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The restoration of the function of p53 in tumors is a therapeutic strategy for the highly frequent mutation of the TP53 tumor suppressor gene. P460 is a wild-type peptide derived from the p53 C-terminus and has been proven to be capable of restoring the tumor suppressor function of p53. The poor accumulation of drugs in tumors is a serious hindrance to tumor treatment. For enhancing the activity of P460, the tumor-targeting sequence Arg–Gly–Asp–Arg (RGDR, C-end rule peptide) was introduced into the C-terminus of P460 to generate the new peptide P462. P462 presented better activity than P460 in inhibiting the proliferation of cancer cells and increasing the number of tumor cells undergoing apoptosis. Cell adhesion analysis and tumor imaging results revealed that P462 showed more specific and extensive binding with tumor cells and greater accumulation in tumors than the wild-type peptide. Importantly, treatment with P462 was more efficacious than that with P460 in vivo and was associated with considerably improved tumor-homing activity. This study highlights the importance of the roles of the tumor-homing sequence RGDR in the enhancement in cell attachment and tumor accumulation. The results of this work indicate that P462 could be a novel drug candidate for tumor treatment. [ABSTRACT FROM AUTHOR]

Introduction: S100A4 promotes the establishment of tumor microenvironment for malignant cancer cells, and knockdown of S100A4 can inhibit tumorigenesis. However, there is no efficient way to target S100A4 in metastatic tumor tissues. Here, we investigated the role of siS100A4-loaded iRGD-modified extracellular vesicles (siS100A4-iRGD-EVs) in postoperative breast cancer metastasis. Methods: siS100A4-iRGD-EVs nanoparticles were engineered and analyzed using TEM and DLS. siRNA protection, cellular uptake, and cytotoxicity of EV nanoparticles were examined in vitro. Postoperative lung metastasis mouse model was created to investigate the tissue distribution and anti-metastasis roles of nanoparticles in vivo. Results: siS100A4-iRGD-EVs protected siRNA from RNase degradation, enhanced the cellular uptake and compatibility in vitro. Strikingly, iRGD-modified EVs significantly increased tumor organotropism and siRNA accumulation in lung PMNs compared to siS100A4-EVs in vivo. Moreover, siS100A4-iRGD-EVs treatment remarkedly attenuated lung metastases from breast cancer and increased survival rate of mice through suppressing S100A4 expression in lung. Conclusions: siS100A4-iRGD-EVs nanoparticles show more potent anti-metastasis effect in postoperative breast cancer metastasis mouse model. [ABSTRACT FROM AUTHOR]

Multi-modal biomedical imaging has played an essential role in tumor diagnosis. However, constructing a multi-modal imaging contrast agent with high affinity to a tumor is challenging. Herein, we studied the design and application of a PET/MRI dual-modal imaging agent based on superparamagnetic iron oxide nanoparticles (SPION). αvβ3-targeting RGD peptide and 64Cu were conjugated onto SPION. Small animal PET and MR imaging in glioblastoma tumor-bearing mice revealed that this dual-modal imaging contrast agent could potentially be utilized for PET/MRI dual-modal imaging for the tumor diagnosis. [ABSTRACT FROM AUTHOR]

Cell membrane vesicles, as delivery carriers of drugs or biological agents in vivo, are an important therapeutic mode in the study of disease treatment. Tumor membrane-derived vesicles have been widely used in tumor therapy because of their good tumor enrichment effect. The most common method is the surface of nanoparticles coated with tumor cell membrane, which can effectively prolong the circulation time of particles in the blood and the enrichment of tumors. In this study, we prepared vesicles of different tumor cell membrane derivate and studied their targeting to tumors detailly. The results showed that homologous vesicles have high targeting to homologous tumor cells. The fluorescence of vesicles in homologous tumor cells was significantly higher than that in other tumor cells. This study will provide a new strategy and guidance for the clinical treatment of cancer based on the tumor cell membrane system. [ABSTRACT FROM AUTHOR]

Melanoma is a highly aggressive cancer which often forms metastatic tumors in the lung, leading to sharply reduced patients' survival rate. Effectively treating these tumors thus could improve late stage melanoma with lung metastasis. In this study, we fabricated a Cys-Arg-Glu-Lys-Ala with N-methylated Glu (CR(NMe)EKA) decorated disk shaped nano vehicle to co-deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and paclitaxel (PTX) to lung melanoma tumor sites (TRAIL-[ND-PTX]CR(NMe)EKA). These nanodisks displayed better tumor-targeting and penetration capability than spherical nanoparticles, while the fibronectin-targeting CR(NMe)EKA motif also increased the tumor accumulation of loaded drugs. The combined usage of TRAIL and PTX both killed tumor cells and reduced local nutrition supply, leading to stronger overall anti-tumor effect. This TRAIL-[ND-PTX]CR(NMe)EKA system performed remarkably better than free paclitaxel and also significantly elongated survival rate of melanoma lung metastasis bearing mice, without displaying significant toxicity. Hence, this designing strategy and the fabricated nanoplatform possess potential for further development. [ABSTRACT FROM AUTHOR]

Research on the roles of the bacteria in tumor development and progression is a rapidly emerging field. Increasing evidence links bacteria with the modification of the tumor immune microenvironment, which greatly influences the antitumor response. In view of the individual immune effects of various bacteria in various tumors, developing personalized bacteria-modulating therapy may be a key to successful antitumor treatment. This review emphasizes the critical role of the bacteria in immune regulation, including both the tumor bacteria and gut bacteria. Aiming at tumor-related bacteria, we focus on various precise modulation strategies and discuss their impact and potential for tumor suppression. Finally, engineered bacteria with tumor-targeting ability could achieve precise delivery of various payloads into tumors, acting as a precision tool. Therefore, a precise tumor-related bacteria therapy may be a promising approach to suppress the development of tumors, as well as an adjuvant therapy to improve the antitumor efficacy of other approaches. Key points: • The mini-review updates the knowledge on complex effect of bacteria in TME. • Insight into the interaction and adjustment of bacteria in gut for TME. • Prospects and limitations of bacteria-related personalized therapy in the clinical anticancer therapy. [ABSTRACT FROM AUTHOR]

In this work, a novel bi-modal imaging probe with enhanced CT contrast efficiency and FL brightness was constructed, in which the combination of a binary CT contrast agent BaHoF5 and Cu-doped QDs served as a vehicle; hyaluronic acid (HA) was employed as a tumor-targeting ligand. With its CT contrast efficiency about 2.1- and 3.9-fold higher than PEG-BaHoF5 and Iohexol, the CT contrast efficiency and the fluorescent brightness of the bi-modal probe were both enhanced. Likewise, its fluorescent brightness is almost 6-fold brighter after Cu-doped QDs loading. The most important contribution of this work lies on the proposed strategy. The inherent contradiction of the imaging sensitivity of CT and FL imaging is well balanced and a great CT/FL bi-modal imaging performance is simultaneously obtained even at low concentration (400 μg/mL) of the probe, which was superior to the previous CT/FL bi-modal probes. Moreover, since BaHoF5 as a binary CT contrast agent was introduced instead of conventional Au and Bi2S3, the CT/FL bi-modal probe would be more suitable for different patients under different operation voltages. In addition, the in vitro tumor cell imaging also demonstrated a good photo-stability, FL brightness, and tumor-targeting capability of the probe, indicating its great potential in practical bi-modal imaging for further tumor diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Currently, prostate cancer is the most frequently diagnosed cancer in males and chemotherapy is often essential for treating advanced prostate cancer. However, common chemotherapies for prostate cancer suffer from serious adverse effects due to poor drug targeting ability and tissue penetration, even with the help of conventional drug delivery systems. Here, encouraged by recent studies showing possible drug retention and tissue penetration advantages of unconventional non-spherical nanoparticles over conventional spherical nanoparticles, we design and construct a novel non-spherical nanodisk drug delivery system for treating prostate cancer. In order to enhance tumor-targeting capability, these nanodisks are further modified with targeting peptide CR(NMe)EKA, which recognizes extracellular matrix fibronectin and its complexes specifically expressed on the walls of tumor vessels and in tumor stroma. Compared with conventional nanospheres, the nanodisks achieve much higher drug accumulation at prostate tumor sites. When loaded with paclitaxel, the CR(NMe)EKA-modified nanodisks display superior antitumor efficacy to free paclitaxel, unmodified nanodisks and nanospheres. In summary, our study provides an attractive therapeutic strategy for targeted therapy against prostate cancer with simple preparation, high efficiency and low toxicity, and supplements a theoretical support for treatments realized by different shaped nanoplatforms. Our study also offers valuable data for understanding biological effects of non-spherical nanodisks and highlights the great potential of unconventional nanoparticles in biomedical applications. [ABSTRACT FROM AUTHOR]

Liposomes possess good biocompatibility and excellent tumor-targeting capacity. However, the rapid premature release of lipophilic drugs from the lipid bilayer of liposomes has negative effect on the tumor-targeted drug delivery of liposomes. In this study, a lipophilic antitumor drug-chlorambucil (CHL)-was encapsulated into the aqueous interior of liposomes with the aid of albumin to obtain the CHL-loaded liposomes/albumin hybrid nanoparticles (CHL-Hybrids). The in vitro accumulative release rate of CHL from CHL-Hybrids was less than 50% within 48 h, while the accumulative CHL release was more than 80% for CHL-loaded liposomes (CHL-Lip). After intravenous injection into rats, the half-life ( t = 5.68 h) and maximum blood concentration ( C = 4.58 μg/mL) of CHL-Hybrids were respectively 1.1 times and 3.5 times higher than that of CHL-Lip. In addition, CHL-Hybrids had better tumor-targeting capacity for it significantly increased the drug accumulation in B16F10 tumors, which contributed to the significantly control of tumor growth compared with CHL-Lip. Furthermore, CHL-Hybrid-treated B16F10 melanoma-bearing mice displayed the longest median survival time of 30.0 days among all the treated groups. Our results illustrated that the proposed hybrids drug delivery system would be a promising strategy to maintain the controlled release of lipophilic antitumor drugs from liposomes and simultaneously facilitate the tumor-targeted drug delivery. [ABSTRACT FROM AUTHOR]

Despite of a growing number of bacterial species that apparently exhibit intrinsic tumor-targeting properties, no bacterium is able to inhibit tumor growth completely in the immunocompetent hosts, due to its poor dissemination inside the tumors. Oxygen and inflammatory reaction form two barriers and restrain the spread of the bacteria inside the tumors. Here, we engineered a Salmonella typhimurium strain named ST8 which is safe and has limited ability to spread beyond the anaerobic regions of tumors. When injected systemically to tumor-bearing immunocompetent mice, ST8 accumulated in tumors at levels at least 100-fold greater than parental obligate anaerobic strain ST4. ST8/pSEndo harboring therapeutic plasmids encoding Endostatin fused with a secreted protein SopA could target vasculature at the tumor periphery, can stably maintain and safely deliver a therapeutic vector, release angiogenic inhibitors through a type III secretion system (T3SS) to interfere with the pro-angiogenic action of growth factors in tumors. Mice with murine CT26 colon cancer that had been injected with ST8/pSEndo showed efficient tumor suppression by inducing more severe necrosis and inhibiting blooding vessel density within tumors. Our findings provide a therapeutic platform for indirectly acting therapeutic strategies such as anti-angiogenesis and immune therapy. [ABSTRACT FROM AUTHOR]

Purpose: To develop a multi-functional theranostic nanoplatform with increased tumor retention, improving antitumor efficacy and decreased side effects of chemotherapy drugs. Methods: GO@Gd nanocomposites was synthesized via decorating gadolinium (Gd) nanoparticles (GdNP) onto graphene oxide (GO), and then functionalized by polyethylene glycol (PEG2000), folic acid (FA), a widely used tumor targeting molecule, was linked to GO@Gd-PEG, finally, doxorubicin (DOX) was loaded onto GO@Gd-PEG-FA and obtained a tumor-targeting drug delivery system (GO@Gd-PEG-FA/DOX). GO@Gd-PEG-FA/DOX was characterized and explored its theranostic applications both in a cultured MCF-7 cells and tumor-bearing mice. Results: GO@Gd-PEG-FA/DOX could efficiently cross the cell membranes, lead to more apoptosis and afford higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 7.6-fold higher DOX uptake of tumor than DOX. Besides, GO@Gd-PEG-FA/DOX also served as a powerful photothermal therapy (PTT) agent for thermal ablation of tumor and a strong T1-weighted contrast agent for tumor MRI diagnosis. The multi-functional nanoplatform also could selectively kill cancer cells in highly localized regions via the excellent tumor-targeting and MRI guided PTT abilities. Conclusions: GO@Gd-PEG-FA/DOX exhibited excellent photothermal-chemotherapeutic efficacy, tumor-targeting property and tumor diagnostic ability. [ABSTRACT FROM AUTHOR]

Introduction: Anti-epidermal growth factor receptor (EGFR)-targeted nanoparticles can be used to deliver a therapeutic and imaging agent to EGFR-overexpressing tumor cells. I-labeled anti-EGFR nanoparticles derived from cetuximab were used as a tumor-targeting vehicle in radionuclide therapy. Methods: This paper describes the construction of the anti-EGFR nanoparticle EGFR-BSA-PCL. This nanoparticle was characterized for EGFR-targeted binding and cellular uptake in EGFR-overexpressing cancer cells by using flow cytometry and confocal microscopy. Anti-EGFR and non-targeted nanoparticles were labeled with I using the chloramine-T method. Analyses of cytotoxicity and targeted cell killing with I were performed using the MTT assay. The time-dependent cellular uptake of I-labeled anti-EGFR nanoparticles proved the slow-release effects of nanoparticles. A radioiodine therapy study was also performed in mice. Results: The EGFR-targeted nanoparticle EGFR-BSA-PCL and the non-targeted nanoparticle BSA-PCL were constructed; the effective diameters were approximately 100 nm. The results from flow cytometry and confocal microscopy revealed significant uptake of EGFR-BSA-PCL in EGFR-overexpressing tumor cells. Compared with EGFR-BSA-PCL, BSA-PCL could also bind to cells, but tumor cell retention was minimal and weak. In MTT assays, the EGFR-targeted radioactive nanoparticle I-EGFR-BSA-PCL showed greater cytotoxicity and targeted cell killing than the non-targeted nanoparticle I-BSA-PCL. The radioiodine uptake of both I-labeled nanoparticles, I-EGFR-BSA-PCL and I-BSA-PCL, was rapid and reached maximal levels 4 h after incubation, but the I uptake of I-EGFR-BSA-PCL was higher than that of I-BSA-PCL. On day 15, the average tumor volumes of the I-EGFR-BSA-PCL and I-BSA-PCL groups showed a slow growth relationship compared with that of the control group. Conclusion: The EGFR-targeted nanoparticle EGFR-BSA-PCL demonstrated superior cellular binding and uptake compared with those of the control BSA-PCL. The EGFR-targeted radioactive nanoparticle I-EGFR-BSA-PCL exhibited favorable intracellular retention of I. Radionuclide therapy using I-EGFR-BSA-PCL, which showed excellent targeted cell killing, suppressed cancer cell growth caused by EGFR overexpression. [ABSTRACT FROM AUTHOR]

Folate-containing dextran ligand (FA-Dextran-DTPA) was synthesized by the incorporation of diethylenetriaminepentaacetic acid (DTPA) and folate (FA) as a tumor-targeting group into dextran as a polymer carrier. This ligand was further reacted with gadolinium chloride to make a dextran gadolinium complex FA-Dextran-DTPA-Gd. The ligand and its gadolinium complex were characterized by H-NMR, FTIR, UV-Vis, average particle sizes and zeta potential, as well. In vitro properties including relaxivity, cytotoxicity assay, cellular uptake assay, and magnetic resonance imaging (MRI) were also evaluated. Compared with Gd-DTPA, FA-Dextran-DTPA-Gd possessed obviously higher relaxation effectiveness and lower cytotoxicity to HeLa cells. FA-Dextran-DTPA-Gd had a high affinity to the H460 and MDA-MB-231 tumor cells and can be taken up selectively by these tumor cells. Moreover, FA-Dextran-DTPA-Gd showed enhanced signal intensities (SI) of MRI and enhanced the contrast of MR images of tumor cells. These results indicated that FA-Dextran-DTPA-Gd showed the potential as a tumor-targeting contrast agent in MRI. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study was to design and fabricate endosomal pH-sensitive dual-ligand-modified micellar nanoparticles to achieve enhanced drug delivery to tumor cells and facilitated intracellular drug release. Methods: End-group-carboxylated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) and cyclic Arg-Gly-Asp-Tyr-Lys- and anti-prostate specific membrane antigen antibody-modified diblock copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) were synthesized and characterized by H NMR and gel permeation chromatography, and self-assembled into micelles. Paclitaxel-loaded dual-ligand-modified micelles were prepared by thin-film hydration method, and characterized by dynamic light scattering, transmission electron microscope, pH-dependent in vitro release and stability. Intracellular paclitaxel delivery was measured by flow cytometry and imaged by confocal microscopy. In vitro cytotoxicity was studied in the 22Rv1 xenograft prostate tumor cell lines. Results: The prepared dual-ligand-modified micelles with about 30 nm in diameter and rapid intracellular drug release behavior at endo/lysosomal pH were very effective in enhancing the cytotoxicity of paclitaxel against 22Rv1 cells by increasing the cellular uptake, which was verified the correlation with the expression of integrin αβ and prostate specific membrane antigen in tumor cells by flow cytometric analysis and confocal microscopy, compared with single ligand-modified micelles. Conclusion: These findings provided valuable information that the application of combining of dual-ligand modifications with pH-sensitivity to polymeric micelles may be a promising approach in the efficient delivery of anticancer drugs for treatment of integrin αβ and prostate specific membrane antigen expressing prostate cancers. [ABSTRACT FROM AUTHOR]

The cationic folic acid (CFA) was prepared by introducing triethylenetetramine into folic acid with EDCI/NHS and characterized by IR, NMR and mass spectra. It was found that approximately one of two carboxyls in the folic acid molecule was substituted to form CFA. The conversion of γ-carboxyl is found to be 59% higher than 30% of α-carboxyl. The CFA and doxorubicin hydrochloride can be loaded on the ionic shell of PTX-encapsulated micelle to form CFA loaded binary drug carrier via static interaction in aqueous solutions. The successful loading was demonstrated by zeta potential measurement and the drug load amount (DLA) of CFA was measured by HPLC. In vitro cytotoxicity results revealed the CFA drug carrier showed higher cytotoxicity to cancer cell MDA-MB-321 than the binary drug carrier without CFA and the positive control, while it showed lower cytotoxicity to normal cell HUVEC than the positive control, and similar cytotoxicity with the binary drug carrier without CFA. These results as well as confocal laser scanning microscopy observation indicate the synthesized CFA drug carrier possesses active tumor-targeting property. [ABSTRACT FROM AUTHOR]

Purpose: The objective of the work was to evaluate the potential of hyaluronan-based nanoparticles as tumor-targeting nano-systems for CD44-overexpressed cancer therapy. Methods: The synthesized amphiphilic cholesteryl succinoyl hyaluronan (Chol-Suc-HA) conjugates self-assembled into docetaxel(DTX)-loaded nanoparticles in the aqueous environment. The physiochemical properties of Chol-Suc-HA-DTX NPs were characterized. The in vitro cytotoxicity of Chol-Suc-HA-DTX NPs against MCF-7, 4T1, A549 and L929 cells was evaluated using MTT and LDH assays. Moreover, the cellular uptake mechanism was investigated using the CLSM and flow cytometry. The in vivo animal experiments of Chol-Suc-HA-DTX NPs including pharmacokinetic evaluation, bio-distribution observed by EX vivo NIRF imaging and antitumor efficacy were also carried out in SD rats or 4T1 tumor-bearing BALB/c mice. Results: The self-assembled Chol-Suc-HA-DTX NPs with different degree of substitution (DS) of hydrophobic moiety exhibited high drug loading, uniform particle size distribution and excellent in vitro stability. However, the plasma stability of Chol-Suc-HA-DTX NPs was significantly influenced by the DS of hydrophobic moiety. The higher the DS was, the more stable the NPs were. Cellular uptake demonstrated that Chol-Suc-HA-DTX NPs were internalized into cancer cells via CD44 receptor-mediated endocytosis. Compared with Taxotere®, Chol-Suc-HA-DTX NPs displayed remarkably higher cytotoxicity to CD44-positive cancer cells (MCF-7, 4T1, A549 cells). In vivo animal experiments confirmed that Chol-Suc-HA-DTX NPs with relatively high DS values exhibited prolonged circulation time, excellent tumor-targeting properties and efficient antitumor effects with extremely low systemic toxicity. In addition, blank Chol-Suc-HA NPs also slightly suppressed the tumor growth. Conclusions: Chol-Suc-HA NPs with a suitable DS value portend to be promising drug vehicles for systemic targeting of CD44-overexpressed cancers. [ABSTRACT FROM AUTHOR]

Purpose: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.Methods: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.Results: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.Conclusions: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.Graphical abstract: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: To establish a NIR (near infrared)-/pH-responsive and sustained-release tumor-targeting drug delivery system (SWNT-PEI/DOX/NGR). Methods: Functionalized SWNTs with polymerised polymeric poly(ethylene imine) was linked NGR (Asn-Gly-Arg) tumor-targeting peptide by DSPE-PEG2000-Maleimide via the maleimide group and sulfhydryl group of cysteine, in the end, doxorubicin (DOX) was attached to SWNT-PEI to obtain a SWNT-PEI/DOX/NGR delivery system. Results: The SWNT-PEI/DOX/NGR delivery system has significantly sustained-release effect and the slow release of DOX in normal tissues contribute to reduced systemic toxicity, while under 808 nm NIR laser irradiation or under lower pH environment the release of DOX can be accelerated. Conclusions: Due to hyperthermia sensitizer effect of DOX, chemo-photothermal exemplified by SWNT-PEI/DOX/NGR tumor-targeting delivery system is a promising approach to anticancer therapy in vivo or in vitro. [ABSTRACT FROM AUTHOR]

The safety of oncolytic viruses, such as conditionally repllcative adenoviruses (CRAds), has been validated in clinical trials for cancer therapy. Their antitumor efficacy is limited by the presence of preexisting neutralizing antibodies (NAbs). Mesenchymal stem cells (MSCs) are attractive as a cellular vehicle to carry antitumor agents, not only because they are easily obtained and expanded to great numbers in vitro, but also because of their ability to migrate and engraft to tumors. MSCs expanded under hypoxic conditions decrease in replicative senescence and increase in proliferation capacity and differentiation potentials. However It remains to be clarified whether these hypoxic MSCs also are good carriers for the delivery of CRAds to tumor cells in the presence of NAbs. This study firstly demonstrated hypoxic MSCs with an increased ability to migrate toward tumors through the upregulatlon of chemokine receptors, such as CXCR4 and CX3CR1. It is then demonstrated that hypoxic MSCs has the capacity to carry CRAds, without inducing apoptosis, for up to one week. Using an in vitro coculture with human colon cancer cells and with intraperitoneally (I.p.) and subcutaneously (s.c.) developed human colon cancer xenografts, It Is demonstrated that hypoxic MSCs are able to protect CRAds from attack by NAbs, thereby successfully delivering them to the target tumor cells. These results show that hypoxic MSCs can serve as cell carriers for CRAds and may help to develop new strategies against cancer. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies have become a mainstay for the targeted treatment of cancer today. Some of the most successful targets of monoclonal antibodies are constituted by the epidermal growth factor receptor family spearheaded by the epidermal growth factor receptor (EGFR). Prompted by studies indicating that IgE compared to IgG may harness alternate effector functions to eradicate malignant cells, we addressed the establishment, engineering, and the potential tumoricidal effects of recombinant anti-EGFR IgE. Therefore, two different therapeutic EGFR-specific antibodies, 225 and 425, were chosen for re-cloning into different chimeric IgE and IgG formats and produced in human cells. Simultaneous antibody binding to the sEGFR demonstrated accessibility of both epitopes for recombinant IgE. Proliferation and cytotoxicity assays demonstrated signal blocking and effector mediating capability of IgE isotypes. Pronounced degranulation in the presence of sEGFR upon activation exclusively with two IgE antibodies verified the epitope proximity and provides evidence that tumor-targeting by anti-EGFR IgE is safe with regard to soluble target structures. Degranulation mediated by tumor cells expressing EGFR could be demonstrated for singular and combined IgE antibodies; however, use of two IgE specificities was not superior to use of one IgE alone. The data suggest that the surface distribution of EGFR is optimally suited to mount a robust effector cell trigger and corroborate the potential and specificity of the IgE/IgE receptor network to react to xenobiotic or pathogenic patterns for targeting malignancies. [ABSTRACT FROM AUTHOR]

We recombine the suicide gene CD, UPRT into plasmid pTRKH2 and clone the recombinant dual suicide gene therapy system into tumor-hypoxia-targeting vector Bifidobacterium infantis and characterize its function. CD gene, UPRT gene and lactic acid bacteria expression plasmid pTRKH2 were digested by restriction endonuclease BamH I and Sal I, and constructed recombinant plasmids pTRKH2/CD and pTRKH2/UPRT in E. coli. The recombinant plasmids were then transfected into Bifidobacterium Infantis by electroporation. Identification of pTRKH2/CD and pTRKH2/UPRT was processed by dual restriction endonuclease digesting and sequencing. RT-PCR and SDS-PAGE were used to examine the expression of CD and UPRT genes at RNA and protein levels. The killing effects on Melanoma B16-F10 cells by pTRKH2/CD and pTRKH2/UPRT suicide gene therapy system with 5-FC were examined by MTT assay. The CD gene and UPRT gene was successfully recombined into lactic acid bacteria expression plasmid pTRKH2. After dual endonuclease digestion of plasmid purified from the positively transfected E. coli, two fragments of 6.9 Kb and 1.3 Kb were found for CD gene and two fragments of 6.9 Kb and 620 bp were found for UPRT gene. The sequencing of CD gene and UPRT gene proved consistent sequences with Genebank published data. A fragment of 1.3 Kb for CD gene and fragment of 620 bp for UPRT gene was found in recombinant Bifidobacterium by RT-PCR. A 52 KDa protein for CD gene was identified in whole-cell protein of recombinant Bifidobacterium and a 26 KDa protein for UPRT gene was identified in supernatant fluid of recombinant Bifidobacterium. The survival rate of tumor cells treated by extracts from culture of recombinant Bifidobacterium with 5-FC showed a strong killing effects of pTRKH2/CD and pTRKH2/UPRT dual suicide gene therapy system on Melanoma B16-F10 cells. CD gene and UPRT gene are successfully inserted into pTRKH2 and transfected into tumor-hypoxia-targeting vector Bifidobacterium Infantis. This dual suicide gene therapy system shows a high efficiency for tumor cells killing. [ABSTRACT FROM AUTHOR]

Glucosylated polyethylenimine (GPEI) was synthesized as a tumor-targeting gene carrier through facilitative glucose metabolism by tumor glucose transporter. Particle sizes of GPEI/ DNA complex increased in proportion to glucose content of GPEI, whereas surface charge of the complex was not dependent on glucosylation, partially due to inefficient shielding of the short hydrophilic group introduced. GPEI with higher glucosylation (36 mol-%) had no cytotoxic effect on cells even at polymer concentrations higher than 200 μg/mL. Compared to unglucosylated PEI, glucosylation induced less than one-order decrease of transfection efficiency. Transfection of GPEI/DNA complex into tumor cells possibly occurred through specific interaction between glucose-related cell receptors and glucose moiety of GPEI. Gamma imaging technique revealed GPEI/DNA complex was distributed in liver, spleen, and tumors. [ABSTRACT FROM AUTHOR]