Comparison of PLLA-PEG and PDLLA-PEG micelles for co-encapsulation of docetaxel and resveratrol.

The interest in combining chemosensitizers with cytostatics in cancer therapy is growing, which causes also a need to develop their delivery systems. Example of the combination with beneficial therapeutic effects is docetaxel (Dtx) and resveratrol (Res). Although poly(lactide)-co-poly(ethylene glycol) (PLA-PEG) micelles have been considered as one of the most promising platforms for drug delivery, their properties may depend on the stereoisomeric form of hydrophobic block. Therefore, the aim of this study was evaluation of the effect of PLA block on co-encapsulation and release rate of Dtx and Res, which has not been studied so far. This article presents a comparison of single- (Dtx or Res) and dual-drug (Dtx and Res) loaded micelles obtained from poly(l,l-lactide)-co-poly(ethylene glycol) (PLLA-PEG) and poly(d,l-lactide)-co-poly(ethylene glycol) (PDLLA-PEG). The analyzes of the micelles have been conducted including morphology, drug(s) encapsulation efficiency, intermolecular interactions, in vitro drug release, and cytotoxicity. Differences in drug loading ability and release profile have been observed between Res and Dtx but also depending on the polymer and number of drugs in micelles (single vs. dual loaded). The PLLA-PEG micelles have a significantly higher Dtx encapsulation capacity than PDLLA-PEG micelles. The highest cytotoxicity was shown for Dtx and Res dual-loaded micelles, regardless of the polymer. The findings may be used for selection of PLA-based drug delivery systems containing Dtx and Res.

Bioresorbable Nonwoven Patches as Taxane Delivery Systems for Prostate Cancer Treatment.

Prostate cancer is the second most common cancer in males. In the case of locally advanced prostate cancer radical prostatectomy is one of the first-line therapy. However, recurrence after resection of the tumor can appear. Drug-eluting bioresorbable implants acting locally in the area of the tumor or the resection margins, that reduce the risk of recurrence would be advantageous. Electrospinning offers many benefits in terms of local delivery so fiber-forming polyesters and polyestercarbonates which are suitable to be drug-loaded were used in the study to obtain CTX or DTX-loaded electrospun patches for local delivery. After a fast verification step, patches based on the blend of poly(glycolide-ε-caprolactone) and poly(lactide-glycolide) as well as patches obtained with poly(lactide-glycolide- ε-caprolactone) were chosen for long-term study. After three months, 60% of the drug was released from (PGCL/PLGA) + CTX and it was selected for final, anticancer activity analysis with the use of PC-3 and DU145 cells to establish its therapeutic potential. CTX-loaded patches reduced cell growth to 53% and 31% respectively, as compared to drug-free patches. Extracts from drug-free patches showed excellent biocompatibility with the PC-3 cell line. Cabazitaxel-loaded bioresorbable patches are a promising drug delivery system for prostate cancer therapy.

Controlled Release of Encapsuled Stromal-Derived Factor 1α Improves Bone Marrow Mesenchymal Stromal Cells Migration.

Stem cell treatment is a promising method of therapy for the group of patients whose conventional options for treatment have been limited or rejected. Stem cells have the potential to repair, replace, restore and regenerate cells. Moreover, their proliferation level is high. Owing to these features, they can be used in the treatment of numerous diseases, such as cancer, lung diseases or ischemic heart diseases. In recent years, stem cell therapy has greatly developed, shedding light on stromal-derived factor 1α (SDF-1α). SDF-1α is a mobilizing chemokine for application of endogenous stem cells to injury sites. Unfortunately, SDF-1α presented short-term results in stem cell treatment trials. Considering the tremendous benefits of this therapy, we developed biodegradable polymeric microspheres for the release of SDF-1α in a controlled and long-lasting manner. The microspheres were designed from poly(L-lactide/glycolide/trimethylene carbonate) (PLA/GA/TMC). The effect of controlled release of SDF-1α from microspheres was investigated on the migration level of bone marrow Mesenchymal Stromal Cells (bmMSCs) derived from a pig. The study showed that SDF-1α, released from the microspheres, is more efficient at attracting bmMSCs than SDF-1α alone. This may enable the controlled delivery of selected and labeled MSCs to the destination in the future.

Comparison of PLA-Based Micelles and Microspheres as Carriers of Epothilone B and Rapamycin. The Effect of Delivery System and Polymer Composition on Drug Release and Cytotoxicity against MDA-MB-231 Breast Cancer Cells.

Co-delivery of epothilone B (EpoB) and rapamycin (Rap) increases cytotoxicity against various kinds of cancers. However, the current challenge is to develop a drug delivery system (DDS) for the simultaneous delivery and release of these two drugs. Additionally, it is important to understand the release mechanism, as well as the factors that affect drug release, in order to tailor this process. The aim of this study was to analyze PLA-PEG micelles along with several types of microspheres obtained from PLA or a mixture of PLA and PLA-PEG as carriers of EpoB and Rap for their drug release properties and cytotoxicity against breast cancer cells. The study showed that the release process of EpoB and Rap from a PLA-based injectable delivery systems depends on the type of DDS, morphology, and polymeric composition (PLA to PLA-PEG ratio). These factors also affect the biological activity of the DDS, because the cytotoxic effect of the drugs against MDA-MB-231 cells depends on the release rate. The release process from all kinds of DDS was well-characterized by the Peppas-Sahlin model and was mainly controlled by Fickian diffusion. The conducted analysis allowed also for the selection of PLA 50/PLA-PEG 50 microspheres and PLA-PEG micelles as a promising co-delivery system of EpoB and Rap.

Electrospun paclitaxel delivery system based on PGCL/PLGA in local therapy combined with brachytherapy.

The local administration of different drugs in anticancer therapy continue to attract attention. Thus, the idea of local delivery of cytostatics from nonwoven-structured polyesters seems to be highly desirable. It could reduce systemic drug levels and provide high local concentration of the chemotherapeutics at the tumor site and contribute to enhance the efficiency of the anticancer therapy. Poly(glycolide-ɛ-caprolactone) (PGCL) and poly(D,L-lactide-co-glycolide) (PLGA) synthesized with zirconium-based initiator have been used to prepare electrospun, drug-eluting patches since they possess very good fiber-forming ability. Well-known chemotherapeutic drug-paclitaxel has been loaded into fibrous structure as a model anticancer agent in order to obtain drug delivery systems for local administration. The drug dose in obtained nonwovens might be regulated by the thickness and total area of the implanted patches. Electrospinning of PGCL/PLGA blend allowed to obtain soft and flexible implantable materials. Flexibility has been important factor since it ensures convenient use when covering a tumor or filling a resection cavity. The effectiveness of designed nonwovens presented in the study has been tested in vivo on mouse model of breast cancer. The growth of the tumors was slowed down during in vivo study in comparison with drug-free nonwovens- The volume of the tumor was 40% lower. Drug-loaded electrospun systems implanted locally to the tumor site was further combined with brachytherapy which improved the effectiveness of the therapy in about 18%. Detailed analysis of the nonwovens before and during degradation process has been performed by means of Scanning Electron Microscopy, Differential Scanning Calorimetry, Nuclear Magnetic Resonance, Gel Permeation Chromatography, X-ray Diffraction. The molar mass changes of the nonwoven were quite rapid contrary to changes of comonomer unit content, thermal properties and morphology of the fiber.

Single- versus Dual-Targeted Nanoparticles with Folic Acid and Biotin for Anticancer Drug Delivery.

Cancer is one of the major causes of death worldwide and its treatment remains very challenging. The effectiveness of cancer therapy significantly depends upon tumour-specific delivery of the drug. Nanoparticle drug delivery systems have been developed to avoid the side effects of the conventional chemotherapy. However, according to the most recent recommendations, future nanomedicine should be focused mainly on active targeting of nanocarriers based on ligand-receptor recognition, which may show better efficacy than passive targeting in human cancer therapy. Nevertheless, the efficacy of single-ligand nanomedicines is still limited due to the complexity of the tumour microenvironment. Thus, the NPs are improved toward an additional functionality, e.g., pH-sensitivity (advanced single-targeted NPs). Moreover, dual-targeted nanoparticles which contain two different types of targeting agents on the same drug delivery system are developed. The advanced single-targeted NPs and dual-targeted nanocarriers present superior properties related to cell selectivity, cellular uptake and cytotoxicity toward cancer cells than conventional drug, non-targeted systems and single-targeted systems without additional functionality. Folic acid and biotin are used as targeting ligands for cancer chemotherapy, since they are available, inexpensive, nontoxic, nonimmunogenic and easy to modify. These ligands are used in both, single- and dual-targeted systems although the latter are still a novel approach. This review presents the recent achievements in the development of single- or dual-targeted nanoparticles for anticancer drug delivery.

Cytotoxic effect of targeted biodegradable epothilone B and rapamycin co-loaded nanocarriers on breast cancer cells.

The new therapeutic solutions for breast cancer treatment are needed, for example, combined therapy consisted of several drugs that characterize different mechanisms of action and modern drug delivery systems. Therefore, we used combination of epothilone B (EpoB) and rapamycin (Rap) to analyze the cytotoxic effect against breast cancer cells (MCF-7; MDA-MB-231). Also, the effect of drugs co-delivered in bioresorbable micelles functionalized with biotin (PLA-PEG-BIO; poly(lactide)-co-poly(ethylene glycol)-biotin) was studied. The comparison of effects of the mixture of free drugs and the micelles co-loaded with EpoB and Rap revealed a significant decrease in the cell metabolic activity and survival. Moreover, the dual drug-loaded PLA-PEG-BIO micelles enhanced the cytotoxicity of EpoB and Rap against the tested cells as compared with the free drugs. The blank PLA-PEG-BIO micelles did not affect the tested cells. We expect that mixture of EpoB and Rap may be promising in breast cancer treatment and PLA-PEG-BIO micelles as carrier of these two drugs can be applicable for successful targeted delivery.

Bioresorbable, electrospun nonwoven for delayed and prolonged release of temozolomide and nimorazole.

Glioblastoma multiforme is the most aggressive and lethal form of brain tumour due to the high degree of cancer cells infiltration into surrounding brain tissue. No form of monotherapy can guarantee satisfactory patient outcomes and is only of palliative importance. To find a potential option of glioblastoma treatment the bioresorbable, layer nonwoven mats for controlled temozolomide and nimorazole release were obtained by classical and coaxial electrospinning. Optimization of fibre structure that enables delayed and controlled drug release was performed. The studied bioresorbable polymers were poly(L-lactide-co-ε-caprolactone) and poly(L-lactide-co-glycolide-co-trimethylene carbonate). The physicochemical properties of polymers were determined as well as drug release profiles of nonwoven mats. A combination of coaxial electrospinning and electrospray technique provided three-phased release profiles of temozolomide and nimorazole: the slow release of very low drug doses followed by accelerated release and saturation phase. Results form the basis for further investigation since both studied polymers possess a great potential as nimorazole and temozolomide delivery systems in the form of layered nonwoven implants.

Cytotoxic Effect of Paclitaxel and Lapatinib Co-Delivered in Polylactide-co-Poly(ethylene glycol) Micelles on HER-2-Negative Breast Cancer Cells.

To find better strategies to enhance the cytotoxic effect of paclitaxel (PTX) and lapatinib (LAP) against breast cancer cells, we analyzed the efficacy of a novel delivery system containing polylactide-co-poly(ethylene glycol) (PLA-PEG) filomicelles of over 100 nm in length and spherical micelles of approximately 20 nm in diameter. The ¹H NMR measurements confirmed the incorporation of PTX and LAP into micelles. Analysis of the drug release mechanism revealed the diffusion-controlled release of LAP and anomalous transport of PTX. Drug content analysis in lyophilized micelles and micellar solution showed their good storage stability for at least 6 weeks. Blank micelles, LAP-loaded micelles and free LAP did not affect MCF-7 breast cancer cell proliferation, suggesting that the cytotoxicity of PTX-, PTX/LAP-loaded micelles, and the binary mixture of free PTX and LAP was solely caused by PTX. PTX/LAP-loaded micelles showed greater toxicity compared to the binary mixture of PTX and LAP after 48 h and 72 h. Only free PTX alone induced P-gp activity. This study showed the feasibility of using a LAP and PTX combination to overcome MDR in MCF-7 cells, particularly when co-loaded into micelles. We suggest that PTX/LAP micelles can be applicable not only for the therapy of HER-2-positive, but also HER-2-negative breast cancers.

Multidrug PLA-PEG filomicelles for concurrent delivery of anticancer drugs-The influence of drug-drug and drug-polymer interactions on drug loading and release properties.

This study aimed to analyze the influence of drug-drug and drug-polymer interactions on drug loading and release properties of multidrug micelles. Three hydrophobic drugs-paclitaxel (Ptx), 17-AAG and rapamycin (Rap) were incorporated in poly(l-lactide)-poly(ethylene glycol) (PLA-PEG) filomicelles. Double loaded micelles containing Ptx and 17-AAG were used for the sake of comparison. (1)H NMR confirmed the effective incorporation of the various drugs in micelles, and HPLC allowed to determine the drug loading contents. FTIR was used to evaluate interactions between particular drugs and between drugs and copolymer. Ptx and 17-AAG present similar loading efficiencies in double loaded micelles probably due to interactions of drugs with each other and also with the copolymer. In contrast, unequal drug loading properties are observed for triple loaded micelles. Rapamycin shows very weak interactions with the copolymer, and displays the lowest loading efficiency. In vitro release of drugs from micelles was realized in pH 7.4 phosphate buffered saline at 37°C, and monitored by HPLC. Similar release profiles are observed for the three drugs: a strong burst followed by slower release. Nevertheless, Ptx release from micelles is significantly slower as compared to 17-AAG and Rap, probably due to interactions of NH and OH groups of Ptx with the carbonyl group of PLA. In vitro cytotoxicity of Ptx/17-AAG/Rap loaded micelles and a mixture of free drugs was determined. Drug loaded micelles exhibit advantageous effect of prolonged drug release and cytotoxic activity against Caco-2 cells, which makes them a promising solution for simultaneous drug delivery to solid tumors. Therefore, understanding of interactions within multidrug micelles should be a valuable approach for the development of concurrent delivery systems of anticancer drugs with tailored properties.

Bioresorbable copolymer of L-lactide and ε-caprolactone for controlled paclitaxel delivery.

Bioresorbable, aliphatic polyesters are known in medicine where serve as orthopedic devices (e.g., rods, pins and screws) or sutures and staples in wound closure. Moreover, such materials are extensively stud- ied as scaffolds--three-dimensional structures for tissue engineering but also drug delivery systems (DDS). The aim of this study was to determine the release profile of paclitaxel, one of the anti-inflammatory, antiprolifera- tive and anti-restenotic agent, from biocompatible copolymer of L-lactide and ε-caprolactone that seems to be very attractive especially for minimally invasive surgery due to its potential shape-memory property. The influ- ence of drug on copolymer hydrolytic degradation was also analyzed. Three types of matrices (3%, 5% of PTX and without drug) were prepared by solvent-casting method and degraded in vitro. The physicochemical changes of copolymer were analyzed by means of nuclear magnetic resonance spectroscopy (NMR), gel per- meation chromatography (GPC) and differential scanning calorimetry (DSC). The amount of drug released into media was monitored with the use of high-pressure liquid chromatography (HPLC). Similar drug release pro- files were obtained for matrices with paclitaxel. The drug-containing matrices degraded slightly slower than drug free matrices, regardless PTX content. Results of this work may be helpful in designing new bioresorbable paclitaxel delivery system applied in anti-cancer therapy or drug-eluting stents technology.

The influence of paclitaxel on hydrolytic degradation in matrices obtained from aliphatic polyesters and polyester carbonates.

Biodegradable polymers have become common materials used in pharmacy and medicine due to their properties such as mechanical strength, biocompatibility and non-toxic degradation products. Different compositions of copolymers and also their chain microstructure may have an effect on matrices degradation and thus on the drug release profile. In our study, we aimed at the influence of paclitaxel content on hydrolytic degradation process of terpolymeric matrices. Hydrolytic degradation of three kinds of matrices (with 5 or 10% of paclitaxel and drug free matrices) prepared from three types of terpolymers was performed in vitro at 37 degrees C in phosphate buffer solution (PBS, pH 7,4). The 1H and 13C NMR spectra of terpolymers were recorded. Thermal properties were monitored by differential scanning calorimetry (DSC). Molecular weight dispersity (D) and molecular weight were determined using gel permeation chromatography (GPC). The surface morphology was studied by means of the scanning electron microscopy (SEM). The most significant degradation was observed in case of poly(L-lactide-co-glycolide-co-epsilon-caprolactone) 44:32:24. Weight loss and water uptake were similar in the event of the same type of matrices obtained from the two poly(L-lactide-co-glycolide-co-TMC). Decelerated paclitaxel release in case of matrices with 51:26:23 molar ratio was noticed and it can be connected with higher content of carbonate units. Knowledge of paclitaxel influence on hydrolytic degradation process may contribute to receive valuable information about its release mechanisms from biodegradable terpolymers.