Poly(HPMA)-based copolymers with biodegradable side chains able to self-assemble into nanoparticles

Poly(N-(2-Hydroxypropyl) methacrylamide) (poly(HPMA)) is gaining pharmaceutical attention in replacement to PEG as a hydrophilic stabilizer for polymer nanoparticles (NPs) devoted to systemic administration.[1] This is due to its biocompatibility, prolonged circulation time and, compared to PEG, to the avoidance of allergic reactions and of the accelerated blood clearance effect.[2, 3] In this work, a lipophilic HPMA-based macromonomer with a predetermined and controllable structure is synthesized for the first time attaching a short oligo(caprolactone) chain obtained via Ring Opening Polymerization (ROP) to the HPMA using a succinic acid unit as a spacer. This biodegradable monomer (hereinafter HPMA-CL) was then used to synthesize well-defined amphiphilic block copolymers comprising a hydrophilic poly(HPMA) block and a hydrophobic poly(HPMA-CL) segment via Reversible Addition-Fragmentation Transfer (RAFT) polymerization. The combination of ROP and RAFT allows the production of a library of polymers with a predetermined and controlled structure that are able to self-assemble in water into biodegradable NPs with different size. In particular, such NPs are designed to degrade in aqueous environment into completely water soluble poly(HPMA), with a molecular weight that is below the critical threshold for the renal excretion. This is a very important feature since it allows to avoid polymer accumulation into the body once the NPs are injected.[4] The degradation time is a function of the number of caprolactone units in the HPMA-CL macromonomer and of its degree of polymerization in the NP forming copolymer. Then, the polymer structure can be adjusted to obtain the desired degradation time. Finally, the possibility for such nanoparticles to physically incorporate and mediate the release of a lipophilic antineoplastic drug was evaluated in the case of Trabectedin. The formulation proved to be biocompatible and to sustainedly release the drug for up to 24 hours. Please click Additional Files below to see the full abstract

Influence of the polymer structure over self-assembly and thermo-responsive properties: The case of PEG-b-PCL grafted copolymers via a combination of RAFT and ROP

During the last years, the field of drug delivery has experienced a growing interest toward the so-called thermo-responsive polymers: synthetic materials that, due to the specific hydrophilic–lipophilic balance of their repeating units, exhibit a lower critical solution temperature (LCST) in water associated to a characteristic coil–globule transition. In this work, thermo-responsive amphiphilic block copolymers are synthesized via reversible addition-fragmentation transfer (RAFT) polymerization starting from thermo-responsive monomers and a hydrophobic biodegradable macromonomer, oligo(caprolactone)methacrylate (CL3MA), produced via ring opening polymerization (ROP). The obtained copolymers exhibit an interesting self-assembly behavior leading to nanoparticles (NPs) as long as temperature is kept below the LCST. Otherwise, once this value is overcome, the destabilization of the NPs causes the formation of hydrophobic superstructures that enhance the release of an entrapped lipophilic drug. This characteristic behavior has been systematically studied and related to the copolymer structure. In particular, the self-assembly behavior as well as temperature-triggered NP destabilization have been related to the relative length of the two blocks constituting the copolymers and to their hydrophilic–lipophilic balance (HLB). Finally, the efficacy of the thermo-responsive triggered drug release has been tested in the case of Paclitaxel (PTX). © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 2919–2931

Self-assembling amphiphilic block copolymer from renewable δ-decalactone and δ-dodecalactone

Aliphatic polyesters have many applications in the biomedical field due to their properties and facile degradation. They are commonly synthesized via ring opening polymerization (ROP) with metal-based catalysts, but as high temperatures are needed and the products contain metal, organocatalysts are now widely adopted to polymerize them at room temperature while also ensuring short reaction times. Here, 1,7,7-triazabicyclo[4.4.0]-dec-5-ene is used to polymerize less reactive but renewably-derived lactones, namely δ-decalactone and δ-dodecalactone. These monomers were chosen in the attempt of creating renewable and highly lipophilic materials for drug delivery applications as alternatives to the more traditional, but non-renewable δ-valerolactone and ɛ-caprolactone. A combination of ROP and living radical polymerization Reversible Addition-Fragmentation Chain Transfer is proposed here to synthesize grafted block copolymers. They are able to self-assemble in water, forming micelles where the lipophilic polyester core is able to entrap a lipophilic drug, thus making the system a good candidate for drug delivery. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 3788–3797

Chemical Images on Fingerprints Revealed with Mass Spectrometry

Commercially available UV-adsorbent TiO2 nanoparticles were used to assist laser/desorption ionization in the course of matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). Titanium nano-powders proved extremely stable and efficient for small molecule ionization, with negligible background noise in the low mass region (m/z < 500 Da). Validation steps were carried out, assessing detection limits and comparing the results to those of the established DESI/Orbitrap technique. The new analytical method was used to reveal the molecular distribution of endogenous (lipids) and exogenous (analgesics and antipyretics) compounds in latent finger marks (LFMs). The detection limits of endogenous fatty acids and small molecules such as caffeine were in the range of fmol/mm2 on LFMs. The technique separated overlapping latent finger marks, exploiting the differences in lipid expression of human skin. Finally, the method was used to prove contact between skin and objects contaminated by different substances, such as credit cards and paper clips, with chemical images that maintain the shape of the objects on the LFM

Determination of Paclitaxel Distribution in Solid Tumors by Nano-Particle Assisted Laser Desorption Ionization Mass Spectrometry Imaging

<div><p>A sensitive, simple and reproducible protocol for nanoparticle-assisted laser desorption/ionization mass spectrometry imaging technique is described. The use of commercially available TiO₂ nanoparticles abolishes heterogeneous crystallization, matrix background interferences and enhances signal detection, especially in the low mass range. Molecular image normalization was based on internal standard deposition on tissues, allowing direct comparison of drug penetration and distribution between different organs and tissues. The method was applied to analyze the distribution of the anticancer drug paclitaxel, inside normal and neoplastic mouse tissue sections. Spatial resolution was good, with a linear response between different <i>in vivo</i> treatments and molecular imaging intensity using therapeutic drug doses. This technique distinguishes the different intensity of paclitaxel distribution in control organs of mice, such as liver and kidney, in relation to the dose. Animals treated with 30 mg/kg of paclitaxel had half of the concentration of those treated with 60 mg/kg. We investigated the spatial distribution of paclitaxel in human melanoma mouse xenografts, following different dosage schedules and found a more homogeneous drug distribution in tumors of mice given repeated doses (5×8 mg/kg) plus a 60 mg/kg dose than in those assigned only a single 60 mg/kg dose. The protocol can be readily applied to investigate anticancer drug distribution in neoplastic lesions and to develop strategies to optimize and enhance drug penetration through different tumor tissues.</p></div

PEGylated Nanoparticles Obtained through Emulsion Polymerization as Paclitaxel Carriers

Polymer nanoparticles (NPs) represent a promising way to deliver poorly water-soluble anticancer drugs without the use of unwanted excipients, whose presence can be the cause of severe side effects. In this work, a Cremophor-free formulation for paclitaxel (PTX) has been developed by employing PEGylated polymer nanoparticles (NPs) as drug delivery carriers based on modified poly(ε-caprolactone) macromonomers and synthesized through free radical emulsion polymerization. Paclitaxel was loaded in the NPs in a postsynthesis process which allowed to obtain a drug concentration suitable for in vivo use. In vivo experiments on drug biodistribution and therapeutic efficacy show comparable behavior between the NPs and the Cremophor formulation, also showing good tolerability of the new formulation proposed

Quantitative analysis by MSI.

<p><b>A)</b> MS ion image of PTX (side chain m/z 284.2 upper panel) in liver of a control mouse treated with vehicle and of mice treated with paclitaxel 30 mg/kg or 60 mg/kg, collected after 15 minutes. Lower panel: internal standard (ion m/z 289.2), spotted 5 pmol/mm² on tissue. <b>B)</b> PTX abundance estimated from normalized ion signal intensity correlates well with the administered dose. Error bars represent standard deviation (n = 3), p<1% (Student’s t test).</p