Cellular uptake and in vivo distribution of mesenchymal-stem-cell-derived extracellular vesicles are protein corona dependent.

Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory properties. Nevertheless, a concern has been raised regarding the rapid clearance of exogenous EVs by phagocytic cells. Here we explore the impact of protein corona on EVs derived from two culturing conditions in which specific proteins acquired from media were simultaneously adsorbed on the EV surface. Additionally, by incubating EVs with serum, simulating protein corona formation upon systemic delivery, further resolved protein corona-EV complex patterns were investigated. Our findings reveal the potential influences of corona composition on EVs under in vitro conditions and their in vivo kinetics. Our data suggest that bound albumin creates an EV signature that can retarget EVs from hepatic macrophages. This results in markedly improved cellular uptake by hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells. This phenomenon can be applied as a camouflage strategy by precoating EVs with albumin to fabricate the albumin-enriched protein corona-EV complex, enhancing non-phagocytic uptake in the liver. This work addresses a critical challenge facing intravenously administered EVs for liver therapy by tailoring the protein corona-EV complex for liver cell targeting and immune evasion.

The interplay of solvent-drug-protein interactions during albumin nanoparticles formulations for temozolomide delivery to brain cancer cells.

OBJECTIVES: Temozolomide (TMZ), the first line for glioma therapy, suffers from stability at physiological pH. TMZ was selected as a challenging model drug for loading into human serum albumin nanoparticles (HSA NPs). Our aim is to optimise the conditions for TMZ loading into HSA NPs while ensuring TMZ stability. METHODS: Blank and TMZ-HSA NPs were fabricated using the de-solvation technique and the effect of different formulation parameters was evaluated. KEY FINDINGS: For blank NPs, crosslinking time had no significant effect on NPs' size while acetone produced significantly smaller particles than ethanol. Upon drug loading, though TMZ was stable in acetone and ethanol as single agents yet, ethanol-based NPs showed misleadingly high EE% due to drug instability in ethanol formulations as evident by the UV spectrum.The optimum conditions for drug-loaded particles were: 10 mg/ml HSA, 4 mg TMZ using acetone, yielded NPs with 145 nm in diameter, ξ of -16.98 mV and 0.16% DL. The selected formula reduced the cell viabilities of GL261 glioblastoma cells and BL6 glioblastoma stem cells to 61.9% and 38.3%, respectively. CONCLUSIONS: Our results corroborated that careful manipulation of TMZ formulation processing parameters is crucial for encapsulating such chemically unstable dug while simultaneously ensuring its chemical stability.

Spatiotemporal tracking of gold nanorods after intranasal administration for brain targeting.

Intranasal administration is becoming increasingly more attractive as a fast delivery route to the brain for therapeutics circumventing the blood-brain barrier (BBB). Gold nanorods (AuNRs) demonstrate unique optical and biological properties compared to other gold nanostructures due to their high aspect ratio. In this study, we investigated for the first time the brain region-specific distribution of AuNRs and their potential as a drug delivery platform for central nervous system (CNS) therapy following intranasal administration to mice using a battery of analytical and imaging techniques. AuNRs were functionalized with a fluorescent dye (Cyanine5, Cy5) or a metal chelator (diethylenetriaminepentaacetic dianhydride, DTPA anhydride) to complex with Indium-111 via a PEG spacer for optical and nuclear imaging, respectively. Direct quantification of gold was achieved by inductively coupled plasma mass spectrometry. Rapid AuNRs uptake in mice brains was observed within 10 min following intranasal administration which gradually reduced over time. This was confirmed by the 3 imaging/analytical techniques. Autoradiography of sagittal brain sections suggested entry to the brain via the olfactory bulb followed by diffusion to other brain regions within 1 h of administration. The presence of AuNR in glioblastoma (GBM) tumors following intranasal administration was also proven which opens doors for AuNRs applications, as nose-to-brain drug delivery carriers, for treatment of a range of CNS diseases.

Poly-γ-glutamic acid coating polymeric nanoparticles enhance renal drug distribution and cellular uptake for diabetic nephropathy therapy.

Poor drug distribution and inefficient renal cellular uptake are the major barriers diminishing the efficacy of nanoparticles in renal targeted therapy. We designed the rhein (RH)-loaded poly-γ-glutamic acid (PGA)-coated polycaprolactone-polyethyleneimine nanoparticles (RGPP) to enhance renal drug distribution and cellular uptake via PGA-mediated receptor-ligand interaction with γ-glutamyltranspeptidase (GGT) expressed highly in the kidney. PGA coating not only ensured the stability, sustained drug release, and biocompatibility of RGPP, but also promoted renal cellular uptake via binding with the GGT on the renal cells. Following intravenous administration, PGA coating protects RGPP from recognition by the reticuloendothelial system, resulting in prolonged blood circulation. RGPP enables targeted RH accumulation in the kidneys of streptozotocin-induced diabetic nephropathy (DN) mice, resulting in significant recovery of renal physiological function. The PGA coating strategy opens a new avenue for the management of renal diseases using nanomedicine.

Combined Facile Synthesis, Purification, and Surface Functionalization Approach Yields Monodispersed Gold Nanorods for Drug Delivery Applications.

Synthesizing gold nanorods (AuNRs) by seed-mediated growth method results in the presence of undesired size and shape particles by-products occupying 10-90% of the population. In this study, AuNRs are synthesized by the seed-mediated growth method using cetyltrimethylammonium bromide (CTAB) as a surfactant. AuNRs with redshifted longitudinal localized surface plasmon resonance (LLSPR) peak, localized in the biological "transparency window" (650-1350 nm), are synthesized after optimizing seed solution, silver nitrate solution, and hydrochloric acid solution volumes, based on the published protocols. A two-step purification method, dialysis followed by centrifugation, is applied to remove excess CTAB and collect LLSPR-redshifted AuNRs with high rod purity (>90%). CTAB is subsequently exchanged with polyethylene glycol (PEG) to improve AuNRs biocompatibility. PEGylated AuNRs are confirmed innocuous to both SN4741 cells and B16F10 cells by the modified MTT assay and the modified lactate dehydrogenase (LDH) assay up to 1 nm and 24 h incubation. In this study, a combined facile synthesis, purification, and surface functionalization approach is proposed to obtain water-dispersible monodispersed AuNRs for drug delivery applications.

Albumin-Embellished Arsenic Trioxide-Loaded Polymeric Nanoparticles Enhance Tumor Accumulation and Anticancer Efficacy via Transcytosis for Hepatocellular Carcinoma Therapy.

Arsenic trioxide (ATO) has efficient anticancer effect on hepatocellular carcinoma (HCC) in clinical trials, but its off-target distribution and side effects have limited its use. Here, we demonstrate an albumin-embellished ATO-loaded polyethylene glycol-polycaprolactone-polyethyleneimine (PEG-PCL-PEI) nanoparticle (AATONP) to enhance the tumor distribution and intratumor drug release of ATO for HCC therapy. AATONP is prepared by surface embellishment with albumin on the cationic ATO-loaded PEG-PCL-PEI nanoparticles (CATONP). Albumin embellishment can reduce the cationic material's hemolytic toxicity in blood cells while maintaining the rapid internalization and lysosome escape abilities of the positively charged CATONP. AATONP provides sustained and low pH-responsive drug release, facilitating the targeted drug release in the intratumor acidic microenvironment. Moreover, AATONP can significantly improve the circulation time and tumor distribution of ATO via albumin-mediated transcytosis in HCC tumor-bearing mice. Compared with free ATO and the clinically used nanomedicine Genexol/PM, AATONP shows potent antitumor activity against a human HCC xenograft mouse model, leading to a higher tumor inhibition rate of 89.4% in HCC therapy. In conclusion, this work presents an efficient strategy to achieve tumor accumulation and the intratumor drug release of ATO for HCC therapy. An albumin-embellished arsenic trioxide (ATO)-loaded polyethylene glycol-polycaprolactone-polyethyleneimine nanoparticle (AATONP) is designed to enhance tumor distribution and intratumor drug release of ATO for hepatocellular carcinoma therapy. AATONP can achieve enhanced tumor distribution via albumin-mediated transcytosis and exhibit intratumor drug release of ATO via tumor acidic microenvironment-response, leading to potent antitumor activity.

A natural protein based platform for the delivery of Temozolomide acid to glioma cells.

Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with âˆ¼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with Ì´ 20% cell viability at 1 mM TMZA after 72 h incubation time. Finally, the fluorescently labelled NPs showed co-localization with the bioluminescent syngeneic BL6 intra-cranial tumour mouse model after intravenous administration.

An "eat me" combinatory nano-formulation for systemic immunotherapy of solid tumors.

Rational: Tumor immunogenic cell death (ICD), induced by certain chemotherapeutic drugs such as doxorubicin (Dox), is a form of apoptosis potentiating a protective immune response. One of the hallmarks of ICD is the translocation of calreticulin to the cell surface acting as an 'eat me' signal. This manuscript describes the development of a stable nucleic acid-lipid particles (SNALPs) formulation for the simultaneous delivery of ICD inducing drug (Dox) with small interfering RNA (siRNA) knocking down CD47 (siCD47), the dominant 'don't eat me' marker, for synergistic enhancement of ICD. Methods: SNALPs loaded with Dox or siCD47 either mono or combinatory platforms were prepared by ethanol injection method. The proposed systems were characterized for particle size, surface charge, entrapment efficiency and in vitro drug release. The ability of the SNALPs to preserve the siRNA integrity in presence of serum and RNAse were assessed over 48 h. The in vitro cellular uptake and gene silencing of the prepared SNALPs was assessed in CT26 cells. The immunological responses of the SNALPs were defined in vitro in terms of surface calreticulin expression and macrophage-mediated phagocytosis induction. In vivo therapeutic studies were performed in CT26 bearing mice where the therapeutic outcomes were expressed as tumor volume, expression of CD4 and CD8 as well as in vivo silencing. Results: The optimized SNALPs had a particle size 122 ±6 nm and an entrapment efficiency > 65% for both siRNA and Dox with improved serum stability. SNALPs were able to improve siRNA and Dox uptake in CT26 cells with enhanced cytotoxicity. siCD47 SNALPs were able to knockdown CD47 by approximately 70% with no interference from the presence of Dox. The siCD47 and Dox combination SNALPs were able to induce surface calreticulin expression leading to a synergistic effect on macrophage-mediated phagocytosis of treated cells. In a tumor challenge model, 50% of mice receiving siCD47 and Dox containing SNALPs were able to clear the tumor, while the remaining animals showed significantly lower tumor burden as compared to either monotreatment. Conclusion: Therefore, the combination of siCD47 and Dox in a particulate system showed potent anti-tumor activity which merits further investigation in future clinical studies.

Green synthesis of methoxy-poly(ethylene glycol)-block-poly(l-lactide-co-glycolide) copolymer using zinc proline as a biocompatible initiator for irinotecan delivery to colon cancer in vivo.

Poly(lactic-co-glycolic acid) (PLGA) is the most commonly described biocompatible copolymer used in biomedical applications. In this work, a green synthetic approach based on the biocompatible zinc proline complex, as an initiator for PLGA synthesis, is reported for the first time for the synthesis of methoxy-poly(ethylene glycol)-block-poly(l-lactic-co-glycolic acid) (mPEG-PLGA). mPEG-PLGA with controlled molecular weight and narrow polydispersity was synthesised. Its potential for delivery of irinotecan (Ir), a poorly water-soluble chemotherapeutic drug used for the treatment of colon and pancreatic cancer, was studied. Nanoparticles of controlled size (140-160 nm), surface charge (∼-10 mV), release properties and cytotoxicity against CT-26 (colon) and BxPC-3 (pancreatic) cancer cells, were prepared. Tumor accumulation was confirmed by optical imaging of fluorescently labelled nanoparticles. Unlike Tween® 80 coated NP-Ir, the Pluronic® F-127 coated NP-Ir exhibits significant tumor growth delay compared to untreated and blank formulation treated groups in the CT-26 subcutaneous tumor model, after 4 treatments of 30 mg irinotecan per kg dose. Overall, this proof-of-concept study demonstrates that the newly synthesized copolymer, via a green route, is proven to be nontoxic, requires fewer purification steps and has potential applications in drug delivery.

A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system.

BACKGROUND: The Traditional Chinese Medicine, arsenic trioxide (ATO, As2O3) could inhibit growth and induce apoptosis in a variety of solid tumor cells, but it is severely limited in the treatment of glioma due to its poor BBB penetration and nonspecifcity distribution in vivo. PURPOSE: The objective of this study was encapsulating ATO in the modified PAMAM den-drimers to solve the problem that the poor antitumor effect of ATO to glioma, which provide a novel angle for the study of glioma treatment. METHODS: The targeting drug carrier (RGDyC-mPEG-PAMAM) was synthesized based on Arg-Gly-Asp (RGDyC) and αvß3 integrin targeting ligand, and conjugated to PEGylated fifth generation polyamidoamine dendrimer (mPEG-PAMAM). It was characterized by nuclear magnetic resonance, fourier transform infrared spectra, Nano-particle size-zeta potential analyzer,etc. The in vitro release characteristics were studied by dialysis bag method. MTT assay was used to investigate the cytotoxicity of carriers and the antitumor effect of ATO formulation. In vitro blood-brain barrier (BBB) and C6 cell co-culture models were established to investigate the inhibitory effect of different ATO formulation after transporting across BBB. Pharmacokinetic and antitumor efficacy studies were investigated in an orthotopic murine model of C6 glioma. RESULTS: The prepared RGDyC-mPEG-PAMAM was characterized for spherical dendrites, comparable size (21.60±6.81 nm), and zeta potential (5.36±0.22 mV). In vitro release showed that more ATO was released from RGDyC-mPEG-PAMAM/ATO (79.5%) at pH 5.5 than that of pH 7.4, during 48 hours. The cytotoxicity of PEG-modified carriers was lower than that of the naked PAMAM on both human brain microvascular endothelial cells and C6 cells. In in vitro BBB model, modification of RGDyC heightened the cytotoxicity of ATO loaded on PAMAM, due to an increased uptake by C6 cells. The results of cell cycle and apoptosis analysis revealed that RGDyC-mPEG-PAMAM/ATO arrested the cell cycle in G2-M and exhibited threefold increase in percentage of apoptosis to that in the PEG-PAMAM/ATO group. Compared with ATO-sol group, both RGDyC-mPEG-PAMAM/ATO and mPEG-PAMAM/ATO groups prolonged the half-life time, increased area under the curve, and improved antitumor effect, significantly. While the tumor volume inhibitory of RGDyC-mPEG-PAMAM/ATO was 61.46±12.26%, it was approximately fourfold higher than the ATO-sol group, and twofold to the mPEG-PAMAM/ATO group. CONCLUSION: In this report, RGDyC-mPEG-PAMAM could enhance the antitumor of ATO to glioma, it provides a desirable strategy for targeted therapy of glioma.

Kidney-targeted drug delivery via rhein-loaded polyethyleneglycol-co-polycaprolactone-co-polyethylenimine nanoparticles for diabetic nephropathy therapy.

INTRODUCTION: Diabetic nephropathy (DN) is the primary root of morbidity and mortality in diabetic patients. Unfortunately, currently, no effective therapeutic strategies are available to ameliorate and reverse the progression of DN. Rhein (RH) is an anthraquinone derivative extracted from herbal medicines with various pharmacological effects on DN. However, its clinical administration is limited by its poor solubility, low bioavailability, reduced distribution into the kidney and adverse effects. METHODS AND RESULTS: To improve the delivery of RH into kidney and the therapeutic effect on DN, we synthesized and utilized polyethyleneglycol-co-polycaprolactone-co-polyethylenimine triblock amphiphilic polymers to prepare RH-loaded polyethyleneglycol-co-polycaprolactone-co-polyethylenimine nanoparticles (PPP-RH-NPs). PPP-RH-NP size was optimized to 75 ± 25 nm for kidney-targeted drug delivery; the positive zeta potential allowed an effective cellular uptake and the polyethylenimine amine groups facilitate the endosomal escape quickly. The distribution and pharmacodynamics of PPP-RH-NPs were studied in a streptozocin-induced DN model, which explicitly demonstrated kidney-targeted distribution and improved the therapeutic effects of RH on DN by ameliorating several pathological indicators. CONCLUSION: Therefore, this study not only stimulates further clinical research on RH but also, more importantly, proposes a promising DN therapy consisting of an effective kidney-targeted drug delivery.

[Preparation and in vitro evaluation of arsenic trioxide glioma targeting drug delivery system loaded by PAMAM dendrimers co-modified with RGDyC and PEG].

Arsenic trioxide (ATO) is an effective component of traditional Chinese medicine arsenic. The existing studies have shown its good inhibition and apoptosis ability on a variety of tumours. However, its toxicity and difficulties in the permeability into the blood brain barrier (BBB) has the limitation in the application of glioma treatment. Polyamide-amine dendrimer (PAMAM) is a synthetic polymer with many advantages, such as a good permeability, stability and biocompatibility. Additionally, the 5th generation of PAMAM is an ideal drug carrier due to its three-dimensional structure. In this study, the 5th generation of PAMAM co-modified with RGDyC and PEG, then confirmed by ¹H-NMR. The average particle size of nanoparticles was about 20 nm according to the nanoparticle size-potential analyser and transmission electron microscopy. in vitro release showed that the nanocarrier not only has the sustained release effect, but also some pH-sensitive properties. The cell results showed that PAMAM co-modified with RGDyC and PEGAM has a lower cytotoxicity than the non-modified group in vitro. Accordingly, the drug delivery system has a better anti-tumour effect across the blood brain barrier (BBB) in vitro, which further proves the tumour targeting of RGDyC.

A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified, DOX-loaded PAMAM dendrimer.

Glioma is the most common primary malignant brain tumour and the effect of chemotherapy is hampered by low permeability across the blood-brain-barrier (BBB). Borneol is a time-honoured 'Guide' drug in traditional Chinese medicine and has been proved to be capable of promoting free drugs into the brain efficiently, but there are still risks that free drugs, especially anti-glioma drugs, may be disassembled and metabolised before penetrating the BBB and caused the whole brain distribution. The purpose of this paper was to investigate whether borneol intervention could facilitate the BBB penetration and assist glioma treatment by combining with doxorubicin (DOX) loaded PAMAM dendrimers drug delivery system modified with Angiopep-2 (a ligand of the low-density lipoprotein receptor-related protein, which overexpress both in the BBB and gliomas). The results demonstrated that Angiopep-2 modification could actually enhance the affinity between the dendrimers and the targeting cells and finally increase the cell uptake and boost the anti-tumour ability. Borneol physical combination could further enhance the anti-tumour efficiency of this targeting drug delivery system (TDDS) after penetrating BBB. Compared with free DOX solution, this TDDS illustrated obviously sustained and pH-dependent drug release. This suggested that this synergetic strategy provided a promising way for glioma therapy.

RGD conjugated liposome-hollow silica hybrid nanovehicles for targeted and controlled delivery of arsenic trioxide against hepatic carcinoma.

The aim of our study was to construct an Arg-Gly-Asp (RGD)-conjugated liposome-hollow silica hybrid nanovehicle for targeted delivery and controlled release of arsenic trioxide (ATO), whose anti-solid tumor effect was hampered by poor pharmacokinetics and dose-limited toxicity. Hydrophobic interactions were used to attach intact lipid membrane to the surface of chlorodimethyloctadecylsilane-modified hollow mesoporous silica nanoparticles. The prepared nanovehicles (RGD-LP-CHMSN) were characterized for uniform structure (silica core of ∼140nm in diameter and liposomal shell of ∼6nm), comparable drug loading efficiency (6.76%), desirable stability and strengthened controlled release. In vitro, RGD-LP-CHMSN showed good biocompatibility and low toxicity on HepG2, MCF-7 and LO2 cells. The targeted delivery of ATO by nanocarriers (RGD-LP-CHMSN-ATO) was demonstrated by an enhanced cellular uptake and a reduced half maximal inhibitory concentration (IC50) value. In pharmacokinetic studies, the RGD-LP-CHMSN-ATO group, compared to the free ATO group, prolonged the half time (t1/2ß) by 1.7 times and increased the area under curve (AUC) by 2.4 times. In addition, in a H22 tumor-xenograft mouse model, nanovehicles improved the targeting efficiency and anticancer potential of ATO. In conclusion, the strategy of constructing a nanocarrier with targeted delivery and controlled release characteristics is prospective to enhance the antitumor effect of ATO.

A single-label fluorescent derivatization method for quantitative determination of neurotoxin in vivo by capillary electrophoresis coupled with laser-induced fluorescence detection.

Neurotoxin (NT), a short-chain α-neurotoxin, is the main neurotoxic protein identified from the venom of Naja naja atra. As an effective drug for the analgesis of advanced cancer patients, NT lasts longer than morphine and does not cause addiction. However, achieving a sensitive and high-resolution measurement of NT is difficult because of the extra-low content of NT in vivo. Therefore, developing a novel method to quantify NT is essential to study its pharmacokinetics in vivo. Although NT contains four primary amine groups that could react with the thiourea in fluorescein isothiocyanate (FITC), we developed a simple and reproducible single-label fluorescent derivatization method for NT which is related to the reaction of N-terminal α-amino of NT alone under optimized derivatization conditions. Furthermore, neurotoxin labelled with fluorescein isothiocyanate (NT-FITC) was prepared by high-performance liquid chromatography (HPLC) with a purity value higher than 99.29% and identified by MALDI-TOF/TOF-MS. Finally, NT-FITC could be detected at 0.8 nmol L(-1) in rat plasma using capillary electrophoresis coupled with laser induced fluorescence detection (CE-LIF). In this paper, the established method robustly and reliably quantified NT labelled with FITC via intravenous and intramuscular administrations in vivo. In addition, this work fully demonstrated the pharmacokinetic characteristics of NT in vivo, which could reduce the risk of drug accumulation, optimize therapies, and provide sufficient evidence for the rational use of NT in clinical and research laboratories.

A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration.

Effective targeting drug delivery system for glioma treatment is still greatly challenged by the existence of the blood-brain barrier (BBB) and the intracranial overspreading of anti-tumor drug. Herein, we presented a dual-functional glioma targeting delivery of doxorubicin based on the PAMAM G5 dendrimer, modified with folic acid (FA) to target tumor cell, also borneol (BO), a well known safe material derived from traditional Chinese medicine, to facilitate the BBB permeability and reduce the toxicity of naked PAMAM. The intracranial transportation and glioma targeting ability were evaluated on the BBB model and C6 glioma cells in vitro. Also, pharmacokinetics and biodistribution were studied on C6 glioma-bearing rats in vivo. It indeed reduced the cytotoxicity of PAMAM against both HBMEC and C6 cells by coupling BO on the surface, while efficiently boosted BBB permeability with the improvement of transportation ratio by 2 folds to the BO-unmodified conjugates. Furthermore, conjugated FA increased total uptake amount by C6 cells leading to strong inhibition with the 3-fold lower IC50 value than FA-unmodified DOX conjugate. In comparison with DOX solution, FA-BO-PAMAM/DOX exhibited significantly prolonged half-life time and increased area under the curve and improved DOX accumulation in brain tumor. The tumor growth inhibition, in vivo, was significantly increased up to 57.4%. The median survival time of xenograft rats after administering FA-BO-PAMAM/DOX (28days) was significantly prolonged compared to free DOX (18days, P<0.05) or other controls. In conclusion, this strategy of novel targeting nanocarrier provides a promising method to increase the drug accumulation in the tumor site for therapy of glioma.

[Preparation and in vitro evaluation of borneol and folic acid co-modified doxorubicin loaded PAMAM drug delivery system].

A novel targeting drug carrier (FA-BO-PAMAM) based on the PAMAM G5 dendrimer modified with borneol (BO) and folic acid (FA) molecules on the periphery and doxorubicin (DOX) loaded in the interior was designed and prepared to achieve the purposes of enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. 1H NMR was used to confirm the synthesis of FA-BO-PAMAM; its morphology and mean size were analyzed by dynamic light scattering (DLS) and transmission electron microscope (TEM). Based on the HBMEC and C6 cells, cytotoxicity assay, transport across the BBB, cellular uptake and anti-tumor activity in vitro were investigated to evaluate the properties of nanocarriers in vitro. The results showed that the nanocarrier of FA-BO-PAMAM was successfully synthesized, which was spherical in morphology with the average size of (22.28 ± 0.42) nm, and zeta potential of (7.6 ± 0.89) mV. Cytotoxicity and transport across the BBB assay showed that BO-modified conjugates decreased the cytotoxicity of PAMAM against both HBMEC and C6 cells and exhibited higher BBB transportation ability than BO-unmodified conjugates; moreover, modification with FA increased the total uptake of DOX by C6 cells and enhanced the cytotoxicity of DOX-polymer against C6 cells. Therefore, FA-BO-PAMAM is a promising nanodrug delivery system in employing PAMAM as a drug carrier and treatment for brain glioma.