Doxorubicin Nanoparticles Research Articles

Effect of co-treatment with doxorubicin and verapamil loaded into chitosan nanoparticles on diethylnitrosamine-induced hepatocellular carcinoma in mice.

This study aimed to investigate the potential role of co-treatment with doxorubicin (DOX) and verapamil (VRP) nanoparticles in experimentally induced hepatocellular carcinoma in mice and to investigate the possible mechanisms behind the potential favorable effect of the co-treatment. DOX and VRP were loaded into chitosan nanoparticles (CHNPs), and cytotoxicity of loaded and unloaded drugs against HepG2 cells was evaluated. Male albino mice were divided into eight groups (n = 15): (1) normal control, (2) diethylnitrosamine, (3) CHNPs, (4) free DOX, (5) CHNPs DOX, (6) free VRP, (7) CHNPs VRP, and (8) CHNPs DOX + CHNPs VRP. Either VRP or DOX loaded into CHNPs showed stronger growth inhibition of HepG2 cells than their free forms. DOX or VRP nanoparticles displayed pronounced anticancer activity in vivo through the decline of vascular endothelial growth factor and B cell lymphoma-2 contents in liver tissues, upregulation of antioxidant enzymes, and downregulation of multidrug resistance 1. Moreover, reduced cardiotoxicity was evident from decreased level of tumor necrosis factor-α and malondialdehyde in heart tissues coupled with decreased serum activity of creatine kinase-myocardial band and lactate dehydrogenase. Co-treatment with CHNPs DOX and CHNPs VRP showed superior results versus other treatments. Liver sections from the co-treatment group revealed the absence of necrosis, enhanced apoptosis, and nearly normal hepatic lobule architecture. Co-treatment with CHNPs DOX and CHNPs VRP revealed enhanced anticancer activity and decreased cardiotoxicity versus the corresponding free forms.

Mesoporous PtPd nanoparticles for ligand-mediated and imaging-guided chemo-photothermal therapy of breast cancer

The synergistic therapy of chemotherapy and photothermal therapy (PTT) has been reported as a promising antitumor strategy. To achieve effective combination therapy, developing more suitable candidate nanomaterials with optimal photothermal property and high chemical drug loading capacity is very necessary. Herein, a bimetallic PtPd nanoparticle was synthesized with the merits of excellent photothermal effect and mesoporous structure for doxorubicin (DOX) loading. We further designed PtPd-ethylene glycol (PEG)-folic acid (FA)-doxorubicin (DOX) nanoparticle for chemo-photothermal therapy of MCF-7 tumor with folic acid engineering to achieve active targeting. Moreover, excellent photoacoustic (PA) imaging of PtPd-PEG-FA-DOX nanoparticles facilitated the precise in vivo tracking and further evaluation of nanoparticles’ targeting effect. The in vitro and in vivo results both demonstrated PtPd-PEG-FA-DOX nanoparticles serve as a safe and promising system for effective treatment of MCF-7 tumor.

Response of pH-Sensitive Doxorubicin Nanoparticles on Complex Tumor Microenvironments by Tailoring Multiple Physicochemical Properties.

Cellular internalization, delivery efficiency, and therapeutic efficacy of nanoparticles vary according to the microenvironmental complexity for tumor types. Adjusting their physicochemical properties, such as surface properties and size, has significant potential for dealing with such complexities. Herein, we prepare four types of pH-sensitive doxorubicin nanoparticles (DOX-D1, DOX-D2, DOX-W1, and DOX-W2 Nano) using simply changing reaction medium or reactant ratio. DOX-D1 and DOX-D2 Nano exhibit similar surface characteristics (surface coating and targeting ligand content) and different size, while both DOX-W Nano examples present similar surface characteristics and size. And they can re-self-assemble into smaller particles in blood-mimic conditions and the order of size is as follows: DOX-D1> DOX-D2 ≈ DOX-W Nano, and DOX-W Nano has a higher targeting ligand content than DOX-D Nano. Thus, the bioactivities in vitro and tumor microenvironment responses of DOX-D1, DOX-D2, and DOX-W1 are further investigated due to their different physicochemical properties. DOX-W1 Nano exhibits a higher cellular uptake, a stronger antiproliferation than DOX-D1 and DOX-D2 Nano attributed to its smaller size, and a higher targeting moiety content. Despite the similar sizes of DOX-W1 and DOX-D2, DOX-D2 Nano shows a greater in vitro blood-brain barrier (BBB) permeability related to its surface coating. Interestingly, DOX-D1 with suitable size and surface property can efficiently bypass the BBB and deliver to an intracranial glioma; in comparison DOX-W1 Nano has excellent targeting efficiency in subcutaneous tumors (glioma and breast cancer). Accordingly, DOX-D1 Nano is preferential for the treatment of intracranial glioma while DOX-W1 Nano exhibits potent killing ability for subcutaneous tumors. Our work suggests tailoring multiple physicochemical properties of nanoparticles can play a significant role in addressing tumor microenvironment complexity.

Engineering peptide-targeted liposomal nanoparticles optimized for improved selectivity for HER2-positive breast cancer cells to achieve enhanced in vivo efficacy

Here, we report rationally engineered peptide-targeted liposomal doxorubicin nanoparticles that have an enhanced selectivity for HER2-positive breast tumor cells with high purity, reproducibility, and precision in controlling stoichiometry of targeting peptides. To increase HER2-positive tumor cell selective drug delivery, we optimized the two most important design parameters, peptide density and linker length, via systematic evaluations of their effects on both in vitro cellular uptake and in vivo tumor accumulation and cellular uptake. The optimally designed nanoparticles were finally evaluated for their tumor inhibition efficacy using in vivo MMTV-neu transplantation mouse model. In vitro, we demonstrated that ~1% peptide density and EG8 linker were optimal parameters for targeted nanoparticle formulations to enhance HER2-positive cancer cellular uptake while preventing non-selectivity. In vivo results demonstrated that at 0.5% peptide density, enhancement of tumor cell uptake over non-targeted nanoparticles was ~2.7 fold and ~3.4 fold higher for targeted nanoparticles with EG8 and EG18 linker, respectively, while their accumulation levels at tumor tissue were similar to the non-targeted nanoparticles. These results were consistent with in vivo efficacy outcomes that ~90% tumor growth inhibition was achieved by Dox-loaded HER2 receptor targeted nanoparticles, TNPHER2pep, over control while all nanoparticle formulations minimized overall systemic toxicity relative to free Dox. This study highlights the significance of understanding and optimizing the effects of liposomal nanoparticle design parameters for enhancement of tumor selectivity to achieve improved in vivo therapeutic outcomes.

Preparation of pH-Responsive Doxorubicin Nanocapsules by Combining High-gravity Antisolvent Precipitation with In-situ Polymerization for Intracellular Anticancer Drug Delivery

Owing to the low pH value in tumor and cancer cells, drug delivery systems based on pH-responsive polymer nanocarriers have been extensively explored for anticancer chemotherapy. Herein, we developed a pH-responsive doxorubicin(DOX) nanocapsule(named as DNanoCapsule) prepared by combining in-situ polymerization technique with high-gravity antisolvent precipitation technique through an amphiphilic polymerized surface ligand. DNanoCapsules show an obvious spherical core-shell structure with a single DOX nanoparticle encapsulated in the polymer layer. Dissolution rate studies prove that the DNanoCapsules have robust drug-release profiles under acidic environments due to the division of the pH-sensitive cross-linker, which triggers the collapse of the polymer layer. The in vitro investigations demonstrated that the DNanoCapsules exhibited high cellular uptake efficiency and cytotoxicity for both HeLa and MCF-7 cancer cells. Therefore, this work may provide a promising strategy to design and develop various stimuli-responsive drug nanocapsules for the treatment of cancer or other diseases.

PH-responsive surface charge reversal carboxymethyl chitosan-based drug delivery system for pH and reduction dual-responsive triggered DOX release

A facile approach was established to fabricate the pH-responsive surface charge reversal carboxymethyl chitosan-based drug delivery system for pH and reduction dual-responsive triggered DOX release, with a reduction responsive sheddable shell via facile organic solvent-free co-precipitation method. In the proposed DDS, DOX was loaded in the pH responsive core of the poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) fragments, which were bioreducibly conjugated onto the PEGylated carboxymethyl chitosan (PEG-CMCS) backbone as reduction responsive sheddable shielding shell. The proposed PEG-CMCS-SS-PDPA/DOX nanoparticles, with a high drug loading capacity of >36 % with drug-loading only in their cores, showed excellent pH and reduction dual-responsive triggered disintegration and DOX release performance with cumulative release >85 % in the simulated tumor intracellular microenvironment but a low drug leakage <8.5 % in the simulated normal physiological medium within 57 h, lower than all the reported CMCS-based DDSs.

Effect simultaneous delivery with P-glycoprotein inhibitor and nanoparticle administration of doxorubicin on cellular uptake and in vitro anticancer activity

Multidrug resistance (MDR) is the most common problem of inadequate therapeutic response in tumor cells. Many trials has been developed to overcome drug efflux by P-glycoprotein (P-gp). For instance, co-administration of a number of drugs called chemosensitizers or MDR modulators with a chemotherapeutic agent to inhibit drug efflux. But for optimal synergy, the drug and inhibitor combination may need to be temporally colocalized in the tumor cells. In this study, we encapsulated the Ver and Dox in PLGA nanoparticles to inhibit the P-gp drug efflux in breast cancer. Moreover, the effect of either Dox solution (DoxS), Dox nanoparticles (DoxNP), DoxS + VerS, DoxNP + VerS, DoxNP + VerNP or Dox-VerNP was evaluated. It was found that co administration of DoxNP with VerNP (70.76%) showed similar cellular uptake of Dox to Dox/Ver combination solution (70.62%). However it is observed that DoxNP + VerNP has the highest apoptotic activity (early apoptotic 13.52 ± 0.06%, late apoptotic 53.94 ± 0.15%) on human breast adenocarcinoma (MCF 7) cells. Hence, it is suggested that DoxNP + VerNP is a promising administration for tumor therapy.

Technetium labeled doxorubicin loaded silk fibroin nanoparticles: Optimization, characterization and in vitro evaluation

The aim of the present research work was to design Tween-80 coated silk fibroin nanoparticles of doxorubicin (DOX) and it's radiolabeling with Technetium-99 m (99mTc). Radiolabeling could be used as a tool to analyze the efficacy of design system through cellular uptake studies. The DOX loaded silk fibroin nanoparticles (SFN) of ~100 nm size were prepared by using desolvation method. Radiolabeling of DOX, and nanoparticles was performed with 99mTc by using stannous chloride. The maximum labeling efficiency of more than 90% was found to be at 1:10 ratio of stannous chloride and DOX at pH 5.5 for 30 min incubation time. The product found to be stable in serum, saline and for transchelation study (less than 5%). Cellular uptake studies showed the higher uptake of radiolabeled formulation of Tween-80 coated silk fibroin nanoparticles (TSFN) i.e 1.16 times higher than plain SFN and 1.62 times higher than free drug for C-6 cell line and 1.18 times higher than plain SFN and 2.10 times higher than free drug for LN-229. The higher uptake of TSFN by cancer cell lines may provide the opportunity to these modified SFN to be used as a vector for the delivery of drugs to the brain.

Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake in vivo.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with “microbubble” ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors.Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes.Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels.Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.

Docetaxel and Doxorubicin Codelivery by Nanocarriers for Synergistic Treatment of Prostate Cancer.

Combination chemotherapy has been proven to be an efficient strategy for the treatment of prostate cancer (PCA). However, the pharmacokinetic distinction between the relevant drugs is an insurmountable barrier to the realization of their synergistic use against cancer. To overcome the disadvantages of combination chemotherapy in the treatment of PCA, targeted nanoparticles (NPs), which can codeliver docetaxel (DOC) and doxorubicin (DOX) at optimal synergistic proportions, have been designed. In this study, the DOC and DOX codelivery nanoparticles (DDC NPs) were constructed by hyaluronic acid (HA) and cationic amphipathic starch (CSaSt) through a self-assembly process. Human PCA cell lines (PC-3, DU-145, and LNCap) and mouse models were then used for evaluation in vitro and in vivo, respectively, of delivery and antitumor effects. The DDC NPs were spherical with rough surfaces, and the size and zeta potential were 68.4 ± 7.1 nm and -22.8 ± 2.2 mV, respectively. The encapsulation efficiencies of DOC and DOX in the NPs were 96.1 ± 2.3% and 91.4 ± 3.7%, respectively, while the total drug loading was 9.1 ± 1.7%. Moreover, the ratio of DOC to DOX in the DDC NPs was approximately 1:400, which aligned with the optimal synergistic proportions of the drugs. The DDC NPs exhibited excellent loading capacities, performed sustained and enzymatic release, and were stable in PBS, medium, and serum. After investigations in vitro, the DDC NPs were as effective as the dual drug combination in terms of cytotoxicity, antimigration, and apoptosis. Internalization results indicated that the DDC NPs could effectively deliver and fully release the payloads into PCA cells, and the process was mediated by the ligand-receptor interaction of HA with the CD44 protein. Low toxicity in vivo was confirmed by acute toxicity and hemolytic assays. The distribution in vivo showed that DDC NPs could enhance the accumulation of drugs in tumors and decrease nonspecific accumulation in normal organs. More importantly, DDC NPs significantly promoted the curative effect of the DOC and DOX combination in the PCA cell xenograft mouse model, indicating that the drugs with NPs did indeed act synergistically. This study suggests that the DDC NPs possess noteworthy potential as prospects for the development of PCA clinical chemotherapy.

Poly[N-(2-hydroxypropyl)methacrylamide]-Modified Magnetic γ-F2 O3 Nanoparticles Conjugated with Doxorubicin for Glioblastoma Treatment.

With the aim to develop a new anticancer agent, we prepared poly[N-(2-hydroxypropyl)methacrylamide-co-methyl 2-methacrylamidoacetate] [P(HP-MMAA)], which was reacted with hydrazine to poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-hydrazinyl-2-oxoethyl)methacrylamide] [P(HP-MAH)] to conjugate doxorubicin (Dox) via hydrazone bond. The resulting P(HP-MAH)-Dox conjugate was used as a coating of magnetic γ-Fe2 O3 nanoparticles obtained by the coprecipitation method. In vitro toxicity of various concentrations of Dox, P(HP-MAH)-Dox, and γ-Fe2 O3 @P(HP-MAH)-Dox nanoparticles was determined on somatic healthy cells (human bone marrow stromal cells hMSC), human glioblastoma line (GaMG), and primary human glioblastoma (GBM) cells isolated from GBM patients both at a short and prolonged exposition time (up to 7 days). Due to hydrolysis of the hydrazone bond in acid milieu of tumor cells and Dox release, the γ-Fe2 O3 @P(HP-MAH)-Dox nanoparticles significantly decreased the GaMG and GBM cell growth compared to free Dox and P(HP-MAH)-Dox in low concentration (10 nM), whereas in hMSCs it remained without effect. γ-F2 O3 @PHP nanoparticles alone did not affect the viability of any of the tested cells.

Uptake and release profiles of PEGylated liposomal doxorubicin nanoparticles: A comprehensive picture based on separate determination of encapsulated and total drug concentrations in tissues of tumor-bearing mice

The PEGylated liposomal nanoparticle has been widely used as a carrier in drug delivery system. To become biologically active, the encapsulated drug must be released from the nanoparticle vehicle. However, due to limitations of current bioanalytical methods, the characterization of this release process has been restricted to determination of total drug in tissues and tumor. As a result, the fate of liposomal nanoparticles including their uptake into target tissue has not been fully characterized. In this study, we developed a novel two-step solid phase extraction on two separated columns procedure to separate liposomes from tissues and tumors without liposomal leakage. This allowed us to determine encapsulated drug, total drug and, by difference, released drug and compare the release and uptake profiles of PEGylated liposomal doxorubicin in tissues and tumor of tumor-bearing mice with corresponding profiles for free doxorubicin. The liposomal nanoparticles released doxorubicin into tumor efficiently and, compared with administration of free drug, increased doxorubicin uptake into tumor by 1.8-fold. It also decreased doxorubicin uptake into heart (0.78-fold lower) with the potential to reduce doxorubicin cardiotoxicity. Drug release reached constant levels in tissues and tumor after 12 h with released doxorubicin concentration remaining at 70–80% of total doxorubicin concentration and in tumor at 86% of total drug concentration. The assay also included determination of the main doxorubicin metabolites. Determination of the metabolites showed that liposomal entrapment delays and decreases the metabolism of doxorubicin but does not alter the metabolic pathway. These results provide a clear and comprehensive picture of the biodistribution of doxorubicin administered in liposomal nanoparticles which may assist in the rational design of other liposomal nanoparticles.

PH‐sensitive carbon quantum dots−doxorubicin nanoparticles for tumor cellular targeted drug delivery

A kind of pH‐responsive carbon quantum dots−doxorubicin nanoparticles drug delivery platform (D‐Biotin/DOX‐loaded mPEG‐OAL/N‐CQDs) was designed and synthesized. The system consists of fluorescent carbon dots as cross‐linkers, and D‐Biotin worked as targeting groups, which made the system have a pH correspondence, doxorubicin hydrochloride (DOX) as the target drug, oxidized sodium alginate (OAL) as carrier materials. Ultraviolet (UV)‐Vis spectrum showed that the drug‐loading rate of DOX is 10.5%, and the drug release in vitro suggested that the system had a pH response and tumor cellular targeted, the drug release rate is 65.6% at the value of pH is 5.0, which is much higher than that at the value of pH is 7.4. The cytotoxicity test and laser confocal fluorescence imaging showed that the synthesized drug delivery system has high cytotoxicity to cancer cells, and the drug‐loaded nanoparticles could enter the cells through endocytosis.

Doxorubicin and ABT-199 Coencapsulated Nanocarriers for Targeted Delivery and Synergistic Treatment against Hepatocellular Carcinoma

For the patients with hepatocellular carcinoma (HCC), conventional chemotherapy is insufficient or has no benefit. Although combination chemotherapy has been proven as an efficient strategy to enhance anti-HCC efficacy, some barriers, such as low bioavailability and side effects, are limiting clinical development. In order to overcome disadvantages of combination chemotherapy in HCC, targeted nanoparticles (NPs) simultaneously loaded with doxorubicin (DOX) and ABT-199 in an optimal synergistic ratio were developed. First, the most synergistic combination with DOX was screened from ABT-199, ABT-263, and ABT-737. Among them, ABT-199 showed optimal synergy with DOX in a ratio of 10 : 1. Then, cationic amphipathic starch (CSaSt) and hyaluronic acid (HA) were used in coencapsulations of those two drugs. Dual-drug synergistic nanoparticles (DDS NPs) were constructed by absorption of DOX NPs around ABT-199 micelles with an optimal ratio via electrostatic interaction. The shape of DDS NPs was similar to a raspberry, and the size was 112.6±13.4 nm. The encapsulation efficiencies of DOX and ABT-199 in DDS NPs were 90.2±4.3% and 94.7±2.8%, respectively; meanwhile, the drug loadings were 1.5±0.4% and 14.1±1.1%, respectively. After 72 h of dialysis, 95% of ABT-199 remained and less than 50% of DOX was released. In vitro investigation showed that the drugs in DDS NPs maintained the treated effect in three HCC cell lines; moreover, DDS NPs could perform intracellular delivery of dual drugs and exhibited continuous release of the drugs into different targets. Low in vivo toxicity was found after the acute toxicity test. In vivo fluorescent imaging revealed that DDS NPs could efficiently target and accumulate in the tumor tissues and be maintained more than 72 h after intravenous injection. Compared with free drugs, DDS NPs with the same dosages exhibited a more significant antitumor effect in the HCC xenograft mouse model. The results indicated that DDS NPs have great potential in HCC chemotherapy.

Abstract 2184: Preclinical verification of the efficacy of targeting peptides linked liposomal nanoparticles for therapy of hepatocellular and nasopharyngeal carcinomas and breast cancer

Abstract The efficacy of systemic cytotoxic chemotherapy has been widely assessed in patients with advanced hepatocellular carcinoma (HCC). For example, doxorubicin is the most commonly studied chemotherapeutic agent for HCC. However, it has been shown to have a response rate of only 10-20% in clinical trial. In addition, its potential benefit has been reduced by the related adverse effect. So far, the multikinase inhibitor, sorafenib, is considered to provide survival benefit over supportive care. However, the long term prognosis of those cancer patients still remain poor. Therefore, in the present experiment, we proposed to use the so-called peptide targeting chemotherapy to overcome the adverse event in the conventional targeted chemotherapy. In order to perform this experiment, we have construct some specific peptides which can bind specifically to the cancer cells and cancer vascular endothelia by using a phage displayed 12-mer random peptide library. We have obtained 3 different peptides and one control peptide. Each contains 12 amino acids: a. L-peptide: RLLDTNRPLLPY (anti-different cancer cell membrane); b. control peptide: RLLDTNRGGGGG; c. SP-94-peptide: SFSHHTPILP (anti-NPC tumor cell and hepatoma cell membranes) and d. PC5-52-peptide: SVSVGMKPSPRP (anti-tumor endothelia). Those L-peptide (L-P), SP-peptide (SP-P), PC5-52-peptide and a control peptide (C-P) were linked to liposomal iron oxide nanoparticles; and also used those peptides to link liposomal doxorubicin (L-D). Using peptide linked liposomal iron oxide, we can localize the peptide targeted tumor cells and tumor endothelia, and then we used those peptides linked liposomal doxorubicin to treat SCID mice bearing different cancer xenografts. Our results showed that when L-P-L-D containing 2mg/kg of SCID mouse body weight was used to treat xenografts bearing SCID mice, the tumor could be well controlled, and no specific adverse event was seen. However, when the control peptide was used to replace the specific peptide, the xenograft size was also shown decrease, but the visceral organs revealed marked apoptotic change. In conclusion, the specific peptides linked liposomal doxorubicin nanoparticles can be used for treatment of SCID mice bearing cancer xenografts with minimal adverse event, especially in the SCID miceγspecies (NGS), which show a remarkable tumor suppression. Note: This abstract was not presented at the meeting. Citation Format: Chin-Tarng Lin, Cheng-Der Wu, Jen-Chien Lee, Han-Chung Wu, Chung-Wei Lee, Ming-Chieh Hsu. Preclinical verification of the efficacy of targeting peptides linked liposomal nanoparticles for therapy of hepatocellular and nasopharyngeal carcinomas and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2184.

Fibrin Gels Entrapment of a Poly-Cyclodextrin Nanocarrier as a Doxorubicin Delivery System in an Orthotopic Model of Neuroblastoma: Evaluation of In Vitro Activity and In Vivo Toxicity.

Fibrin gels (FBGs) are potential delivery vehicles for many drugs, and can be easily prepared from purified components. We previously demonstrated their applicability for the release of different doxorubicin (Dox) nanoparticles used clinically or in an experimental stage, such as its inclusion complex with the amino β-cyclodextrin polymer (oCD-NH2/Dox). Here we extend these studies by in vitro and in vivo evaluations. An in vitro cytotoxicity model consisting of an overlay of a neuroblastoma (NB) cell-containing agar layer above a drug-loaded FBG layer was used. Local toxicity in vivo (histology and blood analysis) was studied in a mouse orthotopic NB model (SHSY5YLuc+ cells implanted into the left adrenal gland). In vitro data show that FBGs loaded with oCD-NH2/Dox have a slightly lower cytotoxicity against NB cell lines than those loaded with Dox. Fibrinogen (FG), and Ca2+ concentrations may modify this activity. In vivo data support a lower general and local toxicity for FBGs loaded with oCD-NH2/Dox than those loaded with Dox. Our results suggest a possible increase of the therapeutic index of Dox when locally administered through FBGs loaded with oCD-NH2/Dox, opening the possibility of using these releasing systems for the treatment of neuroblastoma.

Amylase-Sensitive Polymeric Nanoparticles Based on Dextran Sulfate and Doxorubicin with Anticoagulant Activity.

This study looked into the synthesis and study of Dextrane Sulfate–Doxorubicin Nanoparticles (DS–Dox NP) that are sensitive to amylase and show anticoagulant properties. The particles were obtained by the method of solvent replacement. They had a size of 305 ± 58 nm, with a mass ratio of DS:Dox = 3.3:1. On heating to 37 °C, the release of Dox from the particles was equal to 24.2% of the drug contained. In the presence of amylase, this ratio had increased to 42.1%. The study of the biological activity of the particles included an assessment of the cytotoxicity and the effect on hemostasis and antitumor activity. In a study of cytotoxicity on the L929 cell culture, it was found that the synthesized particles had less toxicity, compared to free doxorubicin. However, in the presence of amylase, their cytotoxicity was higher than the traditional forms of the drug. In a study of the effect of DS–Dox NP on hemostasis, it was found that the particles had a heparin-like anticoagulant effect. Antitumor activity was studied on the model of ascitic Zaidel hepatoma in rats. The frequency of complete cure in animals treated with the DS–Dox nanoparticles was higher, compared to animals receiving the traditional form of the drug.

Selenium Overcomes Doxorubicin Resistance in Their Nano-platforms Against Breast and Colon Cancers.

Colon cancer in men and breast cancer in women are regarded as major health burdens, accounting for majority of cancer diagnoses globally. Doxorubicin (DOX) resistance in breast and colon cancers represents the main reason of unsuccessful therapy. The rationale of this study is to explore whether selenium nanoparticles (nano-Se) can overcome this resistance obstacle of DOX nanoparticles (nano-DOX) in these cancerous cells. Nano-Se and nano-DOX were manufactured and characterized using electron microscopy and Malvern ZetaSizer, applied separately or in the form of combinatorial regimen against human breast cancer cells (MCF7 and MDA-MB-231) and human colorectal cancer cells (HCT 116 and Caco-2). Cytotoxicity, early/late apoptosis, necrosis, cellular zinc, glucose uptake, and redox status were assessed after applying different nano-treatments versus their free counterparts. Nano-DOX induces cytotoxicity in MCF7 and Caco-2 more than MDA-MB-231 and HCT 116 cancerous cells. In addition, nano-DOX plus nano-Se diminish MCF7 and Caco-2 chemoresistance higher than MDA-MB-231 and HCT 116 cancerous cells. Moreover, Se and DOX nano-platforms inhibit glucose uptake. Furthermore, nano-DOX increases nitric oxide (NO) and malondialdehyde (MDA) in cancer cells' media, while nano-DOX combination with nano-Se rebalances the redox status with zinc augmentation. We reported that Caco-2 cancer cells are more sensitive than HCT 116 cancer cells to nano-DOX and nano-Se. Nano-DOX plus nano-Se induces cytotoxicity-mediated late apoptosis in Caco-2 more than HCT 116 cell lines. This de novo strategy could have great power to overcome the problem of DOX resistance during colon cancer therapy.

Polymeric nanoparticles of poly(2-oxazoline), tannic acid and doxorubicin for controlled release and cancer treatment

A straightforward coassembly strategy was developed for the preparation of polymeric nanoparticles driving by the intermolecular hydrogen bond between neutral poly(2-methyl-2-oxaozline) (PMeOx), tannic acid (TA) and doxorubicin hydrochloride (Dox). The occurrence of the hydrogen-bonding amongst the different functionalities within the formed nanoparticles was verified by infrared (IR) spectroscopy. Scanning electron microscopy (SEM), dynamic light scattering (DLS), UV–vis absorption and photoluminescent measurements indicated the rapid formation of uniform and water dispersible/stable nanoparticles. The relative poor stability of PMeOx-TA-Dox in fetal bovine serum (FBS) solution enabled the rapid separation of Dox and PMeOx-TA, facilitating the release of Dox and its entrance into cellular nuclei as revealed by confocal laser scanning microscopy (CLSM). The presented strategy may provide an efficient alternative for the construction of multifunctional nanomedicines.

Characterization of doxorubicin nanoparticles prepared by ionic gelation

Purpose: To prepare and characterise doxorubicin nanopatrticles and study their drug delivery in breast cancer.Methods: Doxorubicin nanoparticles were prepared by ionic gelation method using sodium alginate as polymer. The formulations were optimized by cross-linking CaCl2 with sodium alginate at different concentrations. Zeta sizer Nano ZS (UK) was used to determine the mean particle size distribution of the nanoparticle preparations. The shape and external morphologies of the nanoparticles were evaluated by scanning electron microscopy (SEM). Drug release was determined and kinetic release analysis was applied to determine the mechanism of drug release.Results: Entrapment efficiency and mean particle size values were correlated. Scanning electron micrographs showed that the nanoparticles were spherical with little irregularity but without cracks. Doxorubicin release from the sodium alginate nanoparticles followed Korsmeyer-Peppas model which suggest that drug release from the nanoparticles was by diffusion and dissociation from the natural polymer matrix.Conclusion: The doxorubicin-loaded nanoparticles showed concentration-dependent increases in entrapment efficiency. The nanoparticles displayed anticancer properties in breast cancer cell line, thus indicating its potential fo chemotherapeutic application.Keywords: Doxorubicin, Ionic gelation, Nanoparticles, Sodium alginate, Drug release mechanism, Anticancer