Micellar Nanocarriers Research Articles

Labelled micelles for the delivery of cytotoxic Cu(II) and Ru(III) compounds in the treatment of aggressive orphan cancers: Design and biological in vitro data

A recent study on our metal-dithiocarbamato complexes pointed out the antiproliferative properties and the druglikeness of some new patented derivatives. In this work, the best compounds have been encapsulated in micellar nanocarriers, being also carbohydrate-functionalized on their hydrophilic surface to investigate the possibility of a cancer-selective delivery. In particular, the nonionic block copolymer Pluronic® F127 (PF127) has been chemically modified with sugars and the derivatives characterized by means of NMR spectroscopy and FT-IR spectrophotometry. Then, the two selected complexes (β-[Ru2(PipeDTC)5]Cl (PipeDTC = piperidine dithiocarbamate) and [Cu(ProOMeDTC)2] (ProOMeDTC = L-proline methyl ester dithiocarbamate)), have been loaded into the hydrophobic core of PF127 micelles and cancer-targeting counterparts. These nanoformulations have been studied for their dimensions (DLS, TEM) and stability, and tested for their cytotoxicity against aggressive human cancer cell lines. The in vitro results were paralleled with mechanistic studies through Confocal Laser Scanning Microscopy and xCELLigence analysis.

A Thermal-Responsive Y-Shaped Miktoarm Amphiphilic Block Copolymer Composed of Poly(ε-caprolactone) and Poly(N-isopropylacrylamide) as a Nano-micellar Carrier for Anti-cancer Drugs

A thermal-responsive Y-shaped amphiphilic block copolymer, namely poly(N-isopropylacrylamide-block-[poly(e-caprolactone)]2 (PNIPAAm-b-PCL2), was synthesized through the combination of atom transfer radical polymerization (ATRP) and ring-opening polymerization (ROP) techniques, and its potential as smart anti-cancer drug delivery system was investigated preliminary. The fabricated polymers were characterized using FTIR and 1H NMR spectroscopy, and GPC analysis. The self-assembly behavior of the fabricated PNIPAAm-b-PCL2 copolymer under thermal stimuli was investigated using dynamic light scattering and UV–Vis spectroscopy. The lower critical solution temperature of the synthesized PNIPAAm-b-PCL2 was found to be 39–41°C. The doxorubicin hydrochloride loading and encapsulation capacities of the fabricated PNIPAAm-b-PCL2 were calculated to be 62 ± 3%, and 75 ± 4%, respectively; the drug release value was up to 46.5% during 40 h at 37°C and up to 88% at 40°C.

Photo-Degradable Micelles Capable of Releasing of Carbon Monoxide under Visible Light Irradiation.

Carbon monoxide (CO) has emerged as a potential therapeutic agent for the treatment of many diseases. However, the therapeutic outcome is highly dependent on the dosages and administration sites. Hence, there is mounting interest in the development of CO-releasing materials to accomplish site-specific and dose-controlled delivery of CO. Herein, a micellar nanoparticle platform for the photo-mediated release of CO by using amphiphilic triblock copolymers bearing CO-releasing moieties of 3-hydroxylflavone (3-HF) derivatives within the middle blocks is developed. These micelles are relatively stable without CO leakage but undergo visible light-mediated CO release and simultaneous main chain scission. Moreover, these micellar nanoparticles are cytocompatible regardless of light irradiation, which shows unique anti-inflammatory performance only after light irradiation as a result of photo-triggered CO release. This work may represent the first example of main-chain degradable micellar nanocarriers with controlled CO-releasing performance for potential anti-inflammatory applications.

A Rationally Designed Micellar Nanocarrier for the Delivery of Hydrophilic Methotrexate in Psoriasis Treatment.

Methotrexate (MTX) is broadly applied in the clinic for the treatments of cancers and autoimmune diseases. Targeted delivery of MTX is attractive to improve its efficacy and reduce off-target toxicity. However, MTX encapsulation in nanoparticle is challenging due to its high water solubility. We rationally designed a well-defined telodendrimer (TD) nanocarrier based on MTX structure to sequester it in nanoparticles. Riboflavin (Rf) and positive charges groups were precisely conjugated on TD to form multivalent hydrogen bonds, π-π stacking and electrostatic interactions with MTX. A reverse micelle approach was developed to preset MTX and TD interactions in the core of micelles, which ensures the effective MTX loading upon dispersion into aqueous solution. As results, MTX loading capacity reaches over 20% (w/w) in the optimized nanocarrier with the particle size of 20-30 nm. The nanoformulations sustain the release of MTX in a controlled manner and exhibit excellent hemocompatibility. The in vitro cellular uptake of MTX was significantly improved by the nanoformulations. The potency of MTX nanoformulations is comparable to the free MTX in cytotoxicity. A psoriasis-like skin inflammation model was induced in mouse by imiquimod (IMQ) stimulation. MTX nanoformulations improved the psoriasis targeting and exhibited a superior long-lasting efficacy in reducing skin inflammation compared with the free MTX in psoriasis treatment.

Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano) for Ocular Delivery of Cyclosporine-A.

The physiological protective mechanisms of the eye reduce the bioavailability of topically administered drugs above all for those with high molecular weight and /or lipophilic characteristics, such as Cyclosporine A (CyA). The combined strategy based on the association of nanomicelles and mucoadhesive polymer seems promising since a limited number of commercial products containing CyA have been recently approved. The scope of this investigation was the design of Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano), based on a binary system of two surfactants in combination with hyaluronic acid, and their biopharmaceutical evaluation. The optimisation of the ASMP-Nano in term of the amount of surfactants, CyA-loading and size determined the selection of the clear and stable Nano1HAB-CyA formulation containing 0.105% w/w CyA loaded-nanomicelles with a size of 14.41 nm. The nanostructured system had a protective effect towards epithelial corneal cells with a cell viability of more than 80%. It interacted with cellular barriers favouring the uptake and the accumulation of CyA into the cells as evidenced by fluorescent probe distribution, by hindering CyA permeation through reconstituted corneal epithelial tissue. In pharmacokinetics study on rabbits, the nanomicellar carrier prolonged the CyA retention time in the precorneal area mainly in presence of hyaluronic acid (HA), a mucoadhesive polymer.

Codelivery of Anti-PD-1 Antibody and Paclitaxel with Matrix Metalloproteinase and pH Dual-Sensitive Micelles for Enhanced Tumor Chemoimmunotherapy.

Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual-sensitive micellar nanocarrier showing spatio-temporally controlled release of anti-PD-1 antibody (aPD-1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX-induced immunogenic cell death (ICD), while aPD-1 blocks the PD-1/PD-L1 axis to suppress the immune escape due to PTX-induced PD-L1 up-regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment-sensitive micelles bearing a sheddable PEG layer to mediate site-specific sequential release of aPD-1 and PTX.

Lipid-Based Antimicrobial Delivery-Systems for the Treatment of Bacterial Infections.

Many nanotechnology-based antimicrobials and antimicrobial-delivery-systems have been developed over the past decades with the aim to provide alternatives to antibiotic treatment of infectious-biofilms across the human body. Antimicrobials can be loaded into nanocarriers to protect them against de-activation, and to reduce their toxicity and potential, harmful side-effects. Moreover, antimicrobial nanocarriers such as micelles, can be equipped with stealth and pH-responsive features that allow self-targeting and accumulation in infectious-biofilms at high concentrations. Micellar and liposomal nanocarriers differ in hydrophilicity of their outer-surface and inner-core. Micelles are self-assembled, spherical core-shell structures composed of single layers of surfactants, with hydrophilic head-groups and hydrophobic tail-groups pointing to the micellar core. Liposomes are composed of lipids, self-assembled into bilayers. The hydrophilic head of the lipids determines the surface properties of liposomes, while the hydrophobic tail, internal to the bilayer, determines the fluidity of liposomal-membranes. Therefore, whereas micelles can only be loaded with hydrophobic antimicrobials, hydrophilic antimicrobials can be encapsulated in the hydrophilic, aqueous core of liposomes and hydrophobic or amphiphilic antimicrobials can be inserted in the phospholipid bilayer. Nanotechnology-derived liposomes can be prepared with diameters <100–200 nm, required to prevent reticulo-endothelial rejection and allow penetration into infectious-biofilms. However, surface-functionalization of liposomes is considerably more difficult than of micelles, which explains while self-targeting, pH-responsive liposomes that find their way through the blood circulation toward infectious-biofilms are still challenging to prepare. Equally, development of liposomes that penetrate over the entire thickness of biofilms to provide deep killing of biofilm inhabitants still provides a challenge. The liposomal phospholipid bilayer easily fuses with bacterial cell membranes to release high antimicrobial-doses directly inside bacteria. Arguably, protection against de-activation of antibiotics in liposomal nanocarriers and their fusogenicity constitute the biggest advantage of liposomal antimicrobial carriers over antimicrobials free in solution. Many Gram-negative and Gram-positive bacterial strains, resistant to specific antibiotics, have been demonstrated to be susceptible to these antibiotics when encapsulated in liposomal nanocarriers. Recently, also progress has been made concerning large-scale production and long-term storage of liposomes. Therewith, the remaining challenges to develop self-targeting liposomes that penetrate, accumulate and kill deeply in infectious-biofilms remain worthwhile to pursue.

Poly(ethylene glycol)-poly(ε-caprolactone)-based micelles for solubilization and tumor-targeted delivery of silibinin.

Introduction: Silibinin is a naturally occurring compound with known positive impacts on prevention and treatment of many types of human illnesses in general and cancer in particular. Silibinin is poorly water soluble which results in its insufficient bioavailability and lack of therapeutic efficacy in cancer. Here, we proposed to examine the potential of micelles composed of poly(ethylene glycol) (PEG) as the hydrophilic block and poly(ε-caprolactone) (PCL), poly(α-benzylcarboxylate-ε-caprolactone) (PBCL), or poly(lactide)-(PBCL) (PLA-PBCL) as hydrophobic blocks for enhancing the water solubility of silibinin and its targeted delivery to tumor. Methods: Co-solvent evaporation method was used to incorporate silibinin into PEG-PCL based micelles. Drug release profiles were assessed using dialysis bag method. MTT assay also was used to analyze functional activity of drug delivery in B16 melanoma cells. Results: Silibinin encapsulated micelles were shown to be less than 60 nm in size. Among different structures under study, the one with PEG-PBCL could incorporate silibinin with the highest encapsulation efficiency being 95.5%, on average. PEG-PBCL micelles could solubilize 1 mg silibinin in 1 mL water while the soluble amount of silibinin was found to be 0.092 mg/mL in the absence of polymeric micelles. PEG-PBCL micelles provided the sustained release of silibinin indicated with less than 30% release of silibinin within 24 hours. Silibinin encapsulated in PEG-PBCL micelles resulted in growth inhibitory effect in B16 cancer cells which was significantly higher than what observed with free drug. Conclusion: Our findings showed that PEG-PBCL micellar nanocarriers can be a useful vehicle for solubilization and targeted delivery of silibinin.

Corrigendum: In Vitro Anticancer Drug Delivery Using Amphiphilic Poly(N‐vinylpyrrolidone)‐b‐Polyketal‐b‐Poly(N‐vinylpyrrolidone) Block Copolymer as Micellar Nanocarrier

ChemistrySelectVolume 4, Issue 40 p. 11851-11851 CorrigendumFree Access Corrigendum: In Vitro Anticancer Drug Delivery Using Amphiphilic Poly(N-vinylpyrrolidone)-b-Polyketal-b-Poly(N-vinylpyrrolidone) Block Copolymer as Micellar Nanocarrier This article corrects the following: In Vitro Anticancer Drug Delivery Using Amphiphilic Poly(N-vinylpyrrolidone)-b-Polyketal-b-Poly(N-vinylpyrrolidone) Block Copolymer as Micellar Nanocarrier Kheyanath Mitra, Sumit Kumar Hira, Shikha Singh, Niraj Kumar Vishwakarma, Sambhav Vishwakarma, Uttam Gupta, Partha Pratim Manna, Biswajit Ray, Volume 3Issue 31ChemistrySelect pages: 8833-8843 First Published online: August 16, 2018 Dr. Kheyanath Mitra, Dr. Kheyanath MitraSearch for more papers by this authorDr. Sumit Kumar Hira, Dr. Sumit Kumar HiraSearch for more papers by this authorDr. Shikha Singh, Dr. Shikha SinghSearch for more papers by this authorDr. Niraj Kumar Vishwakarma, Dr. Niraj Kumar VishwakarmaSearch for more papers by this authorSambhav Vishwakarma, Sambhav VishwakarmaSearch for more papers by this authorUttam Gupta, Uttam GuptaSearch for more papers by this authorDr. Partha Pratim Manna, Dr. Partha Pratim MannaSearch for more papers by this authorProf. Biswajit Ray, Prof. Biswajit RaySearch for more papers by this author Dr. Kheyanath Mitra, Dr. Kheyanath MitraSearch for more papers by this authorDr. Sumit Kumar Hira, Dr. Sumit Kumar HiraSearch for more papers by this authorDr. Shikha Singh, Dr. Shikha SinghSearch for more papers by this authorDr. Niraj Kumar Vishwakarma, Dr. Niraj Kumar VishwakarmaSearch for more papers by this authorSambhav Vishwakarma, Sambhav VishwakarmaSearch for more papers by this authorUttam Gupta, Uttam GuptaSearch for more papers by this authorDr. Partha Pratim Manna, Dr. Partha Pratim MannaSearch for more papers by this authorProf. Biswajit Ray, Prof. Biswajit RaySearch for more papers by this author First published: 05 November 2019 https://doi.org/10.1002/slct.201903976AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume4, Issue40October 25, 2019Pages 11851-11851 RelatedInformation

FRET in a Polymeric Nanocarrier: IR-780 and IR-780-PDMS.

We introduce a method to monitor the integrity of micellar nanocarriers using a novel fluorescent dye, IR-780-PDMS and Förster resonance energy transfer (FRET) as a readout. In addition, these dye-loaded nanocarriers can be used as a phototoxic agent in vitro. Mainly, a nanocarrier was designed, based on a previously described amphiphilic ABA-copolymer (Pip-PMOXA-PDMS-PMOXA-Pip) scaffold that incorporates the fluorescent FRET dye partners IR-780-PDMS (donor) and IR-780 (acceptor). The confirmation of FRET (that only occurs when donor and acceptor are in the required close proximity of less than ∼10 nm) in the nanocarriers is used to prove that the acceptor dye (IR-780) is still contained in its hydrophobic core. We measured such FRET signals of the nanocarriers also upon cellular uptake into HeLa cells using fluorescence-lifetime imaging microscopy (FLIM). Confocal laser scanning microscopy after incubation with nanocarriers demonstrated the intracellular uptake of the particles and their localization in an intracellular granular pattern. To demonstrate the intactness of the nanocarriers by detection of FRET we measured the fluorescence lifetime (FLIM) of the donor dye. FLIM showed that both types of lifetimes, that of the quenched donor, and that of the unquenched donor were present, in a granular pattern and homogeneously in the cytosol, respectively, indicating the presence of intracellular intact and disintegrated micellar nanocarriers. These data show that the herewith-described FRET method allows monitoring the intactness of nanocarriers while en route to the target, and also that the cargo is delivered and released within a potential target cell. In addition, near-infrared (NIR) irradiation of IR-780-loaded micellar nanocarriers leads to photocytotoxicity, which we demonstrated in in vitro experiments. Our findings open potential avenues in photodynamic therapy (PDT) of cancer.

S96SMALL-SCALE SOMATIC STRUCTURAL VARIANTS IN FETAL AND ADULT HUMAN BRAINS

Selenium (Se) incorporated into organic frameworks has demonstrated anticancer activity against several cancer types. One of the drawbacks of most of these constructs is their poor solubility and bioavailability, which can be overcome with the use of suitable nanocarriers. We have synthesized a series of 5-substituted amide selenodiazoles, based on the parent structure of ebselen, an organoselenium drug with proven cytoprotective activity, and solubilized them in polymeric micelles of poloxamines, poly(ethylene oxide)-poly(propylene oxide) X-shaped tetrablock-copolymers. Scattering methods (SANS and DLS) were employed to characterize the micellar nanocarriers. MTT biological evaluation highlights the selectivity of the Se-compounds towards cancer cells, with MCF-7 standing as the most responsive line. The alkylation of the heterocycle with a 12-carbon hydrophobic tail displays the highest activity, showing a 100-fold increase with respect to ebselen. This compound also exhibits the greatest increase in solubility in poloxamine micelles, overall resulting in a one-fold increase in activity with respect to the non-formulated form, making it a hit compound for further optimization.

ROS-Responsive Polymeric Nanocarriers with Photoinduced Exposure of Cell-Penetrating Moieties for Specific Intracellular Drug Delivery.

In situ modulation of the surface properties on the micellar drug delivery nanocarriers offers an efficient method to improve the drug delivery efficiency into cells while maintaining stealth and stability during blood circulation. Light has been demonstrated to be a temporally and spatially controllable tool to improve cellular internalization of nanoparticles. Herein, we develop reactive oxygen species (ROS)-responsive mixed polymeric micelles with photoinduced exposure of cell-penetrating moieties via photodynamic ROS production, which can facilitate cellular internalization of paclitaxel (PTX) and chlorin e6 (Ce6)-coloaded micelles for the synergistic effect of photodynamic and chemotherapy. The thioketal-bond-linked block polymers poly(ε-caprolactone)-TL-poly(N,N-dimethylacrylamide) (PCL-TL-PDMA) with a long PDMA block are used to self-assemble into mixed micelles with PCL-b-poly(2-guanidinoethyl methacrylate) (PCL-PGEMA) consisting of a short PGEMA block, which are further used to coencapsulate PTX and Ce6. After intravenous injection, prolonged blood circulation of the micelles guarantees high tumor accumulation. Upon irradiation by 660 nm light, ROS production of the micelles by Ce6 induces cleavage of PDMA to expose PGEMA shells for significantly improved cellular internalization. The combination of photodynamic therapy and chemotherapy inside the tumor cells achieves improved antitumor efficacy. The design of ROS-responsive mixed polymeric nanocarriers represents a novel and efficient approach to realize both long blood circulation and high-efficiency cellular internalization for combined photodynamic and chemotherapy under light irradiation.

The effect of the saturation degree of phospholipid on the formation of a novel self-assembled nano-micellar complex carrier with enhanced intestinal permeability.

The aim of this research was to formulate a novel nano-micellar complex carrier with intrinsically enhanced intestinal permeability for rosuvastatin calcium (RSV); as a model of BCS class III active pharmaceutical ingredients (APIs). The model drug is used primarily for treating hypercholesterolemia. Three phospholipid types with different degrees of saturation were chosen for the study. The saturation degree of the phospholipids was calculated accurately by proton NMR. A D-optimal statistical design was utilized to correlate the saturation degree of the phospholipids with the physico-chemical characteristics of the prepared nano-micellar carrier. The nature of the interaction between the phospholipids and the model drug was studied by proton NMR, photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM). Molecular docking and molecular dynamics simulations were performed to understand the formation mechanism of the complex micelles on a molecular level. The results demonstrated that the interaction of the hydrophilic drug molecule with the polar head of a saturated phospholipid induces an intramolecular self-coiling of phospholipid saturated acyl chain leading to a structural transformation from a two-tailed cylindrical configuration into a one-tailed, surfactant-like configuration owing to the flexibility of the saturated chains. This transformation leads to the construction of a novel nano-micellar structure in which the drug has lower water solubility but higher lipophilicity than in traditional micelles. Permeability studies conducted on Caco-2 cells demonstrated that the novel nano-micellar carrier had superior permeability to that of the un-complexed hydrophilic drug. The optimized nano-micellar formulation showed significantly (P < 0.5) superior bioavailability in rats to that of the aqueous drug solution in terms of both the rate and extent of drug absorption. Overall, the results confirmed that the formation of the phospholipid nano-micellar complex increased the permeability of the hydrophilic BCS class III drug and converted it to a class BCS I drug by a simple and effective formulation technique.

Poly(ethylene glycol) crosslinked multi-armed poly(ε-benzyloxycarbonyl-L-lysine)s as super-amphiphiles: Synthesis, self-assembly, and evaluation as efficient delivery systems for poorly water-soluble drugs

Polymeric micelles with high thermodynamic stability and loading capacity are of tremendous significance for their potential applications in drug delivery. In the present study, super-amphiphiles in the form of poly(ethylene glycol)-crosslinked multi-armed polyethylenimine-g-poly(ε-benzyloxycarbonyl-L-lysine)s (PEZ-alt-PEG) were designed, synthesized, and optimized as nanocarriers for hydrophobic drugs. In an aqueous solution, the copolymer PEZ-alt-PEG self-assembled into sub-100-nm spherical shell crosslinked micelles with low toxicity in vitro and in vivo. The crosslinked super-amphiphilic structure of PEZ-alt-PEG could not only enhance the thermodynamic stability of polymeric micelles, but it could also significantly improve the loading capacity of hydrophobic drugs, such as curcumin (CUR). CUR-loaded PEZ-alt-PEG micelles could mediate effective drug delivery with sustained and complete CUR release. The use of PEZ-alt-PEG micellar nanocarriers remarkably improved the cellular uptake of CUR and therefore exhibited effective inhibitory activity on the growth of human hepatoma (HepG2) cells. Compared to free CUR, CUR-loaded polymeric micelles significantly accelerated the apoptosis rate of HepG2 cells. Therefore, PEZ-alt-PEG polymeric micelles, with their high thermodynamic stability, high drug-loading capacity, enhanced drug uptake and improved pharmacodynamic effects, could serve as efficient and promising nanocarriers for poorly water-soluble drugs.

PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy

A novel triblock amphiphilic copolymer (PAL-PEG-Birinapant) was designed and synthesized as a dual-functional micellar carrier utilizing birinapant (an inhibitor of inhibitor-of-apoptosis proteins) as a pH-sensitive segment and inhibitor-of-apoptosis proteins-targeting ligand. The mixed micelles comprised of PAL-PEG-Birinapant (PPB) and mPEG2k-PDLLA2k (MPP), named as PPB/MPP (2/1,w/w) micelles were developed for enhanced solubility and antitumor potency of hydrophobic drugs as paclitaxel (PTX). In vitro cell viability and cytotoxicity studies revealed that the PTX–loaded PPB/MPP micelles were more potent than the commercial PTX formulation (Taxol®), as well as the in vitro cell apoptosis study. Clear differences in the intracellular uptake of free coumarin-6 (C6) solution and C6-loaded PPB/MPP micelles were observed and indicated that the PPB/MPP micelles could efficiently deliver chemical compound into tumor cells. PPB copolymer and PTX–loaded PPB/MPP micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of above 1.2 g copolymer/kg and above 100 mg PTX/kg in mice respectively in contrast to 20˜24 mg/kg of Taxol®. The near infrared (NIR) fluorescence imaging showed that PPB/MPP micelles persisted for a relatively long time in the circulation and accumulated preferentially in tumor tissue. Moreover, PTX loaded PPB/MPP micelles significantly inhibited the tumor growth both in MDA-MB-231 and Ramos cancer xenograft mice models without obvious toxicity. Collectively, our study presents a new dual-functional micelles that improve the therapeutic efficacy of PTX in vitro and in vivo.

Modeling the internal structure of micelles in a delivery system based on 4-arm star shaped polymers

A previously studied drug delivery systems based on 4-arm star shaped polyacids with pentaerythritol core have been proposed as excellent micellar nanocarriers with adjustable characteristics for drug loading and release, including anti-inflammatory drugs. A series of experiments to measure the release of drugs by micelles of various composition were conducted. Here we model this release process by mathematical methods and conclude about the structure and loading capability of the obtained micelles in relation to their composition. Our method is a random walk simulation in a potential field. The results predict a decreasing dependency of the micelle core size on hydrophobic content which relates to the loading capability and release kinetics. We link this phenomenon to the packing quality of the micelle’s core, which is reflected by the values of the drug’s binding energy to the core and the probability to incorporate the drug into the core.

Creatine based polymer for codelivery of bioengineered MicroRNA and chemodrugs against breast cancer lung metastasis

Metastasis is the major cause for breast cancer related mortality. The combination of miRNA-based therapy and chemotherapy represents a promising approach against breast cancer lung metastasis. The goal of this study is to develop an improved therapy that co-delivers a novel bioengineered miRNA prodrug (tRNA-mir-34a) and doxorubicin (DOX) via a multifunctional nanomicellar carrier that is based on a conjugate of amphiphilic copolymer POEG-VBC backbone with creatine, a naturally occurring cationic molecule. Co-delivery of DOX leads to more effective processing of tRNA-mir-34a into mature miR-34a and down-regulation of target genes. DOX + tRNA-mir-34a/POEG-PCre exhibits potent synergistic anti-tumor and anti-metastasis activity in vitro and in vivo. Interestingly, the enhanced immune response contributes to the overall antitumor efficacy. POEG-PCre may represent a safe and effective delivery system for an optimal chemo-gene combination therapy.

Quantifying Associations between an Endogenous Protein Model and mPEG-Pcl Micellar Nanocarriers

A promising technique for drug administration involves the use of polyethylene glycol (PEG)-based nanocarriers, which have demonstrated exceptional aptitude for evading immune responses within the body. Such antifouling properties are ideal for designing delivery systems capable of avoiding early removal by the spleen and liver, allowing prolonged circulation of the drug. However, recent studies have shown that many PEGylated nanocarriers actually trigger an immunogenic response, called the accelerated blood clearance (ABC) phenomenon, upon sequential doses of the carriers. This response suggests the existence of non-specific interactions between the carriers and endogenous proteins, making the degree of these interactions an important metric for developing improved PEGylated nanocarriers. Therefore, we sought to elucidate a baseline for non-specific PEG-protein interactions between mPEG-b-polycaprolactone (PCL) micelles and bovine serum albumin (BSA) using pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). Here we report the measured mobility and dimerization affinities of nile red labeled mPEG-PCL and fluorescein conjugated BSA.

MDM2 antagonist-loaded targeted micelles in combination with doxorubicin: effective synergism against human glioblastoma via p53 re-activation

p53, The tumour suppressor protein encoded by P53 gene, is the most commonly altered protein in the human malignancies. MDM2 controls the p53 activity through an autoregulatory feedback loop. p53 activates the expression of MDM2 and in return, MDM2 blocks the p53 activity through various mechanisms. Nutlins, including nutlin-3, are a new class of small molecules that bind to MDM2 and prevent its interaction with p53. This antagonism results in increased p53 activity and can also re-activates the p53 pathway and resensitize the glioblastoma cells to apoptosis. Here we used nutlin-3 in combination with another potent anticancer drug, doxorubicin, to investigate the synergism between these drugs. We encapsulated both water-insoluble drugs in the PEG-PE-based micellar nanocarriers efficiently and evaluate their efficacy against U87MG cells in 2 D and 3 D models. These nanomedicine formulations successfully re-activated the p53 levels in cells, increased the apoptosis and showed strong synergistic cytotoxic effect.

Tumor targeted micellar nanocarriers assembled from epipodophyllotoxin-based amphiphiles.

Micelle-forming amphiphilic drug conjugates were synthesized starting from a biologically active epipodophyllotoxin derivative which was covalently inserted in between a hydrophilic PEG unit and a hydrophobic stearyl chain. The epipodophyllotoxin-containing amphiphiles were assembled into the corresponding micelles which were evaluated in vivo for their tumor targeting properties.