Polymer-based systems for controlled release and targeting of drugs

The current need to find new advanced approaches to carry biologically active substances (conventional organic drugs, peptides, proteins (such as antibodies), and nucleic acid-based drugs (NABDs such as siRNA and miRNA)) in the body fluids, to realize targeted therapies and even personalized ones, goes hand in hand with research on the performance of new materials to better realize appropriate drug vectors [...]

Inulin for Cancer Therapy: Present and Perspectives

Inulin is an extremely adaptable polysaccharides consisting of glucopyranose end-capped (\u3b2-1,2) fructose repeating units and, as it is, can be classified as an inherently multifunctional polymeric scaffold. It may be further functionalized employing mild conditions to give rise desired biological and physicochemical properties exploitable for targeted anticancer applications (e.g., active targeting toward specific cytotypes, self-assembling behavior, selective cytoxicity and hyperthermia features). In this review, the main chemical features and the inulin derivatives applications in the field of targeted anticancer therapy is reported and discusse

Photocrosslinkable polyaspartamide/polylactide copolymer and its porous scaffolds for chondrocytes

With the aim to produce, by a simple and reproducible technique, porous scaffolds potentially employable for tissue engineering purposes, in this work, we have synthesized a methacrylate (MA) copolymer of \u3b1,\u3b2-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) and polylactic acid (PLA). PHEA-PLA-MA has been dissolved in organic solvent at different concentrations in the presence of NaCl particles with different granulometry, and through UV irradiation and further salt leaching technique, various porous scaffolds have been prepared. Obtained samples have been characterized by scanning electron microscopy and their porosity has been evaluated as well as their degradation profile in aqueous medium in the absence or in the presence of esterase from porcine liver. PHEA-PLA-MA scaffold that has shown homogeneous porosity and the best degradation profile has been further characterized to study its mechanical properties along with its capacity to incorporate and to control the release of dexamethasone. Finally, the ability to allow a three-dimensional culture of bovine articular chondrocytes have been also investigate

Folic acid-functionalized graphene oxide nanosheets via plasma etching as a platform to combine NIR anticancer phototherapy and targeted drug delivery

PEGylated graphene oxide (GO) has shown potential as NIR converting agent to produce local heat useful in breast cancer therapy, since its suitable photothermal conversion, high stability in physiological fluids, biocompatibility and huge specific surface. GO is an appealing nanomaterial for potential clinical applications combining drug delivery and photothermal therapy in a single nano-device capable of specifically targeting breast cancer cells. However, native GO sheets have large dimensions (0.5-5 mu m) such that tumor accumulation after a systemic administration is usually precluded. Herein, we report a step-by-step synthesis of folic acid-functionalized PEGylated GO, henceforth named GO-PEG-Fol, with small size and narrow size distribution (similar to 30 +/- 5 nm), and the ability of efficiently converting NIR light into heat. GO-PEG-Fol consists of a nano-GO sheet, obtained by fragmentation of GO by means of non-equilibrium plasma etching, fully functionalized with folic acid-terminated PEG(2000) chains through amidic coupling and azide-alkyne click cycloaddition, which we showed as active targeting agents to selectively recognize breast cancer cells such as MCF7 and MDA-MB-231. The GO-PEG-Fol incorporated a high amount of doxorubicin hydrochloride (Doxo) (> 33%) and behaves as NIR-light-activated heater capable of triggering sudden Doxo delivery inside cancer cells and localized hyperthermia, thus provoking efficient breast cancer death. The cytotoxic effect was found to be selective for breast cancer cells, being the IC50 up to 12 times lower than that observed for healthy fibroblasts. This work established plasma etching as a cost-effective strategy to get functionalized nano-GO with a smart combination of properties such as small size, good photothermal efficiency and targeted cytotoxic effect, which make it a promising candidate as photothermal agent for the treatment of breast cancer

Inulin-iron complexes: A potential treatment of iron deficiency anaemia

The aim of this work was that to synthesize macromolecular derivatives based on inulin able to complex iron and useful in the treatment of iron deficiency anaemia. Carboxylated or thiolated/carboxylated inulin derivatives were obtained by single or double step reactions, respectively. The first one was obtained by reaction of inulin (INU) with succinic anhydride (SA) alone obtaining INU-SA derivative; the second one was obtained by the reaction of INU with succinic anhydride and subsequent reaction of INU-SA with cysteine; both derivatives were treated with ferric chloride in order to obtain the INU-SA-Fe-III and INU-SA-Cys-Fe-III complexes. Both complexes showed an excellent biodegradability in the presence of inulinase and pronounced mucoadhesion properties; in particular, thiolated derivative INU-SA-Cys showed greater mucoadhesive properties than polyacrylic acid chosen, as a positive reference polymer, and a good iron release profile in condition mimicking the intestinal tract. These results suggest the potential employment of such systems in the oral treatment of iron deficiency anaemia or as supplement of iron in foods. (c) 2007 Elsevier B.V. All rights reserved

New graft copolymers of hyaluronic acid and polylactic acid: Synthesis and characterization

New graft copolymers have been synthesized, using hyaluronic acid (HA) as a hydrophilic backbone and polylactic acid (PLA) as an aliphatic polyester in order to obtain new polymeric derivatives of HA able to hydrophobically associate in an aqueous medium. Hyaluronic acid with low molecular weight was made soluble in organic solvent by transformation to its tetrabutylammonium (TBA) salt. Using the HA-TBA derivative, the reaction was performed in dimethylsulfoxide adding as a reagent the N-hydroxysuccinimide derivative of PLA. Two HA-PLA graft copolymers have been synthesized and characterized by FT-IR, H-1 NMR spectroscopy and gel permeation chromatography. The interaction between these samples and an aqueous medium has been evaluated by rheological measurements. The obtained data evidenced that both HA-PLA graft copolymers show in aqueous medium a clear tendency for hydrophobic interaction dependent on the amount of PLA chains linked to the HA backbone. (c) 2006 Elsevier Ltd. All rights reserved

Peculiar Mechanism of Solubilization of a Sparingly Water Soluble Drug into Polymeric Micelles. Kinetic and Equilibrium Studies

Complementary kinetic and equilibrium studies on the solubilization process of the sparingly water soluble tamoxifen (TAM) drug in polymeric aqueous solutions have been performed by using the spectrophotometric method. In particular, the amphiphilic copolymers obtained by derivatization of polymeric chain of poly(N-2-hydroxyethyl)-DLaspartamide, PHEA, with poly(ethylene glycol)s, PEG (2000 or 5000 Da), and/or hexadecylamine chain, C16, namely PHEA-PEG2000-C16, PHEA-PEG5000-C16, PHEA-C16, have been employed. Preliminary to the kinetic and equilibrium data quantitative treatment, the molar absorption coefficient of TAM in polymeric micelle aqueous solution has been determined. By these studies the solubization sites of TAM into the polymeric micelles have been determined and the solubilization mechanism has been elucidated through a nonconventional approach by considering the TAM partitioned between three pseudophases, i.e., the aqueous pseudophase, the hydrophilic corona, and the hydrophobic core. The simultaneous solution of the rate laws associated with each step of the proposed mechanism allowed the calculation of the rate constants associated with the involved processes, the values of which are independent of both the copolymer concentration and nature, with the exception of the rate of the TAM transfer from the corona to the core. This has been attributed to the steric barrier, represented by the corona, which hampers the solubilization into the core. The binding constant values of the TAM to the hydrophilic corona of the polymeric micelles, calculated through the quantitative analysis of the equilibrium data, depend on the thickness of the hydrophilic headgroup, while those of the hydrophobic core are almost independent of the copolymer type. Further confirmation to the proposed solubilization mechanism has been provided by performing the kinetic and equilibrium measurements in the presence of PHEA-PEG2000 and PHEAPEG5000 copolymers

Carbon nanodots for on demand chemophotothermal therapy combination to elicit necroptosis: Overcoming apoptosis resistance in breast cancer cell lines

Background: Engineered luminescent carbon nanodots (CDs) are appealing nanomaterials for cancer image-guided photothermal therapy combining near infrared (NIR)–triggered hyperthermia, imaging, and drug delivery in a single platform for efficient killing of cancer cells. This approach would allow eliciting synergistic regulated cell death (RCD) routes such as necroptosis, targeting breast cancer cells refractory to apoptosis, thus overcoming drug resistance. Methods: We report the preparation of CDs bearing biotin as a targeting agent (CDs-PEG-BT), which are able to load high amounts of irinotecan (23.7%) to be released in a pulsed on-demand fashion. CDs-PEG-BT have narrow size distribution, stable red luminescence, and high photothermal conversion in the NIR region, allowing imaging of MDA-MB231 and MCF-7 cancer cells and killing them by photothermal and chemotherapeutic insults. Results: Cellular uptake, viability profiles, and RCD gene expression analyses provided insights about the observed biocompatibility of CDs-PEG-BT, indicating that necroptosis can be induced on-demand after the photothermal activation. Besides, photothermal activation of drug-loaded CDs-PEG-BT implies both necroptosis and apoptosis by the TNFα and RIPK1 pathway. Conclusions: The controlled activation of necroptosis and apoptosis by combining phototherapy and on-demand release of irinotecan is the hallmark of efficient anticancer response in refractory breast cancer cell lines in view of precision medicine applications

Rapamycin-loaded polymeric nanoparticles as an advanced formulation for macrophage targeting in atherosclerosis

Recently, rapamycin (Rapa) represents a potential drug treatment to induce regression of atherosclerotic plaques; however, its use requires site-specific accumulation in the vessels involved in the formation of the plaques to avoid the systemic effects resulting from its indiscriminate biodistribution. In this work, a stable pharmaceutical formulation for Rapa was realized as a dried powder to be dispersed extemporaneously before administration. The latter was constituted by man-nitol (Man) as an excipient and a Rapa-loaded polymeric nanoparticle carrier. These nanoparticles were obtained by nanoprecipitation and using as a starting polymeric material a polycaprolactone (PCL)/α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) graft copolymer. To obtain nanoparti-cles targeted to macrophages, an oxidized phospholipid with a high affinity for the CD36 receptor of macrophages, the 1-(palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdia-PC), was added to the starting organic phase. The chemical–physical and technological characterization of the obtained nanoparticles demonstrated that: both the drug loading (DL%) and the entrapment efficiency (EE%) entrapped drug are high; the entrapped drug is in the amorphous state, protected from degradation and slowly released from the polymeric matrix; and the KOdia-PC is on the nanoparticle surface (KP-Nano). The biological characterization demonstrated that both systems are quickly internalized by macrophages while maintaining the activity of the drug. In vitro studies demonstrated that the effect of KP-Nano Rapa-loaded, in reducing the amount of the Phospo-Ser757-ULK1 protein through the inhibition of the mammalian target of rapamycin (mTOR), is comparable to that of the free drug

Mucoadhesive solid lipid microparticles for controlled release of a corticosteroid in the chronic obstructive pulmonary disease treatment.

AIM: Therapeutic efficacy of pulmonary diseases is often limited and drug delivery systems offer new solutions to clinical problems. Solid lipid microparticles (SLMs) are suggested as systems for the delivery of therapeutics to the lung as, because of their size, they are able to deposit into secondary bronchi. MATERIALS & METHODS: Here, we describe two novel different SLMs using chitosan and alginate such as mucoadhesive polymers and we also studied their biocompatibility and their effectiveness compared with the free drug in controlling senescence and inflammatory processes in cigarette smoke extracts. RESULTS: Data reported show that fluticasone propionate (FP)-loaded SLMs are more effective than FP alone in controlling oxidative stress. CONCLUSION: The therapeutic approach using FP-loaded microparticles could be a promising strategy for the treatment of the chronic inflammatory pulmonary diseases