Synthesis of cleavable multi-functional mikto-arm star polymer by RAFT polymerization: example of an anti-cancer drug 7-ethyl-10-hydroxycamptothecin (SN-38) as functional moiety

Multi-functional mikto-arm star polymers containing three different arms [hydrophilic, SN-38-P(OEGMA_8–9)₁₁, cationizable, SN-38-P(DMAEMA)₃₈ and hydrophobic, SN-38-P(BMA)₂₆] were prepared by RAFT polymerization via an arm-first approach using a cleavable cross-linker. The star polymers were cleaved to the linear arms with tributylphosphine as a reducing agent. The decrease in molecular weight observed is consistent with the initial stars having approximately five arms. Blue fluorescence was observed when a solution of mikto-arm star was irradiated under a 365 nm light proving the retention of the SN-38 moiety during star formation by RAFT polymerization. Thus these polymer-drug conjugates can be considered as potential delivery vehicles for cancer therapy. The P(DMAEMA) arms can be quaternized using iodomethane, allowing star polymers to bind negatively charged small interfering RNA (siRNA) and potentially be used as a carrier for that material.     

Mechanism and kinetics of dithiobenzoate‐mediated RAFT polymerization. I. The current situation

Investigations into the kinetics and mechanism of dithiobenzoate‐mediated Reversible Addition–Fragmentation Chain Transfer (RAFT) polymerizations, which exhibit nonideal kinetic behavior, such as induction periods and rate retardation, are comprehensively reviewed. The appreciable uncertainty in the rate coefficients associated with the RAFT equilibrium is discussed and methods for obtaining RAFT‐specific rate coefficients are detailed. In addition, mechanistic studies are presented, which target the elucidation of the fundamental cause of rate retarding effects. The experimental and theoretical data existing in the literature are critically evaluated and apparent discrepancies between the results of different studies into the kinetics of RAFT polymerizations are discussed. Finally, recommendations for further work are given. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5809–5831, 2006     

Consistent values of rate parameters in free radical polymerization systems. II. Outstanding dilemmas and recommendations

The problems of determining reliable, well-characterized values of kinetic parameters in free-radical polymerizations are discussed. The origins of the fact that experimental determinations of rate coefficients of ostensibly identical systems often result in quite different values being reported can be ascribed to subtle mechanistic assumptions made in data interpretation, which are considered in detail. A series of recommendations to assist in overcoming these problems, and to highlight their origins, are presented, with emphasis placed on new techniques including those employing laser photolysis and EPR.     

Experimental confirmation of the importance of orientation in the anomalous chiral sensitivity of second harmonic generation

Macromolecular interactions were demonstrated to yield large chiroptical effects in second harmonic generation measurements of ultrathin surface films. Second harmonic generation (SHG) has recently shown to be several orders of magnitude more sensitive to chirality in oriented systems than common linear methods, including absorbance circular dichroism (CD) and optical rotary dispersion (ORD). Numerous mechanisms have been developed to explain this anomalous sensitivity, with a general emphasis on understanding the molecular origins of the chromophore chirality. In this work, orientational effects alone are shown to be the dominant factor for generating large SHG chiral dichroic ratios in many surface systems. Three distinct uniaxial surface films of SHG-active achiral chromophores oriented at chiral templated surfaces were observed to yield chiral dichroic ratios as great as 40% in magnitude.     

Developments in the synthesis of maleated polyolefins by reactive extrusion

The maleation of conventional and metallocene linear low density polyethylenes by reactive extrusion has been explored with a view to defining the conditions necessary for a robust process that provides both high grafting efficiencies (>80%) and minimal degradation or cross-linking. The dependence of grafting efficiency on various operating parameters (maleic anhydride level, maleic anhydride:initiator ratio, throughput rate, direction of screw rotation, temperature) has been established. Literature methods for characterization of the grafted product based on FTIR or ¹H NMR analysis have been critically examined with respect to their ability to distinguish between single unit and oligomeric maleic anhydride grafts and found to yield ambiguous results.     

Evaluation of propagation rate constants for the free radical polymerization of methacrylonitrile by pulsed laser photolysis

Propagation rate constants for the free radical polymerization of methacrylonitrile (MAN) have been obtained by pulsed laser photolysis (PLP). The temperature dependence of the propagation rate constants indicates a frequency factor of 10^{(6,43 ± 0,26)} L · mol⁻¹ · s⁻¹ and an activation energy of 29,7 ± 1,5 kJ · mol⁻¹. These parameters suggest that the relatively slow rate of propagation in MAN polymerization in relation to other common monomers (methyl methacrylate, styrene) can be attributed to the relative steric bulk and stability of the propagation species.     

A Critical Survey of Dithiocarbamate Reversible Addition‐Fragmentation Chain Transfer (RAFT) Agents in Radical Polymerization

This article provides a critical review of the properties, synthesis, and applications of dithiocarbamates Z′Z″NC(=S)SR as mediators in reversible addition‐fragmentation chain transfer (RAFT) polymerization. These are among the most versatile RAFT agents. Through choice of substituents on nitrogen (Z′, Z″), the polymerization of most monomer types can be controlled to provide living characteristics (i.e., low dispersities, high end‐group fidelity, and access to complex architectures). These include the more activated monomers (MAMs; e.g., styrenes and acrylates) and the less activated monomers (LAMs; e.g., vinyl esters and vinylamides). Dithiocarbamates with balanced activity (e.g., 1H‐pyrazole‐1‐carbodithioates) or switchable RAFT agents [e.g., a N‐methyl‐N‐(4‐pyridinyl)dithiocarbamate] allow control MAMs and LAMs with a single RAFT agent and provide a pathway to low‐dispersity poly(MAM)‐block‐poly(LAM). © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 216–227     

Exploitation of Compartmentalization in RAFT Miniemulsion Polymerization to Increase the Degree of Livingness

It is demonstrated that the degree of livingness (chain‐end fidelity) in RAFT polymerization for a given degree of polymerization can be markedly increased in miniemulsion polymerization relative to the corresponding homogeneous bulk system. Polymerization of styrene was conducted using a poly(methyl methacrylate) benzodithioate as macroRAFT agent in both miniemulsion and bulk. The substantially higher polymerization rate in miniemulsion, which is attributed to the segregation effect (compartmentalization) causing a reduction in the rate of bimolecular termination, makes it possible to reach a given degree of polymerization in a significantly shorter time than in the corresponding bulk system. As a consequence, fewer initiating radicals are required throughout the polymerization, leading to higher livingness in the more rapid miniemulsion system. It is demonstrated how this approach facilitates synthesis of high‐molecular‐weight block copolymers comprising slowly propagating monomers such as styrene and methacrylates. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1938–1946