Hydrophobic Anticancer Drug Research Articles

Lysosomal sequestration of weak base drugs, lysosomal biogenesis, and cell cycle alteration

Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true.We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis.Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.

Targeting Colorectal Cancer Cells with Niosomes Systems Loaded with Two Anticancer Drugs Models; Comparative In Vitro and Anticancer Studies.

Colorectal cancer (CRC) is considered one of the most commonly diagnosed malignant diseases. Recently, there has been an increased focus on using nanotechnology to resolve most of the limitations in conventional chemotherapy. Niosomes have great advantages that overcome the drawbacks associated with other lipid drug delivery systems. They are simple, cheap, and highly stable nanocarriers. This study investigated the effectiveness of using niosomes with their amphiphilic characteristics in the incorporation of both hydrophilic and hydrophobic anticancer drugs for CRC treatment. Methods: Drug-free niosomes were formulated using a response surface D-optimal factorial design to study the cholesterol molar ratio, surfactant molar ratio and surfactant type effect on the particle size and Z-potential of the prepared niosomes. After numerical and statistical optimization, an optimized formulation having a particle size of 194.4 ± 15.5 nm and a Z-potential of 31.8 ± 1.9 mV was selected to be loaded with Oxaliplatin and Paclitaxel separately in different concentrations. The formulations with the highest entrapment efficiency (EE%) were evaluated for their drug release using the dialysis bag method, in vitro antitumor activity on HT-29 colon cancer cell line and apoptosis activity. Results: Niosomes prepared using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) at a molar ratio 4, cholesterol (2 molar ratio) and loaded with 1 molar ratio of either Oxaliplatin or Paclitaxel provided nanosized vesicles (278.5 ± 19.7 and 251.6 ± 18.1 nm) with a Z-potential value (32.7 ± 1.01 and 31.69 ± 0.98 mV) with the highest EE% (90.57 ± 2.05 and 93.51 ± 2.97) for Oxaliplatin and Paclitaxel, respectively. These formulations demonstrated up to 48 h drug release and increased the in vitro cytotoxicity and apoptosis efficiency of both drugs up to twice as much as free drugs. Conclusion: These findings suggest that different formulation composition parameters can be adjusted to obtain nanosized niosomal vesicles with an accepted Z-potential. These niosomes could be loaded with either hydrophilic drugs such as Oxaliplatin or hydrophobic drugs such as Paclitaxel. Drug-loaded niosomes, as a unique nanomicellar system, could enhance the cellular uptake of both drugs, resulting in enhanced cytotoxic and apoptosis effects against HT-29 colon cancer cells. Oxaliplatin–niosomes and Paclitaxel–niosomes can be considered promising alternative drug delivery systems with enhanced bioavailability of these two anticancer drugs for colorectal cancer treatment.

Fabrication and Characterization of Paclitaxel Loaded ATO-5 Nano-Lipid Carriers (NLC’s) for Extended Drug Release

Objective: The objective of current study was to formulate and characterize nanolipid carriers of paclitaxel with increased solubility and % release profile of the drug which leads improvement of bioavailability. Methods: It is proposed to incorporate the hydrophobic anticancer drug such as paclitaxel in NLCs to increase the bioavailability and solubility of the therapeutic agent and to assess the developed formulation’s efficacy by in-vitro drug release profile. The main intents of the study are to utilize the various attributes of the proposed biopolymer (glycerol caprate) for the preparation of NLCs to encapsulate paclitaxel. The objectives of the study are to appraise the morphological, physiochemical characteristics of the developed system with their in-vitro performance. Result: The result of the NLCs characterization was evaluated by Zeta potential, poly dispersity index (PDI), percentage entrapment efficiency, drug loading, solubility and partition co-efficient. Conclusion: The result concluded stable NLCs formulation with improved solubility and extended in-vitro drug release.

Engineered Stable Bioactive Per Se Amphiphilic Phosphorus Dendron Nanomicelles as a Highly Efficient Drug Delivery System To Take Down Breast Cancer In Vivo.

Conventional small molecular chemical drugs always have challenging limitations in cancer therapy due to their high systemic toxicity and low therapeutic efficacy. Nanotechnology has been applied in drug delivery, bringing new promising potential to realize effective cancer treatment. In this context, we develop here a new nanomicellar drug delivery platform generated by amphiphilic phosphorus dendrons (1-C17G3.HCl), which could form micelles for effective encapsulation of a hydrophobic anticancer drug doxorubicin (DOX) with a high drug loading content (42.4%) and encapsulation efficiency (96.7%). Owing to the unique dendritic rigid structure and surface hydrophilic groups, large steady void space of micelles can be created for drug encapsulation. The created DOX-loaded micelles with a mean diameter of 26.3 nm have good colloidal stability. Strikingly, we show that the drug-free micelles possess good intrinsic anticancer activity and act collectively with DOX to take down breast cancer cells in vitro and the xenografted tumor model in vivo through upregulation of Bax, PTEN, and p53 proteins for enhanced cell apoptosis. Meanwhile, the resulting 1-C17G3.HCl@DOX micelles significantly abolish the toxicity relevant to the free drug. The findings of this study demonstrate a unique nanomicelle-based drug delivery system created with the self-assembling amphiphilic phosphorus dendrons that may be adapted for chemotherapy of different cancer types.

A small-molecule self-assembled nanodrug for combination therapy of photothermal-differentiation-chemotherapy of breast cancer stem cells

The combination therapy with different treatment modalities has been widely applied in the clinical applications of cancer treatment. However, it stills a considerable challenge to achieve co-delivery of different drugs because of distinct drug encapsulation mechanisms, low drug loading, and high excipient-related toxicity. Cancer stem cells (CSCs) are closely related to tumor metastasis and recurrence due to high chemoresistance. Herein, we report a stimuli-responsive and tumor-targeted small-molecule self-assembled nanodrug for the combination therapy against CSCs and normal cancer cells. The hydrophobic differentiation-inducing agent (all-trans retinoic acid, ATRA) and hydrophilic anticancer drug (irinotecan, IRI) constitute this amphiphilic nanodrug, which could self-assemble into stable nanoparticles and encapsulate the photothermal agent IR825. Upon cellular uptake, this nanodrug display good release profiles in response to acid and esterase microenvironments by ester linkage. The released drugs not only increase chemotherapy sensitivity by the differentiation of CSCs into non-CSCs, but also exhibit superior cytotoxicity in cancer cells. In addition, IR825 within this nanodrug enables in vivo fluorescence/photoacoustic (PA) imaging allowing for tracking drug distribution. Moreover, the DSPE-PEG-RGD-functionalized nanodrug displayed high tumor accumulation and good biocompatibility, enabling efficient inhibition of tumor growth and tumor metastasis in tumor-bearing mice.

An injectable thermosensitive hydrogel/nanomicelles composite for local chemo-immunotherapy in mouse model of melanoma.

Recently, cancer immunotherapy and its combination with chemotherapy has been considered to improve therapeutic efficacy with lower systemic toxicity. Here, we prepared a thermosensitive hydrogel based hyaluronic acid (HA) encapsulated with macrophage colony-stimulating factor (GM-CSF) and paclitaxel (PTX) for chemoimmunotherapy of cancer. For this purpose, the micelles were prepared with the mixture of pluronic F127 (PF127) and tocopheryl polyethylene glycol (TPGS) and loaded with PTX. In the following step, thermosensitive hydrogel using PF127 and HA was prepared and co-encapsulated with the micelles and GM-CSF. Rheological performance, friability, release patterns for PTX and GM-CSF, and stability of GM-CSF in the hydrogel were evaluated in details. In-vitro and in vivo immunologic activities of GM-CSF in the hydrogel were also evaluated via numbering macrophages and recruited DCs in transwells and after subcutaneous injection of the GM-CSF-loaded hydrogel. Finally, mouse model of subcutaneous melanoma was induced in female C57 mice using B16 F10 cell line and the effect of optimized formulation was evaluated based on tumor volume and histological analysis. The hydrogel could maintain the biological activity of the incorporated drugs and exhibited a more prolonged release for PTX compared to GM-CSF. GM-CSF-releasing HA/PF127 hydrogel successfully recruited macrophages in vitro. Moreover, the most potent anti-tumor effect was observed following the intra-tumoral injection of the optimized formulation in melanoma bearing mice, compared to immunization by the GM-CSF and PTX alone. The current formulation shows a great promise to conquer resistant malignancies and provides a new approach for co-encapsulating of hydrophobic anticancer drugs and growth factor.

Synthesis of Novel Conjugated Linoleic Acid (CLA)-Coated Superparamagnetic Iron Oxide Nanoparticles (SPIONs) for the Delivery of Paclitaxel with Enhanced In Vitro Anti-Proliferative Activity on A549 Lung Cancer Cells.

The application of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) as a nanomedicine for Non-Small Cell Lung Carcinoma (NSCLC) can provide effective delivery of anticancer drugs with minimal side-effects. SPIONs have the flexibility to be modified to achieve enhanced oading of hydrophobic anticancer drugs such as paclitaxel (PTX). The purpose of this study was to synthesize novel trans-10, cis-12 conjugated linoleic acid (CLA)-coated SPIONs loaded with PTX to enhance the anti-proliferative activity of PTX. CLA-coated PTX-SPIONs with a particle size and zeta potential of 96.5 ± 0.6 nm and −27.3 ± 1.9 mV, respectively, were synthesized. The superparamagnetism of the CLA-coated PTX-SPIONs was confirmed, with saturation magnetization of 60 emu/g and 29 Oe coercivity. CLA-coated PTX-SPIONs had a drug loading efficiency of 98.5% and demonstrated sustained site-specific in vitro release of PTX over 24 h (i.e., 94% at pH 6.8 mimicking the tumor microenvironment). Enhanced anti-proliferative activity was also observed with the CLA-coated PTX-SPIONs against a lung adenocarcinoma (A549) cell line after 72 h, with a recorded cell viability of 17.1%. The CLA-coated PTX-SPIONs demonstrated enhanced suppression of A549 cell proliferation compared to pristine PTX, thus suggesting potential application of the nanomedicine as an effective site-specific delivery system for enhanced therapeutic activity in NSCLC therapy.

Synthesis of Inherently Fluorescent Core–Shell Nanoparticles for Cell Imaging and Targeting Therapy: An In Vitro Evaluation

AbstractFluorescent polymer nanoparticles (NPs) have great potential as bioimaging and therapeutic agents in the biomedical field. Here, a subtle method is developed to synthesize inherently fluorescent core–shell NPs with diameters less than 100 nm. The permanent fluorescence comes from the rigid conjugated structure between benzene and chloromethyl groups in the crosslinked poly(chloromethylstyrene) (PCMSt) core, which is able to be applied for the determination of Fe3+ with a detection limit of 1.39 × 10−6 m. It is further demonstrated that the galactose modification (poly (6‐O‐acryloyl‐d‐galactose), PADGal) shell can efficiently· facilitate the selective internalization of NPs by human hepatocellular carcinoma cells (HepG2), and the cells are more prone to uptake the NPs with medium crosslinking degree. The hydrophobic anticancer drug 10‐hydroxycamptothecin (HCPT) is then loaded onto PADGal@PCMSt NPs. Benefiting from the specific interactions between asialoglycoprotein (ASGP) receptors and the galactose moiety, the PADGal@PCMSt NPs can deliver HCPT with the highest efficiency to HepG2 cells in comparison with the human cervical cancer cells (HeLa), the human alveolar adenocarcinoma basal epithelial cells (A549), the mouse breast cancer cells (4T1), and the mouse fibroblast cells (NIH3T3). The present study provides a new strategy to build small‐size fluorescent polymer NPs with both bioimaging and therapeutic functions.

Utilizing in vitro drug release assays to predict in vivo drug retention in micelles

In the present work, we aim at developing an in vitro release assay to predict circulation times of hydrophobic drugs loaded into polymeric micelles (PM), upon intravenous (i.v.) administration. PM based on poly (ethylene glycol)-b-poly (N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) block copolymer were loaded with a panel of hydrophobic anti-cancer drugs and characterized for size, loading efficiency and release profile in different release media. Circulation times in mice of two selected drugs loaded in PM were evaluated and compared to the in vitro release profile. Release of drugs from PM was evaluated over 7 days in PBS containing Triton X-100 and in PBS containing albumin at physiological concentration (40 g/L). The results were utilized to identify crucial molecular features of the studied hydrophobic drugs leading to better micellar retention. For the best and the worst retained drugs in the in vitro assays (ABT-737 and BCI, respectively), the circulation of free and entrapped drugs into PM was examined after i.v. administration in mice. We found in vivo drug retention at 24 h post-injection similar to the retention found in the in vitro assays. This demonstrates that in vitro release assay in buffers supplemented with albumin, and to a lesser degree Triton X-100, can be employed to predict the in vivo circulation kinetics of drugs loaded in PM. Utilizing media containing acceptor molecules for hydrophobic compounds, provide a first screen to understand the stability of drug-loaded PM in the circulation and, therefore, can contribute to the reduction of animals used for circulation kinetics studies.

Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug.

Water-soluble amphiphilic random copolymers composed of tri(ethylene glycol) methacrylate (TEGMA) or poly(ethylene glycol) methyl ether methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) were synthesized by ARGET-ATRP, and their self-assembling and thermoresponsive behavior in water was studied by dynamic light scattering (DLS) and UV-vis spectroscopy. The copolymer ability to self-fold in single-chain nano-sized structures (unimer micelles) in aqueous solutions was exploited to encapsulate Combretastatin A-4 (CA-4), which is a very hydrophobic anticancer drug. The cloud point temperature (Tcp) was found to linearly decrease with increasing drug concentration in the drug/copolymer system. Moreover, while CA-4 was preferentially incorporated into the unimer micelles of TEGMA-ran-FA, the drug was found to induce multi-chain, submicro-sized aggregation of PEGMA-ran-FA. Anyway, the encapsulation efficiency was very high (≥81%) for both copolymers. The drug release was evaluated in PBS aqueous solutions both below and above Tcp for TEGMA-ran-FA copolymer and below Tcp, but at two different drug loadings, for PEGMA-ran-FA copolymer. In any case, the release kinetics presented similar profiles, characterized by linear trends up to ≈10–13 h and ≈7 h for TEGMA-ran-FA and PEGMA-ran-FA, respectively. Then, the release rate decreased, reaching a plateau. The release from TEGMA-ran-FA was moderately faster above Tcp than below Tcp, suggesting that copolymer thermoresponsiveness increased the release rate, which occurred anyway by diffusion below Tcp. Cytotoxicity tests were carried out on copolymer solutions in a wide concentration range (5–60 mg/mL) at 37 °C by using Balb/3T3 clone A31 cells. Interestingly, it was found that the concentration-dependent micro-sized aggregation of the amphiphilic random copolymers above Tcp caused a sort of “cellular asphyxiation” with a loss of cell viability clearly visible for TEGMA-ran-FA solutions (Tcp below 37 °C) with higher copolymer concentrations. On the other hand, cells in contact with the analogous PEGMA-ran-FA (Tcp above 37 °C) presented a very good viability (≥75%) with respect to the control at any given concentration.

Synergistic effect of avidin/biotin system with biofunctionalized graphene oxide based nanocarrier in targeted co‐delivery of hydrophobic anticancer drug SN‐38

AbstractCo‐delivery of chemotherapeutic drugs with protein (avidin) within a solitary nanocarrier system has emerged as a promising combination therapy approach for treating cancers owing to their synergistic effect. In this study, we developed a potential nanocarrier by using graphene oxide (GO), activated folic acid (FA), polyethylene glycol (PEG), and TiO2 nanoparticles. PEG was introduced to enhance the nanocarrier's water solubility and biocompatibility. Further the synthesized primary nanocarrier that is, GO–FA–PEG–TiO2 employed with avidin‐biotin (Avi/Bio) system and synthesized more efficient nanocarrier that is, GO–FA–PEG–TiO2–Avi/Bio to enhance potential anti‐tumor activity and targeted co‐delivery of anticancer drug, SN‐38. The morphological analysis of nanocarrier GO–FA–PEG–TiO2–Avi/Bio was confirmed by basic characterization techniques including RAMAN, Fourier transforms infrared, Thermo gravimetric Analyzer, and Field Emission Scanning Electron Microscopy. The loading capacity of SN‐38 revealed that the nanocarrier integrated with Avi/Bio complex possessed higher adsorption capability than nanocarrier without Avi/Bio system. Furthermore, GO–FA–PEG–TiO2–Avi/Bio showed pH‐responsive behavior of releasing SN‐38. In‐vitro experiments confirmed sustained release of the drug, with a better performance at physiological pH (7.4) than at acidic pH (5.0). The developed nanocarrier with Avi/Bio complex showed higher cytotoxic effects than the GO–FA–PEG–TiO2 system. The cytotoxicity screening of GO–FA–PEG–TiO2–SN‐38 and GO–FA–PEG–TiO2–Avi/Bio–SN‐38 was conducted with MDA‐MB‐231 cells. Thus, GO–FA–PEG–TiO2–Avi/Bio system, when used as nanocarriers, showed high payload capacity to target cancer cells with increased cytotoxicity.

Sonochemical fabrication of reduction-responsive alginate-based nanocapsules with folate targeting for drug delivery

Smart drug delivery systems for anti-cancer treatment applications have been attractive gradually. Development of suitable smart drug carriers with targeted drug delivery capability and stimuli-responsive drug release ability is of crucial importance for accurate transport anti-cancer drugs to tumor cells and their efficient release. In the study, the biocompatible folate-modified reductive-responsive alginate-based nanocapsules (FA-RANCs) was developed using FA decorated thiolated alginate via sonochemical method for targeted delivery and controlled release of hydrophobic drugs. The wall of FA-RANCs was constructed by disulfide bonds formed from hydrosulfuryl groups and the hydrophobic drug dispersed in the oil phase to be encapsulated into nanocapsules. The FA-RANCs were endowed with folate targeting function owing to the grafting of folic acid on the surface of the capsules and FA-RANCs could be taken into Hela cells via folate-receptor (FR)-mediated endocytosis effect. Moreover, the FA-RANCs showed excellent reduction-responsive release property for hydrophobic anti-cancer drugs on account of the disulfide bonds in the shell of nanocapsules. According to the above results, FA-RANCs would be a promising controllable drug delivery system for targeted delivery and triggered release of hydrophobic drugs in biomedical area.

Nucleus-selective codelivery of proteins and drugs for synergistic antitumor therapy.

Subcellular organelle targeted transport is of great significance for accurately delivering drugs to active sites for better pharmacological effects, but there are still a lot of challenges due to transport problems. In addition, the killing effect of one kind of drug on cells is limited. Therefore, it is necessary to develop a multifunctional nanoplatform that can co-deliver synergistic therapeutic agents. Here, we prepare a simple amphiphilic nanocarrier (LC) with rapid endosomal escape ability for nucleus-selective delivery of hydrophilic active protein deoxyribonuclease I (DNase I) and hydrophobic anticancer drug doxorubicin (DOX). LC has been applied to effectively encapsulate DNase I just by simply mixing their aqueous solutions together. In addition, DOX modified with adamantane groups via a redox-responsive linker is incorporated into the architecture of DNase I nanoformulations through host–guest interaction. This multi-component nanoplatform can quickly escape from the endolysosomes into the cytoplasm and make DNase I and DOX highly accumulate in the nucleus and consequently induce strong synergistic anticancer efficacy both in vitro and in vivo. This work illustrates a new platform for codelivery of proteins and drugs that target subcellular compartments for functions.

Dual-sensitive GO-based self-assembly for the delivery of a hydrophobic anti-cancer drug

A novel pH and GSH stimuli-responsive GO-based self-assembly for precise and controlled drug release.

Hydrophobic modified poly(l‐glutamic acid) graft copolymer micelles with ultrahigh drug loading capacity for anticancer drug delivery

AbstractSelf‐assembled polymeric nanoparticle (NP) drug carriers are capable of encapsulated and controlled delivery, facilitating improvements in the therapeutic efficiency of drugs. Here we report a series of poly(l‐glutamic acid)‐g‐methoxy poly(ethylene glycol)/4‐phenylbutyl ester (PLG‐g‐mPEG/PB) copolymers, which were synthesized by esterification of 4‐phenylbutanol (PB) and PLG‐g‐mPEG in different feed ratios. The copolymers obtained form into nano‐sized micelles in aqueous solution by a self‐assembly process, with lower critical micelle concentration value for higher PB ratio in the copolymers. Variable temperature infrared spectroscopy and circular dichroism were used to prove the breaking of intermolecular hydrogen bonds after PB modification. Podophyllotoxin (PPT), an effective anticancer agent, was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interaction between the drug and the PB‐modified copolymers. Both the drug loading content and the loading efficiency increased with PB content in the PLG‐g‐mPEG/PB copolymers and reached an ultrahigh value of 28.2 wt% and 94%, respectively. The PPT‐encapsulated micelles (PPT‐NPs) were stable at pH 7.4 but dissociated and released 80% of loaded PPT in a weak acidic environment (pH 5.0). The in vitro proliferation of non‐small‐cell lung cancer cells (A549) was significantly inhibited by PPT‐NPs in a cytotoxicity assay. These results demonstrate that hydrophobic modification is an efficient route for tuning the self‐assembly behaviour and drug encapsulation of PLG‐g‐mPEG copolymers, and our PLG‐g‐mPEG/PB will serve as a promising carrier for hydrophobic anticancer drug delivery. © 2021 Society of Industrial Chemistry.

Stimuli-sensitivity and dynamics in the self-assembly structure of TEMPO-containing nonamphiphilic nanoparticles and their triggering hydrophobic drug release

Understanding the dynamics of stimuli-sensitive self-assembled nanomaterials is crucial for their potential applications, however, it is relatively difficult to quantitatively probe the dynamics using conventional analytical techniques because of the low sensitivity and selectivity of these techniques. In this research, TEMPO-containing nonamphiphilic copolymers are synthesized and highly sensitive, selective and non-destructive electron spin resonance (ESR) spectroscopy is applied to study their dynamics in stimuli-sensitive self-assembled nanostructures in different microenvironments. ESR spectroscopy reveals the structural changes of the smart supramolecular nanoparticles (SNPs) in their controlled assemblies by observing the molecular-level interactions. In order to obtain the dynamical evidence, several spectroscopic parameters such as rotational correlation time, hyperfine splitting constant, intensity increase/decrease and anisotropy parameters are determined from the ESR spectra. The stimuli-sensitivity and dynamics strongly depend on the SNPs’ microenvironment correlated to several chemical and physiological parameters such as radical concentration, pH, redox agent, temperature, polarity and viscosity. The results provide quantitative insights into the interface of the supramolecular assemblies. The nanoparticles showed good biocompatibility confirmed by the hemolysis test and the MTT assay. Furthermore, proof-of-concept experiments were carried out to demonstrate the SNPs’ stimuli-sensitive performance as a hydrophobic anticancer drug nanocarrier. This effort can be used to design other colloidal nano-platforms for the potential application in cancer treatment.

Preparation of Cationic Amphiphilic Nanoparticles with Modified Chitosan Derivatives for Doxorubicin Delivery

Polymeric micelle-like nanoparticles have demonstrated effectiveness for the delivery of some poorly soluble or hydrophobic anticancer drugs. In this study, a hydrophobic moiety, deoxycholic acid (DCA) was first bonded on a polysaccharide, chitosan (CS), for the preparation of amphiphilic chitosan (CS-DCA), which was further modified with a cationic glycidyltrimethylammounium chloride (GTMAC) to form a novel soluble chitosan derivative (HT-CS-DCA). The cationic amphiphilic HT-CS-DCA was easily self-assembled to micelle-like nanoparticles about 200 nm with narrow size distribution (PDI 0.08–0.18). The zeta potential of nanoparticles was in the range of 14 to 24 mV, indicating higher positive charges. Then, doxorubicin (DOX), an anticancer drug with poor solubility, was entrapped into HT-CS-DCA nanoparticles. The DOX release test was performed in PBS (pH 7.4) at 37 °C, and the results showed that there was no significant burst release in the first two hours, and the cumulative release increased steadily and slowly in the following hours. HT-CS-DCA nanoparticles loaded with DOX could easily enter into MCF-7 cells, as observed by a confocal microscope. As a result, DOX-loaded HT-CS-DCA nanoparticles demonstrated a significant inhibition activity on MCF-7 growth without obvious cellular toxicity in comparison with blank nanoparticles. Therefore, the anticancer efficacy of these cationic HT-CS-DCA nanoparticles showed great promise for the delivery of DOX in cancer therapy.

Self-assembled Janus graphene nanostructures with high camptothecin loading for increased cytotoxicity to cancer cells

The sequential functionalization of graphene (Gr) with oleylamine (ODA) and diethanolamine (DEA) was performed to produce amphiphilic Janus-type graphene nanosheets (DEA-f-Gr-f-ODA). The Janus graphene was self-assembled in 3D superstructures with hydrophilic external surface and hydrophobic internal space. The DEA-f-Gr-f-ODA nanoparticles were investigated as platforms for the hydrophobic anticancer drug camptothecin (CPT). The colloidal stability, drug loading and drug release properties of the DEA-f-Gr-f-ODA nanoparticles were determined. The viability of A549 cancer cells in the presence of increasing concentrations of free CPT and blank and drug-loaded DEA-f-Gr-f-ODA nanoparticles was assessed with MTT accompanied with PI/Annexin-V apoptosis assessment with flow cytometry. The uptake of DEA-f-Gr-f-ODA nanoparticles by the A549 cells was also evaluated with flow cytometry. The hemocompatibility of DEA-f-Gr-f-ODA nanoparticles was assessed with a hemolysis assay. The Janus graphene nanoparticles could host an exceptionally large amount of CPT, achieving more than double CPT loading compared to graphene-based CPT platforms reported so far, and released it in a slow biphasic fashion. The cytotoxicity and hemolysis assays provided evidence for the biocompatibility of the DEA-f-Gr-f-ODA nanoparticles and the CPT-loaded DEA-f-Gr-f-ODA nanoparticles were more cytotoxic against a human cancer cell line than free CPT, inducing a higher degree of apoptosis to the cancer cells.

Design and synthesis of targeted star-shaped micelle for guided delivery of camptothecin: In vitro and in vivo evaluation

This study aimed to synthesize a star-shaped micelle using 3-azido-2,2-bis(azidomethyl)propan-1-ol (pentaerythritol triazide) core, as an initiator for the synthesis of three-arm polylactic acid (PLA) block. Then, the ends of the PLA arms were converted to PLA triazide followed by conjugation to the three alkyne-PEG-maleamide through click reaction. The maleamide ends were available for coupling with sulfhydryl-modified DNA aptamer against epithelial cell adhesion molecule in order to offer targeted delivery of encapsulated drug, camptothecin to the site of action. The successful synthesis of the star-shaped polymers was confirmed via1HNMR. Hydrophobic anti-cancer drug, camptothecin was encapsulated into the micelles core implementing solvent switching method providing loading content (LC%) and encapsulation efficiency (EE%) of 3.7 ± 0.4 and 73.7 ± 8.2, respectively. The size of both non-targeted and aptamer-targeted micelles was determined to be 154 and 192 nm, respectively with polydispersity index below 0.3. In vitro drug release evaluation at 37 °C, pH 7.4 showed a controlled release pattern for camptothecin during 72 h. In vitro cytotoxicity of the prepared non-targeted and targeted micelles was carried out on human colorectal adenocarcinoma (HT29) and mouse colon carcinoma (C26) as EpCAM positive cell lines and Chinese hamster ovary (CHO) as EpCAM negative cell line. The results verified significantly higher cytotoxicity of the targeted micelles on HT29 and C26 cell lines, while no obvious difference was observed between targeted and non-targeted formulation on CHO cell line. The in vivo therapeutic efficiency investigation on BALB/c C26 tumor-bearing mice showed superior capability of the targeted formulation on tumor suppression and survival rate of the treated mice. The developed platform exhibited excellent characteristics to diminish camptothecin drawbacks and its adverse effects while considerably increasing its therapeutic index.

Lung targeted electrosprayed chitosan nanocomposite microparticles boost the cytotoxic activity of magnolol

Large scale production of therapeutic nanoparticles (NPs) is still challenging. Herein, we report a facile single step electrospray process for the production of a nanocarrier platform made of hybridized chitosan (CS)/ polyvinyl alcohol (PVA) matrix. The method was adapted to achieve the lowest NPs size for carrying and delivering a hydrophobic anti-cancer drug, magnolol (Mag). To improve the inhalation properties of the optimized NPs formulation, the spray drying method was adopted to generate Mag loaded nano embedded-in-microparticles (Mag-NEM). The impact of the characteristics of CS and PVA blended solutions with and without Mag on the developed systems was investigated. The viscosity of the polymers solution played a major role on the size of electrosprayed NPs. NPs could only be obtained at CS:PVA ratio 7:3 and 8:2 for low molecular weight CS and at only 8:2 ratio for the medium molecular weight. Mag-NPs scoring 415.7 nm with a high drug encapsulation efficiency of 95.5% ±2.5 were successfully prepared at 0.1 mL/h flow rate, 15 cm tip to collector distance and 25 kV applied voltage. Optimized Mag-NEM exhibited good aerosolization properties with effective inhalation index of 64.69% and showed a two-fold decrease in IC50 when challenged against lung cancer cells A549.