Biocompatible Amphiphilic Copolymers Research Articles

Synthesis and Characterization of Macroinitiators Based on Polyorganophosphazenes for the Ring Opening Polymerization of N-Carboxyanhydrides

Among the various biocompatible amphiphilic copolymers, biodegradable ones are the most promising for the preparation of drug delivery systems since they are destroyed under physiological conditions, that, as a rule, reduce toxicity and provide controlled release of the drug. Hybrid graft-copolymers consisting of the main inorganic polyphosphazene chain and polypeptide side chains are of considerable interest for the development of delivery systems with a controlled degradation rate, since the main and side chains will have different degradation mechanisms (chemical and enzymatic hydrolysis, respectively). Variable particle degradation rate, controlled by the adjusting the composition of substituents, will allow selective delivery in vivo and controlled drug release. The present work proposes the preparation of biodegradable macroinitiators based on polyorganophosphazenes for the synthesis of hybrid copolymers. Synthesis of novel biodegradable macroinitiators based on polyorganophosphazenes was performed via macromolecular substitution of a polydichlorophosphazene chain with the sodium alcoholates, amines and amino acids. The composition of copolymers obtained was calculated using NMR. These polyorganophosphazenes bearing primary amino groups can be considered as convenient macroinitiators for the polymerization of NCA of α-amino acids in order to prepare hybrid copolymers polyphosphazene-graft-polypeptide. The developed macroinitiators were amphiphilic and self-assembled in the aqueous media into nanoparticles. Furthermore, the ability to encapsulate and release a model substance was demonstrated. In addition, the in vitro cytotoxicity of synthesized polymers was evaluated using two cell lines.

Co-delivery of paclitaxel and doxorubicin using mixed micelles based on the redox sensitive prodrugs

A strategy of preparing mixed micelles containing both DOX prodrug and PTX prodrug was developed, i.e., synthesizing a DOX conjugate and a PTX conjugate started with the same biocompatible amphiphilic copolymer, TPGS and DTDPA, a linker containing disulfide bond. The mixed micelles were prepared by co-assembling the two conjugates with a particle size about 98.5 nm. The mixed micelles could release anticancer drug DOX and PTX upon cellular reduction once they came into the cancerous cells. Moreover, the mixed micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo.

Doxorubicin-loaded protease-activated near-infrared fluorescent polymeric nanoparticles for imaging and therapy of cancer.

IntroductionDespite significant progress in the field of oncology, cancer remains one of the leading causes of death. Chemotherapy is one of the most common treatment options for cancer patients but is well known to result in off-target toxicity. Theranostic nanomedicines that integrate diagnostic and therapeutic functions within an all-in-one platform can increase tumor selectivity for more effective chemotherapy and aid in diagnosis and monitoring of therapeutic responses.Material and methodsIn this work, theranostic nanoparticles were synthesized with commonly used biocompatible and biodegradable polymers and used as cancer contrast and therapeutic agents for optical imaging and treatment of breast cancer. These core–shell nanoparticles were prepared by nanoprecipitation of blends of the biodegradable and biocompatible amphiphilic copolymers poly(lactic-co-glycolic acid)-b-poly-l-lysine and poly(lactic acid)-b-poly(ethylene glycol). Poly-l-lysine in the first copolymer was covalently decorated with near-infrared fluorescent Alexa Fluor 750 molecules.ResultsThe spherical nanoparticles had an average size of 60–80 nm. The chemotherapeutic drug doxorubicin was encapsulated in the core of nanoparticles at a loading of 3% (w:w) and controllably released over a period of 30 days. A 33-fold increase in near-infrared fluorescence, mediated by protease-mediated cleavage of the Alexa Fluor 750-labeled poly-l-lysine on the surface of the nanoparticles, was observed upon interaction with the model protease trypsin. The cytocompatibility of drug-free nanoparticles and growth inhibition of drug-loaded nanoparticles on MDA-MB-231 breast cancer cells were investigated with a luminescence cell-viability assay. Drug-free nanoparticles were found to cause minimal toxicity, even at high concentrations (0.2–2,000 µg/mL), while doxorubicin-loaded nanoparticles significantly reduced cell viability at drug concentrations >10 µM. Finally, the interaction of the nanoparticles with breast cancer cells was studied utilizing fluorescence microscopy, demonstrating the potential of the nanoparticles to act as near-infrared fluorescence optical imaging agents and drug-delivery carriers.ConclusionDoxorubicin-loaded, enzymatically activatable nanoparticles of less than 100 nm were prepared successfully by nanoprecipitation of copolymer blends. These nanoparticles were found to be suitable as controlled drug delivery systems and contrast agents for imaging of cancer cells.

Interaction of spin-labeled HPMA-based nanoparticles with human blood plasma proteins - the introduction of protein-corona-free polymer nanomedicine.

In this paper, we revised the current understanding of the protein corona that is created on the surface of nanoparticles in blood plasma after an intravenous injection. We have focused on nanoparticles that have a proven therapeutic outcome. These nanoparticles are based on two types of biocompatible amphiphilic copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA): a block copolymer, poly(ε-caprolactone) (PCL)-b-poly(HPMA), and a statistical HPMA copolymer bearing cholesterol moieties, which have been tested both in vitro and in vivo. We studied the interaction of nanoparticles with blood plasma and selected blood plasma proteins by electron paramagnetic resonance (EPR), isothermal titration calorimetry, dynamic light scattering, and cryo-transmission electron microscopy. The copolymers were labeled with TEMPO radicals at the end of hydrophobic PCL or along the hydrophilic HPMA chains to monitor changes in polymer chain dynamics caused by protein adsorption. By EPR and other methods, we were able to probe specific interactions between nanoparticles and blood proteins, specifically low- and high-density lipoproteins, immunoglobulin G, human serum albumin (HSA), and human plasma. It was found that individual proteins and plasma have very low binding affinity to nanoparticles. We observed no hard corona around HPMA-based nanoparticles; with the exception of HSA the proteins showed no detectable binding to the nanoparticles. Our study confirms that a classical "hard corona-soft corona" paradigm is not valid for all types of nanoparticles and each system has a unique protein corona that is determined by the nature of the NP material.

Polymer-Drug Nanoparticles Combine Doxorubicin Carrier and Heparin Bioactivity Functionalities for Primary and Metastatic Cancer Treatment.

Here, a biocompatible amphiphilic copolymer of low molecular weight heparin (LMWH) and doxorubicin (DOX) connected by an acid-sensitive hydrazone bond for enhanced tumor treatment efficacy and safety has been designed and tested. The conjugate combines DOX delivery with LMWH antimetastatic capabilities. After the nanoparticles reach the tumor site, the acidic tumor microenvironment triggers the breakage of the hydrazone bond releasing DOX from the nanoparticles, which results in an increase in the cellular uptake and enhanced in vivo antitumor efficacy. A 3.4-fold and 1.5-fold increase in tumor growth inhibition were observed compared to the saline-treated control group and free DOX treated group, respectively. The LMWH-based nanoparticles effectively inhibited interactions between tumor cells and platelets mediated by P-selectin reducing metastasis of cells in both in vitro and in vivo models. The improved safety and therapeutic effect of LMWW-DOX nanoparticles offers new potential for tumor therapy.

Biocompatible Stimuli-Responsive W/O/W Multiple Emulsions Prepared by One-Step Mixing with a Single Diblock Copolymer Emulsifier

Multiple water-in-oil-in-water (W/O/W) emulsions are promising materials in designing carriers of hydrophilic molecules or drug delivery systems, provided stability issues are solved and biocompatible chemicals can be used. In this work, we designed a biocompatible amphiphilic copolymer, poly(dimethylsiloxane)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMS-b-PDMAEMA), that can stabilize emulsions made with various biocompatible oils. The hydrophilic/hydrophobic properties of the copolymer can be adjusted using both pH and ionic strength stimuli. Consequently, the making of O/W (oil in water), W/O (water in oil), and W/O/W emulsions can be achieved by sweeping the pH and ionic strength. Of importance, W/O/W emulsions are formulated over a large pH and ionic strength domain in a one-step emulsification process via transitional phase inversion and are stable for several months. Cryo-TEM and interfacial tension studies show that the formation of these W/O/W emulsions is likely to be correlated to the interfacial film curvature and microemulsion morphology.

Studies on the synthesis, characterization and self-assembly of biocompatible amphiphilic copolymers of poly[2-(methacryloyloxy)ethylphosphorylcholine] modified poly(ε-caprolactone)

Studies on the synthesis, characterization and self-assembly of biocompatible amphiphilic copolymers of poly[2-(methacryloyloxy)ethylphosphorylcholine] modified poly(ε-caprolactone)

Light-Induced Functionalization of Amphiphilic Block Copolymers: Application to Nanoparticles for Drug Targeting

Photografting of bifunctional photolinker on biocompatible amphiphilic copolymers, such as PCL-b-PEGs and PLGA-b-PEGs, has been developed as a practical and versatile strategy for the materials functionalisation. Depending on the copolymer nature (block length, % of crystallinity) and the experimental conditions we could selectively direct the grafting on the hydrophilic PEG segments. The resulting copolymers were further derivatized with molecules of interest (RGD-peptides, LDV-peptides, “home-made”peptidomimetics, mannose derivatives,…) by substitution of the O-succinimidyl ester of the photolinker. The derivatization rates were controlled by radiolabelling, colorimetric assay and XPS spectroscopy. The functionalized copolymers were used in the formulation of nanoparticles displaying the ligands on their outer-shell. This nanoparticulate system was successfully employed for the oral vectorisation of antigen and for the targeted delivery of an anticancer drug.

Stability and release performance of a series of pegylated copolymeric micelles.

The aim of this work is to evaluate the capability of a series of biocompatible amphiphilic copolymers as a nano-sized drug carrier. The influences of the type of lactone monomer, the feed molar ratios of lactone/PEG, and the molecular weight of PEG on the performance and release behavior of micelles are investigated. These pegylated amphiphilic copolymers efficiently form micelles with a low CMC value in the range of 10(6)-10(-7) M. The average particle size of micelles is approximately 100 nm. The phenomenon of increasing particle size as increasing the chain length of poly(lactone) block is observed. The different hydrophobicity, based on chemical structure of poly(lactone), accounts for different interaction strength between indomethacin and hydrophobic inner core, which further influences the drug loading in copolymeric micelles and their release character. In addition, the PCL/PEG/PCL micellar solutions maintain their sizes at 4 degrees C for 8 weeks without occurring significant aggregation or dissociation. A series of biocompatible pegylated amphiphilic copolymers have been elucidated possessing micellization potential to form nano-sized micelles in an aqueous environment, which enable incorporate hydrophobic drug and regulate drug release.