) tumor-targeted nanoparticles were produced with a supercritical antisolvent (SAS) technique by using dimethyl sulfoxide (DMSO) as a solvent and carbon dioxide as an antisolvent. A factorial design was used to reveal the effect of various process parameters on the mean particle size (MPS) and morphology of the particles formed. Under the optimum operation conditions, Fa-DEX-CPT nanoparticles with a MPS of 182.21 nm were obtained. Drug encapsulation efficiency and loading efficiency were 62.13% and 36.12%, respectively. It was found that the concentrations of the camptothecin (CPT) and dextran solution had a major influence upon morphology and shape of the final product. In addition, the samples were characterized by Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) with the purpose of developing a suitable targeted drug delivery system for cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Chitosan and its derivatives have shown great potential as non-viral vectors for gene delivery therapy. Folic acid receptor (FR) is an important anti-cancer therapy target that is applicable to many cancer types. In this study, we developed an efficient and targeted delivery of antisense oligodeoxynucleotides asODNs, using folic acid (FA) conjugated hydroxypropyl-chitosan (HPCS). These nanoparticles were designed to reduce production of P-gp, in order to overcome tumor drug resistance. Nanoparticles prepared were found to be 181 nm in diameter. Spectrofluorimetry was utilized to evaluate the effect of charge ratio of the nanoparticles on loading efficiency. In PBS buffer, 40% of asODNs were released from the nanoparticles at first 24 h. However, just another 15% was released between 24 and 48 h. The antitumor effect of the nanoparticles was evaluated in KB-A-1 cells implanted in Balb/c-nu/nu mice. They inhibited the growth of tumor by 35% compared to the bare asODNs. The FA–HPCS–asODNs nanoparticles demonstrated significantly inhibition of the multi drug resistance (MDR) 1 gene levels and P-gp levels in vitro and in vivo, respectively, related with bare asODNs and HPCS–asODNs ones. During in vivo studies, FA–HPCS–asODNs nanoparticles were also found to bind specifically and efficiently to FR high-expressing cancer cells. These results suggested that the use of targeted, antisense agent nanoparticles would be potential approach to overcome tumor drug resistance. [Copyright &y& Elsevier]