Doxorubicin-loaded Nanoparticles Research Articles

Platelet Activation-Induced In Situ Trapping Metastatic Tumor Cells Strategy for Post-Surgery Tumor Recurrence Immunochemotherapy.

The reasons for the high recurrence and metastasis after triple-negative breast cancer (TNBC) surgery are the potential presence of micrometastases and disseminated tumor cells in the circulation, as well as the immunosuppressive microenvironment caused by the surgery. To address these issues, this work proposed a platelets (PLTs) based hydrogel delivery system for immuno-chemotherapy, (IL-12+NPD-PLT)@dAlg. To utilize the targeting ability of PLTs toward tumor cells and maintain the activity of PLTs, doxorubicin-loaded nanoparticles (NPD) were attached on the surface of PTLs (NPD-PLT). Under the conditions of the post-surgical tumor microenvironment (TME), these PTLs responsively released small-sized drug-loaded vesicles (NPD-PMP) trapping metastatic tumor cells, inducing immunogenic cell death (ICD) of tumor cells. Additionally, immunomodulatory drugs, IL-12, was combined in the hydrogel to synergistically activate CD8+ T cells within the body and induce the polarization of tumor-associated macrophages (TAMs) toward M1 cells, thereby improving the immunosuppressive microenvironment post-surgery. In a 4T1 tumor recurrence and metastasis mouse model, (IL-12+NPD-PLT)@dAlg has shown effective inhibition of tumor recurrence and metastasis, reversing the tumor immune environment, and prolonging survival.

Pluronic-Based Nanoparticles for Delivery of Doxorubicin to the Tumor Microenvironment by Binding to Macrophages.

The active targeting drug delivery system based on special types of endogenous cells such as macrophages has emerged as a promising strategy for tumor therapy, owing to its tumor homing property and biocompatibility. In this work, the active tumor-targeting drug delivery system carrying doxorubicin-loaded nanoparticles (DOX@MPF127-MCP-1, DMPM) on macrophage (RAW264.7) surfaces via the mediation of interaction with the CCR2/MCP-1 axis was exploited. Initially, the amphiphilic block copolymer Pluronic F127 (PF127) was carboxylated to MPF127 at the hydroxyl terminus. Subsequently, MPF127 was modified with MCP-1 peptide to prepare MPF127-MCP-1 (MPM). The DOX was wrapped in MPM to form DMPM nanomicelles (approximately 100 nm) during the self-assembly process of MPM. The DMPM spontaneously bound to macrophages (RAW264.7), which resulted in the construction of an actively targeting delivery system (macrophage-DMPM, MA-DMPM) in vitro and in vivo. The DOX in MA-DMPM was released in the acidic tumor microenvironment (TME) in a pH-responsive manner to increase DOX accumulation and enhance the tumor treatment effect. The ratio of MA-DMPM homing reached 220% in vitro compared with the control group, indicating that the MA-DMPM was excellently capable of tumor-targeting delivery. In in vivo experiments, nonsmall cell lung cancer cell (NCI-H1299) tumor models were established. The results of the fluorescence imaging system (IVIS) showed that MA-DMPM demonstrated tremendous tumor-targeting ability in vivo. The antitumor effects of MA-DMPM in vivo indicated that the proportion of tumor cell apoptosis in the DMPM-treated group was 63.33%. The findings of the tumor-bearing mouse experiment proved that MA-DMPM significantly suppressed tumor cell growth, which confirmed its immense potential and promising applications in tumor therapy.

Doxorubicin loaded cerium substituted hydroxyapatite nanoparticles: A promising new therapeutic approach for bone regeneration, doxorubicin delivery, and cancer treatment

The current study used the precipitation method to prepare pure calcium hydroxyapatite (HA) and cerium-substituted hydroxyapatite (Ce-HA) nanoparticles, where cerium ions were exchanged into the HA structure at different concentrations ranging from 3 to 7 wt%. X-ray powder diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM), Fourier transform infrared (FTIR) spectroscopy, Brunauer-Emmett-Teller (BET) surface area measurements, and zeta potential were used to examine the structural characteristics of the nanoparticles. Additionally, the antibacterial and antifungal effects of the produced materials on Gram-positive, Gram-negative, and fungal bacterial species were studied. Nanoparticles with cerium doping showed effective antibacterial and antifungal properties. All samples were tested for bioactivity in simulated body fluid (SBF), and the formation of an apatite layer on their surfaces was highlighted using SEM in conjunction with energy-dispersive X-rays (EDX).Doxorubicin (DOX) release from Ce-HA nanoparticles and pure HA was tested in phosphate-buffered saline (PBS) for up to 28 days. Both nanoparticles were able to release the drug while still being semi-fully loaded. Similarly, the cytotoxic effect of all produced samples on the MG-63 cell line was evaluated, and all samples showed good cytocompatibility. The cytotoxic effect of doxorubicin-loaded nanoparticles showed promising anticancer activity against bone cancer cells, especially samples with high cerium content. The resulting nanoparticles show excellent promising ability for the delivery of doxorubicin to bone cancer with the capacity for bone regeneration.

Hydrophobicity-enhanced ferritin nanoparticles for efficient encapsulation and targeted delivery of hydrophobic drugs to tumor cells.

Ferritin, a naturally occurring iron storage protein, has gained significant attention as a drug delivery platform due to its inherent biocompatibility and capacity to encapsulate therapeutic agents. In this study, we successfully genetically engineered human H ferritin by incorporating 4 or 6 tryptophan residues per subunit, strategically oriented towards the inner cavity of the nanoparticle. This modification aimed to enhance the encapsulation of hydrophobic drugs into the ferritin cage. Comprehensive characterization of the mutants revealed that only the variant carrying four tryptophan substitutions per subunit retained the ability to disassemble and reassemble properly. As a proof of concept, we evaluated the loading capacity of this mutant with ellipticine, a natural hydrophobic indole alkaloid with multimodal anticancer activity. Our data demonstrated that this specific mutant exhibited significantly higher efficiency in loading ellipticine compared to human H ferritin. Furthermore, to evaluate the versatility of this hydrophobicity-enhanced ferritin nanoparticle as a drug carrier, we conducted a comparative study by also encapsulating doxorubicin, a commonly used anticancer drug. Subsequently, we tested both ellipticine and doxorubicin-loaded nanoparticles on a promyelocytic leukemia cell line, demonstrating efficient uptake by these cells and resulting in the expected cytotoxic effect.

P07.08.A DEVISING AN EXOSOMES CONTROLLED-RELEASE HYDROGEL FOR GLIOBLASTOMA THERAPY

Abstract BACKGROUND An efficient therapeutic method for glioblastoma hasn’t been founded. Nowadays, the combination of tumor surgery resection and chemoradiotherapy show limited outcomes even implanting a drug-loaded wafer on the tumor resection cavity during the surgery. Although Local drug delivery improves the adverse effects of intravenous chemotherapy drug injection, the low efficiency of drug transmembrane transportation still leads to poor therapeutic outcomes. Meanwhile, the stiff wafer is not able to perfectly match the irregular shape of the resection cavity. Recently, drug-loaded nanoparticles coated by tumor-derived exosomes applied in tumor-targeting drug delivery were frequently reported. The unique feature of tumor-homing, immune evasion of tumor-derived exosomes was used to improve the delivery efficiency, however, the therapeutic efficiency is weakened by liver filtration and the blood-brain barrier. MATERIAL AND METHODS For enhancing the therapeutic efficacy and compatibility of tumor resection cavity, in this project, a novel injectable hydrogel carrying DOX-loaded nanoparticles coated by tumor-derived exosomes, called Exo-DMSNs@CS, for intra-operative therapy of glioblastoma was devised. The doxorubicin-loaded nanoparticles encapsulated by tumor-derived exosomes (Exo-DMSNs) were integrated into body-temperature sensitive chitosan hydrogel, then injected into the tumor resection cavity and gelation along the shape. By passing the blood-brain barrier, the therapeutic efficacy can be improved by elevating the delivery efficiency induced by the released tumor-targeting Exo-DMSNs. RESULTS The hydrogel Exo-DMSNs@CS was successfully fabricated and contained features of thermosensitive, in vivo controlled releasing, in vitro tumor-targeting, and biocompatible. For simulating the scenario of intra-operative therapy, the Exo-DMSNs@CS was evaluated in the mice orthotopic GBM resection model. The decreased relapse speed and extended survival showed in the Exo-DMSNs@CS compared to DMSNs@CS demonstrated that the tumor-exosomes improve the prognosis of the mice. Moreover, the acceptable side effect was also confirmed. CONCLUSION The Eco-DMSNs@CS is suitable for therapy with better efficiency compared to traditional local drug delivery. This research provides a new strategy for glioblastoma patients and data support for similar product devising.

Preparation and Properties of Natural Polysaccharide-Based Drug Delivery Nanoparticles.

In recent years, natural polysaccharides have been widely used in the preparation of drug delivery systems. In this paper, novel polysaccharide-based nanoparticles were prepared by layer-by-layer assembly technology using silica as a template. The layers of nanoparticles were constructed based on the electrostatic interaction between a new pectin named NPGP and chitosan (CS). The targeting ability of nanoparticles was formed by grafting the RGD peptide, a tri-peptide motif containing arginine, glycine, and aspartic acid with high affinity to integrin receptors. The layer-by-layer assembly nanoparticles (RGD-(NPGP/CS)3NPGP) exhibited a high encapsulation efficiency (83.23 ± 6.12%), loading capacity (76.51 ± 1.24%), and pH-sensitive release property for doxorubicin. The RGD-(NPGP/CS)3NPGP nanoparticles showed better targeting to HCT-116 cells, the integrin αvβ3 high expression human colonic epithelial tumor cell line with higher uptake efficiency than MCF7 cells, the human breast carcinoma cell line with normal integrin expression. In vitro antitumor activity tests showed that the doxorubicin-loaded nanoparticles could effectively inhibit the proliferation of the HCT-116 cells. In conclusion, RGD-(NPGP/CS)3NPGP nanoparticles have potential as novel anticancer drug carriers because of their good targeting and drug-carrying activity.

Interaction of M2 macrophages with hepatocellular carcinoma co-culture system in the presence of doxorubicin-loaded nanoparticles

Tumor-associated macrophages (TAMs) play a crucial role in the proliferation and metastasis of cancer cells in solid tumors. TAMs-cancer cell co-culture models provide the opportunity to study the impact of TAMs on the efficiency of therapeutic agents in combination with drug delivery systems. In this study, we aimed to investigate the impact of M0 and M2 phenotypes of TAMs on the cytotoxicity of doxorubicin-loaded poly (n-butyl cyanoacrylate) nanoparticles on hepatocellular carcinoma cells using a co-culture model. In this study, THP-1 cells were polarized into M0 and M2 phenotypes and co-cultured with the cancer cells. The results indicated that M2 cells represented a higher expression of CD14, CD16, CD80, and CD86 markers compared to M0 cells. Moreover, NPs demonstrated higher cytotoxicity in the co-culture model compared to the conventional 2D culture model. Besides, the proliferation of the cancer cells significantly declined following treatment with the serum-free supernatant of the NPs-treated M2 cells after incubation of 48 h, while the supernatant of untreated cells promoted the proliferation of the cancer cells. In addition, the intracellular cytokines levels of TAMs did not significantly change following treatment by the NPs. In conclusion, TAMs play a determinant role in the cytotoxicity aspect of the NPs for hepatocellular carcinoma cells.

Does Oncocalyxone A (oncoA) have intrinsic fluorescence?

BackgroundOncocalyxone A (oncoA) is a quinone extracted from the Cordia oncocalyx plant. This compound has pharmacological properties, such as anti-inflammatory, analgesic, and cytotoxic activities, among others. OncoA presents a similar chemical structure to doxorubicin, a drug used in cancer treatment, which possesses an intrinsic fluorescence explored in various studies, including those using doxorubicin-loaded nanoparticles. Thus, due to the chemical structural similarity, the question arose whether oncoA could also show autofluorescence. Therefore, this study proposed to characterize the absorption and emission spectral profiles of oncoA and analyze if this compound could be used as a fluorescent probe. MethodsFor this, fucoidan-coated polyisobutylcyanoacrylate (PIBCA) nanoparticles containing oncoA were prepared, and an uptake study was performed using a human metastatic breast cancer cell line (MDA-MB-231 cells). ResultsOncoA presented a maximum emission wavelength in the blue region, near 430 nm, at 350 nm excitation, compatible with standard microscope optics. Fluorescence microscopy analyses showed that oncoA-loaded PIBCA nanoparticles were internalized by MDA-MB-231 cells under incubation times as shorter as 15 min. ConclusionAccording to these findings, oncoA-encapsulated nanoparticles are promising fluorescent probes and could be useful for cellular uptake studies.

Magnetic Resonance Imaging combined with Computed Tomography in the Diagnosis of Multiple Myeloma and the Killing Effect of Doxorubicin Nano-drug Delivery System on Myeloma Cells

It was to adopt magnetic resonance imaging (MRI) combined with computed tomography (CT) to diagnose multiple myeloma (MM) and evaluate the therapeutic effect of the doxorubicin nano-drug delivery system on MM, providing a more effective method for the treatment of MM. For this aim, eighty-eight patients with MM admitted to our Hospital from June 2019 to July 2020.7 were selected as study subjects and divided into a control group (treated with doxorubicin) and an observation group (treated with doxorubicin-loaded nanoparticles) according to the random number table, 44 cases for each group. MRI and CT were used to examine the two groups of patients to assess the clinical efficacy and side effects of the two treatments and to compare the myeloma cell survival rate and apoptosis rate. Results showed that the diameter of nanoparticles was about 50 nm, the particle size was uniform, the distribution was dense, and the stability was good; the lesion was well-circumscribed on CT scan, and a soft tissue mass could be detected on MRI. The number of patients with effective treatment in the observation group was significantly higher than that in the control group (42 cases vs 34 cases) (P< 0.05); the number of patients with small plate reduction, increased myocardial enzymes, alopecia, liver failure, gastrointestinal reactions, peripheral neuritis, and other adverse reactions in the observation group was significantly lower than that in the control group (total number of patients 48 vs 101) (P< 0.05); the survival rate of myeloma cells in the observation group was obviously inferior to that in the control group (61.3 % vs 88.31 %) (P< 0.05). Conclusion: MRI combined with CT examination can be better used for the diagnosis of the disease, and the study shows that doxorubicin nano-drug delivery preparation is safer and more effective in the treatment of MM disease, which is worthy of clinical promotion.

Interaction of M2 Macrophages with Hepatocellular Carcinoma Co-Culture System in the Presence of Doxorubicin-Loaded Nanoparticles

Interaction of M2 Macrophages with Hepatocellular Carcinoma Co-Culture System in the Presence of Doxorubicin-Loaded Nanoparticles

PH-Sensitive nanoparticles based on amphiphilic imidazole/cholesterol modified hydroxyethyl starch for tumor chemotherapy

pH-Responsive nanoparticles (NPs) have emerged as an effective antitumor drug delivery system, promoting the drugs accumulation in the tumor and selectively releasing drugs in tumoral acidic microenvironment. Herein, we developed a new amphiphilic modified hydroxyethyl starch (HES) based pH-sensitive nanocarrier of antitumor drug delivery. HES was first modified by hydrophilic imidazole and hydrophobic cholesterol to obtain an amphiphilic polymer (IHC). Then IHC can self-assemble to encapsulate doxorubicin (DOX) and form doxorubicin-loaded nanoparticles (DOX/IHC NPs), which displayed good stability for one week storage and acidic sensitive long-term sustained release of DOX. As a result, cancer cell endocytosed DOX/IHC NPs could continuously release doxorubicin into cytoplasm and nucleus to effectively kill cancer cells. Additionally, DOX/IHC NPs could be effectively enriched in the tumor tissue, showing enhanced tumor growth inhibition effect compared to free doxorubicin. Overall, our amphiphilic modified HES-based NPs possess a great potential as drug delivery system for cancer chemotherapy.

Early response evaluation of doxorubicin-nanoparticle-microbubble therapy in orthotopic hepatocellular carcinoma rat model using contrast-enhanced ultrasound and intravoxel incoherent motion-diffusion MRI.

PurposeThis study aimed to apply doxorubicin-loaded nanoparticle microbubble (Dox-NP-MB) therapy in an orthotopic rat model of hepatocellular carcinoma (HCC) and investigate the utility of contrast-enhanced ultrasound (CEUS) and intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI) for response evaluation.MethodsTwenty-eight N1S1 HCC model rats were treated with either Dox-NP-MB (group [G] 1, n=8), doxorubicin (Dox) alone (G2, n=7), nanoparticle microbubbles alone (G3, n=7), or saline (G4, control, n=6) on days 0 and 7, and were sacrificed on day 11. IVIM-DWI and CEUS were performed before each treatment and before euthanasia. Efficacy was estimated by the percentage of tumor volume growth inhibition compared with control. Toxicity was assessed by body weight changes and blood tests. Post-treatment changes in IVIM-DWI and CEUS parameters were analyzed.ResultsTumor volume growth was inhibited by 48.4% and 90.2% in G1 and G2 compared to G4, respectively. Compared to G2, G1 had a significantly lower degree of body weight change (median, 91.0% [interquartile range, 88.5%-97.0%] vs. 88.0% [82.5%-88.8%], P<0.05) and leukopenia (1.75×103 cells/μL [1.53-2.77] vs. 1.20×103 cells/μL [0.89-1.51], P<0.05). After the first treatment, an increase in peak enhancement, wash-in rate, and wash-in perfusion index on CEUS was observed in G3 and G4 but suppressed in G1 and G2; the apparent diffusion coefficients, true diffusion coefficients, and perfusion fractions significantly increased in G1 and G2 compared to baseline (P<0.05).ConclusionDox-NP-MB showed reduced Dox toxicity. Early changes in some CEUS and IVIM-DWI parameters correlated with the therapeutic response.

Dual-Targeted Hyaluronic Acid/Albumin Micelle-Like Nanoparticles for the Vectorization of Doxorubicin.

Drug targeting of tumor cells is one of the great challenges in cancer therapy; nanoparticles based on natural polymers represent valuable tools to achieve this aim. The ability to respond to environmental signals from the pathological site (e.g., altered redox potential), together with the specific interaction with membrane receptors overexpressed on cancer cells membrane (e.g., CD44 receptors), represent the main features of actively targeted nanoparticles. In this work, redox-responsive micelle-like nanoparticles were prepared by self-assembling of a hyaluronic acid–human serum albumin conjugate containing cystamine moieties acting as a functional spacer. The conjugation procedure consisted of a reductive amination step of hyaluronic acid followed by condensation with albumin. After self-assembling, nanoparticles with a mean size of 70 nm and able to be destabilized in reducing media were obtained. Doxorubicin-loaded nanoparticles modulated drug release rate in response to different redox conditions. Finally, the viability and uptake experiments on healthy (BALB-3T3) and metastatic cancer (MDA-MB-231) cells proved the potential applicability of the proposed system as a drug vector in cancer therapy.

Doxorubicin Intracellular Release Via External UV Irradiation of Dextran-g-poly(o-nitrobenzyl acrylate) Photosensitive Nanoparticles.

In the present study, innovative doxorubicin-loaded nanoparticles (NPs) made of a photosensitive poly(o-nitrobenzyl acrylate) (PNBA) hydrophobic matrix and an hydrophilic dextran (Dex) shell were first formulated by the emulsion-solvent evaporation process. Doxorubicin (DOX), a very well-known anticancer drug, was herein chosen as the model. DOX-loaded NPs were successfully produced by covering the hydrophobic PNBA core with Dex chains either physically adsorbed or covalently linked by changing process parameters as the presence of a catalyst (CuBr or CuSO4/ascorbic acid). It was then proved that the neutralization of DOX optimized drug loading. DOX loading and release were independent of the coverage mechanism if the catalyst used to covalently link the shell to the core was correctly chosen. Second, the kinetics of DOX release were investigated by simple diffusion or light irradiation of the NPs. Experiments showed that less than 20% of DOX was released by simple diffusion after 48 h in PBS or DMEM media when 45% of DOX released after only 30 s of light irradiation of the NPs. Finally, the impact of the phototriggered DOX release on cell viability was investigated on various cell lines [Caco-2, HepG2, HCT-116, and HT-29 cells as well as murine macrophages (RAW 264.7)]. Cellular mortality was evaluated to be dependent on the cell lines tested. Our approach provided an improved DOX release toward the human liver cancer cell line, and a high internalization of the PNBA-based NPs into HepG2 cells was observed using fluorescence microscopy.

Evaluation of controlled release from doxorubicin-loaded nanoparticles under ultrasound irradiation

Evaluation of controlled release from doxorubicin-loaded nanoparticles under ultrasound irradiation

Meticulous Doxorubicin Release from pH-Responsive Nanoparticles Entrapped within an Injectable Thermoresponsive Depot.

The dual stimuli-controlled release of doxorubicin from gel-embedded nanoparticles is reported. Non-cytotoxic polymer nanoparticles are formed from poly(ethylene glycol)-b-poly(benzyl glutamate) that, uniquely, contain a central ester link. This connection renders the nanoparticles pH-responsive, enabling extensive doxorubicin release in acidic solutions (pH 6.5), but not in solutions of physiological pH (pH 7.4). Doxorubicin-loaded nanoparticles were found to be stable for at least 31 days and lethal against the three breast cancer cell lines tested. Furthermore, doxorubicin-loaded nanoparticles could be incorporated within a thermoresponsive poly(2-hydroxypropyl methacrylate) gel depot, which forms immediately upon injection of poly(2-hydroxypropyl methacrylate) in dimethyl sulfoxide solution into aqueous solution. The combination of the poly(2-hydroxypropyl methacrylate) gel and poly(ethylene glycol)-b-poly(benzyl glutamate) nanoparticles yields an injectable doxorubicin delivery system that facilities near-complete drug release when maintained at elevated temperatures (37 °C) in acidic solution (pH 6.5). In contrast, negligible payload release occurs when the material is stored at room temperature in non-acidic solution (pH 7.4). The system has great potential as a vehicle for the prolonged, site-specific release of chemotherapeutics.

Dendrimer-like AB2-type star polymers as nanocarriers for doxorubicin delivery to breast cancer cells: synthesis, characterization, in-vitro release and cytotoxicity studies

Novel Pentaerythritol (PTL)- and dipentaerythritol (DPTL)-cored dendrimer-like star polymers with AB2 miktoarms [A = poly(L-Lactide); poly(ethylene glycol)-folate] (1g and 2g) were synthesized and characterized by proton magnetic resonance spectroscopy, fourier transform infrared, gel permeation chromatography and differential scanning calorimetric techniques. Anticancer drug doxorubicin was encapsulated into the star polymer nanoparticles using nanoprecipitation technique. The doxorubicin-loaded nanoparticles of the star polymer with PTL core (1g-NPs-DOX) and DPTL core (2g-NPs-DOX) were spherical and had average diameters of 185.88 ± 27.53 nm and 203.66 ± 20.69 nm, and zeta potential of −19.54 ± 0.57 mV and − 14.77 ± 1.16 mV, respectively. 2g-NPs-DOX had higher doxorubicin loading and encapsulation efficiency (14.59% ± 0.001; 87.54% ± 0.003) than those of 1g-NPs-DOX (12.88% ± 0.006; 77.29% ± 0.039). In vitro release studies showed that an initial burst release of doxorubicin was followed by a sustained release over 7 days, which were significantly higher at pH 5.3 than at pH 7.4. Both drug-free nanoparticles 1g-NPs and 2g-NPs exhibited low cytotoxic effect against MCF-7 and MCF-10a with over 80% cell viability at maximum concentration (100 μM) after 72 h of incubation. Due to sustained release, the IC50 values (72 h) of 1g-NPs-DOX and 2g-NPs-DOX against MCF-7 cells were 22.5 μM and 19.5 μM respectively, as compared to 41.0 μM and 32.0 μM against MCF-10a cells, which suggested that 1g-NPs-DOX and 2g-NPs-DOX are more effective in inhibiting the breast cancer cell viability. Hence, the dendrimer-like star polymers, 1g and 2g, showed good potential as nanocarriers for preferential delivery of doxorubicin to the breast cancer cells.

High-affinity mutant Interleukin-13 targeted CAR T cells enhance delivery of clickable biodegradable fluorescent nanoparticles to glioblastoma

Glioblastoma (GBM), the deadliest form of brain cancer, presents long-standing problems due to its localization. Chimeric antigen receptor (CAR) T cell immunotherapy has emerged as a powerful strategy to treat cancer. IL-13-receptor-α2 (IL13Rα2), present in over 75% of GBMs, has been recognized as an attractive candidate for anti-glioblastoma therapy. Here, we propose a novel multidisciplinary approach to target brain tumors using a combination of fluorescent, therapeutic nanoparticles and CAR T cells modified with a targeted-quadruple-mutant of IL13 (TQM-13) shown to have high binding affinity to IL13Rα2-expressing glioblastoma cells with low off-target toxicity. Azide-alkyne cycloaddition conjugation of nanoparticles to the surface of T cells allowed a facile, selective, and high-yielding clicking of the nanoparticles. Nanoparticles clicked onto T cells were retained for at least 8 days showing that the linkage is stable and promising a suitable time window for in vivo delivery. T cells clicked with doxorubicin-loaded nanoparticles showed a higher cytotoxic effect in vitro compared to bare T cells. In vitro and in vivo T cells expressing TQM-13 served as delivery shuttles for nanoparticles and significantly increased the number of nanoparticles reaching brain tumors compared to nanoparticles alone. This work represents a new platform to allow the delivery of therapeutic nanoparticles and T cells to solid tumors.

Biphenyl Wrinkled Mesoporous Silica Nanoparticles for pH-Responsive Doxorubicin Drug Delivery.

Biphenyl wrinkled mesoporous silica nanoparticles with controlled particle size and high surface area were evaluated for the storage and delivery of doxorubicin. The average particle size and surface area were ~70 nm and ~1100 m2/g. The doxorubicin loading efficiency was 38.2 ± 1.5 (w/w)% and the release was pH dependent. The breast cancer cell line, MCF-7 (Michigan Cancer Foundation-7) was used for the in vitro drug release study. The cytotoxicity of doxorubicin-loaded nanoparticles was significantly higher than free doxorubicin. Fluorescence images showed biphenyl wrinkled mesoporous silica (BPWS) uptake by the MCF-7 cells. The biphenyl bridged wrinkled silica nanoparticles appear promising for hydrophobic drug loading and delivery.

PH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate for targeted synergistic cancer therapy

To promote the targeted cancer therapy, the pH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate was successfully constructed. Herein, water-soluble vitamin B6 with pKa (5.6) was chemically conjugated to lipid-soluble vitamin E succinate (α-TOS), which showed selective cancer cell killing ability and this amphiphilic small molecule vitamin conjugate could self-assemble to be free nanoparticles (NPs) and doxorubicin-loaded NPs (α-TOS-B6-NPs-DOX). The small molecule nanodrugs could perform the following characteristic: (i) stability in the sodium dodecyl sulfonate (SDS) solution and long-term storage stability in PBS via surface negative charge; (ii) tumor accumulation by enhanced penetration and retention (EPR) effect; (iii) improved cellular internalization by means of vitamin B6 transporting membrane carrier (VTC); and (iv) facilitating endosomal escape and rapid drug release for synergistic toxicity to tumor cells via charge reversal and ester hydrolysis at intracellular pH and/or esterase. Moreover, α-TOS-B6-NPs-DOX exhibited long blood circulation stability and significant tumor accumulation and inhibition with the decreased side effects in vivo. Thus, the pH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate could be the potential drug carriers in targeted synergistic cancer therapy.