Amino Acid Polymerization on Silica Surfaces.

The polymerization of unactivated amino acids (AAs) is an important topic because of its applications in various fields including industrial medicinal chemistry and prebiotic chemistry. Silica as a promoter for this reaction, is of great interest owing to its large abundance and low cost. The amide/peptide bond synthesis on silica has been largely demonstrated but suffers from a lack of knowledge regarding its reaction mechanism, the key parameters, and surface features that influence AA adsorption and reactivity, the selectivity of the reaction product, the role of water in the reaction, etc. The present review addresses these problems by summarizing experimental and modeling results from the literature and attempts to rationalize some apparent divergences in published results. After briefly presenting the main types of silica surface sites and other relevant macroscopic features, we discuss the different deposition procedures of AAs, whose importance is often neglected. We address the possible AA adsorption mechanisms including covalent grafting and H-bonding and show that they are highly dependent on silanol types and density. We then consider how the adsorption mechanisms determine the occurrence and outcome of AA condensation (formation of cyclic dimers or of long linear chains), and outline some recent results that suggest significant polymerization selectivity in systems containing several AAs, as well as the formation of specific elements of secondary structure in the growing polypeptide chains.

Elucidating the reaction mechanism of SO2 with Cu-CHA catalysts for NH3-SCR by X-ray absorption spectroscopy.

The application of Cu-CHA catalysts for the selective catalytic reduction of NOx by ammonia (NH3-SCR) in exhaust systems of diesel vehicles requires the use of fuel with low sulfur content, because the Cu-CHA catalysts are poisoned by higher concentrations of SO2. Understanding the mechanism of the interaction between the Cu-CHA catalyst and SO2 is crucial for elucidating the SO2 poisoning and development of efficient catalysts for SCR reactions. Earlier we have shown that SO2 reacts with the [Cu2II(NH3)4O2]2+ complex that is formed in the pores of Cu-CHA upon activation of O2 in the NH3-SCR cycle. In order to determine the products of this reaction, we use X-ray absorption spectroscopy (XAS) at the Cu K-edge and S K-edge, and X-ray emission spectroscopy (XES) for Cu-CHA catalysts with 0.8 wt% Cu and 3.2 wt% Cu loadings. We find that the mechanism for SO2 uptake is similar for catalysts with low and high Cu content. We show that the SO2 uptake proceeds via an oxidation of SO2 by the [Cu2II(NH3)4O2]2+ complex, resulting in the formation of different CuI species, which do not react with SO2, and a sulfated CuII complex that is accumulated in the pores of the zeolite. The increase of the SO2 uptake upon addition of oxygen to the SO2-containing feed, evidenced by X-ray adsorbate quantification (XAQ) and temperature-programmed desorption of SO2, is explained by the re-oxidation of the CuI species into the [Cu2II(NH3)4O2]2+ complexes, which makes them available for reaction with SO2.

Cyclic or Linear? Parameters Determining the Outcome of Glycine Polymerization in Silica Surface Prebiotic Scenarios.

The parameters that determine the formation of linear peptides and cyclic dimers (diketopiperazine, DKP) on silica surfaces of different surface area, silanol and siloxane ring populations, controlled by thermal treatments, are investigated upon glycine deposition from gas and liquid phases. The formed products were characterized by infrared and Raman spectroscopies, X-ray diffraction and thermogravimetric analysis. The results reveal the importance of "nearly-free" silanols to form ester centers as primers for the formation of linear peptides over DKP, on surfaces with medium silanol density (1.4 to 2.7 nm-2 ). Quenched reactivity is seen on isolated silanols (density≤0.7 nm-2 ), while silanols involved in hydrogen bonding (density of 4.5 nm-2 ) weakly interact with Gly resulting in its cyclization to DKP. Deposition of glycine from liquid phase may also form both DKP and linear polymers, depending on its loading and silica surface. These conclusions demonstrate the complexity of glycine surface chemistry in the polymerization reaction and highlight the interest of a surface science approach to evaluate geochemical prebiotic scenarios.

Polypeptide Chain Growth Mechanisms and Secondary Structure Formation in Glycine Gas-Phase Deposition on Silica Surfaces.

Peptide formation by amino acids condensation represents a crucial reaction in the quest of the origins of life as well as in synthetic chemistry. However, it is still poorly understood in terms of efficiency and reaction mechanism. In the present work, peptide formation has been investigated through thermal condensation of gas-phase glycine in fluctuating silica environments as a model of prebiotic environments. In-situ IR spectroscopy measurements under a controlled atmosphere reveal that a humidity fluctuating system subjected to both temperature and water activity variations results in the formation of more abundant peptides compared to a dehydrated system subjected only to temperature fluctuations cycles. A model is proposed in which hydration steps result in the hydrolysis and redistribution of the oligomers formed during previous deposition in dry conditions. This results in the formation of self-assembled aggregates with well-defined secondary structures (especially ß-sheets). Upon further monomers feeding, structural elements are conserved in newly growing chains, with indications of templated polymerization. The structural dynamics of peptides were also evaluated. Rigid self-assembled structures with a high resistance to further wetting/drying cycles and inaccessibility to isotopic exchange were present in the humidity fluctuating system compared to more flexible structures in the dehydrated system. The resistance and growth of self-assembled structures were also investigated for an extended duration of Gly deposition using isotope labeling.

Emergence of Order in Origin-of-Life Scenarios on Mineral Surfaces: Polyglycine Chains on Silica.

The polymerization of amino acids (AAs) to peptides on oxide surfaces has attracted interest owing to its high importance in biotechnology, prebiotic chemistry, and origin of life theories. However, its mechanism is still poorly understood. We tried to elucidate the reactivity of glycine (Gly) from the vapor phase on the surface of amorphous silica under controlled atmosphere at 160 °C. Infrared (IR) spectroscopy reveals that Gly functionalizes the silica surface through the formation of ester species, which represent, together with the weakly interacting silanols, crucial elements for monomers activation and polymerization. Once activated, ß-turns start to form as initiators for the growth of long linear polypeptides (poly-Gly) chains, which elongate into ordered structures containing both ß-sheet and helical conformations. The work also points to the role of water vapor in the formation of further self-assembled ß-sheet structures that are highly resistant to hydrolysis.

Influence of ion mobility on the redox and catalytic properties of Cu ions in zeolites.

This contribution aims at analysing the current understanding about the influence of Al distribution, zeolite topology, ligands/reagents and oxidation state on ions mobility in Cu-zeolites, and its relevance toward reactivity of the metal sites. The concept of Cu mobilization has been originally observed in the presence of ammonia, favouring the activation of oxygen by formation of NH3 oxo-bridged complexes in zeolites and opening a new perspective about the chemistry in single-site zeolite-based catalysts, in particular in the context of the NH3-mediated Selective Catalytic Reduction of NO x (NH3-SCR) processes. A different mobility of bare Cu+/Cu2+ ions has been documented too, showing for Cu+ a better mobilization than for Cu2+ also in absence of ligands. These concepts can have important consequences for the formation of Cu-oxo species, active and selective in other relevant reactions, such as the direct conversion of methane to methanol. Here, assessing the structure, the formation pathways and reactivity of Cu-oxo mono- or multimeric moieties still represents a challenging playground for chemical scientists. Translating the knowledge about Cu ions mobility and redox properties acquired in the context of NH3-SCR reaction into the field of direct conversion of methane to methanol can have important implications for a better understanding of transition metal ions redox properties in zeolites and for an improved design of catalysts and catalytic processes.

Assessing the Influence of Zeolite Composition on Oxygen-Bridged Diamino Dicopper(II) Complexes in Cu-CHA DeNOx Catalysts by Machine Learning-Assisted X-ray Absorption Spectroscopy.

Cu-exchanged chabazite is the catalyst of choice for NOx abatement in diesel vehicles aftertreatment systems via ammonia-assisted selective catalytic reduction (NH3-SCR). Herein, we exploit in situ X-ray absorption spectroscopy powered by wavelet transform analysis and machine learning-assisted fitting to assess the impact of the zeolite composition on NH3-mobilized Cu-complexes formed during the reduction and oxidation half-cycles in NH3-SCR at 200 °C. Comparatively analyzing well-characterized Cu-CHA catalysts, we show that the Si/Al ratio of the zeolite host affects the structure of mobile dicopper(II) complexes formed during the oxidation of the [CuI(NH3)2]+ complexes by O2. Al-rich zeolites promote a planar coordination motif with longer Cu-Cu interatomic distances, while at higher Si/Al values, a bent motif with shorter internuclear separations is also observed. This is paralleled by a more efficient oxidation at a given volumetric Cu density at lower Si/Al, beneficial for the NOx conversion under NH3-SCR conditions at 200 °C.

SO2 Poisoning of Cu-CHA deNO x Catalyst: The Most Vulnerable Cu Species Identified by X-ray Absorption Spectroscopy.

Cu-exchanged chabazite zeolites (Cu-CHA) are effective catalysts for the NH3-assisted selective catalytic reduction of NO (NH3-SCR) for the abatement of NO x emission from diesel vehicles. However, the presence of a small amount of SO2 in diesel exhaust gases leads to a severe reduction in the low-temperature activity of these catalysts. To shed light on the nature of such deactivation, we characterized a Cu-CHA catalyst under well-defined exposures to SO2 using in situ X-ray absorption spectroscopy. By varying the pretreatment procedure prior to the SO2 exposure, we have selectively prepared CuI and CuII species with different ligations, which are relevant for the NH3-SCR reaction. The highest reactivity toward SO2 was observed for CuII species coordinated to both NH3 and extraframework oxygen, in particular for [CuII 2(NH3)4O2]2+ complexes. Cu species without either ammonia or extraframework oxygen ligands were much less reactive, and the associated SO2 uptake was significantly lower. These results explain why SO2 mostly affects the low-temperature activity of Cu-CHA catalysts, since the dimeric complex [CuII 2(NH3)4O2]2+ is a crucial intermediate in the low-temperature NH3-SCR catalytic cycle.

Investigating the role of Cu-oxo species in Cu-nitrate formation over Cu-CHA catalysts.

The speciation of framework-interacting CuII sites in Cu-chabazite zeolite catalysts active in the selective catalytic reduction of NOx with NH3 is studied, to investigate the influence of the Al content on the copper structure and their reactivity towards a NO/O2 mixture. To this aim, three samples with similar Cu densities and different Si/Al ratios (5, 15 and 29) were studied using in situ X-ray absorption spectroscopy (XAS), FTIR and diffuse reflectance UV-Vis during pretreatment in O2 followed by the reaction. XAS and UV-Vis data clearly show the main presence of Z2CuII sites (with Z representing a framework negative charge) at a low Si/Al ratio, as predicted. EXAFS wavelet transform analysis showed a non-negligible fraction of proximal Z2CuII monomers, possibly stabilized into two 6-membered rings within the same cage. These sites are not able to form Cu-nitrates by interaction with NO/O2. By contrast, framework-anchored Z[CuII(NO3)] complexes with a chelating bidentate structure are formed in samples with a higher Si/Al ratio, by reaction of NO/O2 with Z[CuII(OH)] sites or structurally similar mono- or multi-copper Zx[CuIIxOy] sites. Linear combination fit (LCF) analysis of the XAS data showed good agreement between the fraction of Z[CuII(OH)]/Zx[CuIIxOy] sites formed during activation in O2 and that of Z[CuII(NO3)] complexes formed by reaction with NO/O2, further confirming the chemical inertia of Z2CuII towards these reactants in the absence of solvating NH3 molecules.

Structure and Reactivity of Oxygen-Bridged Diamino Dicopper(II) Complexes in Cu-Ion-Exchanged Chabazite Catalyst for NH3-Mediated Selective Catalytic Reduction.

The NH3-mediated selective catalytic reduction (NH3-SCR) of NOx over Cu-ion-exchanged chabazite (Cu-CHA) catalysts is the basis of the technology for abatement of NOx from diesel vehicles. A crucial step in this reaction is the activation of oxygen. Under conditions for low-temperature NH3-SCR, oxygen only reacts with CuI ions, which are present as mobile CuI diamine complexes [CuI(NH3)2]+. To determine the structure and reactivity of the species formed by oxidation of these CuI diamine complexes with oxygen at 200 °C, we have followed this reaction, using a Cu-CHA catalyst with a Si/Al ratio of 15 and 2.6 wt% Cu, by X-ray absorption spectroscopies (XANES and EXAFS) and diffuse reflectance UV-Vis spectroscopy, with the support of DFT calculations and advanced EXAFS wavelet transform analysis. The results provide unprecedented direct evidence for the formation of a [Cu2(NH3)4O2]2+ mobile complex with a side-on µ-η2,η2-peroxo diamino dicopper(II) structure, accounting for 80-90% of the total Cu content. These [Cu2(NH3)4O2]2+ are completely reduced to [CuI(NH3)2]+ at 200 °C in a mixture of NO and NH3. Some N2 is formed as well, which suggests the role of the dimeric complexes in the low-temperature NH3-SCR reaction. The reaction of [Cu2(NH3)4O2]2+ complexes with NH3 leads to a partial reduction of the Cu without any formation of N2. The reaction with NO results in an almost complete reduction to CuI, under the formation of N2. This indicates that the low-temperature NH3-SCR reaction proceeds via a reaction of these complexes with NO.

EXAFS wavelet transform analysis of Cu-MOR zeolites for the direct methane to methanol conversion.

Cu-exchanged zeolites have been shown to possess Cu-oxo species active towards the direct methane to methanol (DMTM) conversion, carried out through a chemical-looping approach. Different Cu-zeolites have been investigated for the DMTM process, with Cu-mordenite (Cu-MOR) being among the most active. In this context, an accurate determination of the local structure and nuclearity of selective Cu-oxo species responsible for an efficient DMTM conversion still represents an ongoing challenge for characterization methods, including synchrotron-based X-ray absorption spectroscopy (XAS). Herein, we explore the potential of an alternative analysis of Extended X-ray Absorption Fine Structure (EXAFS) data using wavelet transform (WT) to enhance the technique sensitivity to multimeric Cu species hosted in the MOR framework. Combining ex situ XAS measurements under model red-ox conditions with in situ data collected after the key steps of the DMTM process, we demonstrate how EXAFS-WT enables unambiguous detection of Cu-Cu scattering contributions from multimeric Cu-species. As also confirmed by complementary in situ IR spectroscopy results, these are observed to dynamically respond to the chemical environment over the different conditions probed. We finally report a proof-of-concept EXAFS fit using the WT representation, applied to the structural refinement of O2-activated Cu-MOR. The fitting results reveal a Cu local coordination environment consistent with mono-(µ-oxo) di-copper cores, with Cu-Cu separation of ∼3.1 Å, paving the way to future applications and developments of the method in the field of Cu-zeolite research and beyond.

Sonochemically-Promoted Preparation of Silica-Anchored Cyclodextrin Derivatives for Efficient Copper Catalysis.

Silica-supported metallic species have emerged as valuable green-chemistry catalysts because their high efficiency enables a wide range of applications, even at industrial scales. As a consequence, the preparation of these systems needs to be finely controlled in order to achieve the desired activity. The present work presents a detailed investigation of an ultrasound-promoted synthetic protocol for the grafting of ß-cyclodextrin (ß-CD) onto silica. Truly, ultrasound irradiation has emerged as a fast technique for promoting efficient derivatization of a silica surface with organic moieties at low temperature. Three different ß-CD silica-grafted derivatives have been obtained, and the ability of ß-CD to direct and bind Cu when CD is bonded to silica has been studied. A detailed characterization has been performed using TGA, phenolphthalein titration, FT-IR, diffuse reflectance (DR), DR UV-Vis, as well as the inductively-coupled plasma (ICP) of the ß-CD silica-grafted systems and the relative Cu-supported catalysts. Spectroscopic characterization monitored the different steps of the reaction, highlighting qualitative differences in the properties of amino-derivatized precursors and final products. In order to ensure that the Cu-ß-CD silica catalyst is efficient and robust, its applicability in Cu(II)-catalyzed alkyne azide reactions in the absence of a reducing agent has been explored. The presence of ß-CD and an amino spacer has been shown to be crucial for the reactivity of Cu(II), when supported.

Uptake and intracellular fate of biocompatible nanocarriers in cycling and noncycling cells.

AIM: To elucidate whether different cytokinetic features (i.e., presence or absence of mitotic activity) may influence cell uptake and distribution of nanocarriers, in vitro tests on liposomes, mesoporous silica nanoparticles, poly(lactide-co-glycolide) nanoparticles and nanohydrogels were carried out on C2C12 murine muscle cells either able to proliferate as myoblasts (cycling cells) or terminally differentiate into myotubes (noncycling cells). MATERIALS & METHODS: Cell uptake and intracellular fate of liposomes, mesoporous silica nanoparticles, poly(lactide-co-glycolide) nanoparticles and nanohydrogels were investigated by confocal fluorescence microscopy and transmission electron microscopy. RESULTS: Nanocarrier internalization and distribution were similar in myoblasts and myotubes; however, myotubes demonstrated a lower uptake capability. CONCLUSION: All nanocarriers proved to be suitably biocompatible for both myoblasts and myotubes. The lower uptake capability of myotubes is probably due to different plasma membrane composition related to the differentiation process.

Strategies to Obtain Encapsulation and Controlled Release of Pentamidine in Mesoporous Silica Nanoparticles.

Pentamidine (PTM), an antiprotozoal agent used in clinics as pentamidine isethionate salt (PTM-S), recently showed high potential also for the treatment of cancer and myotonic dystrophy type I. However, a severe limit to the systemic administration of PTM is represented by its nephrotoxicity, leading to the need for a system able to achieve a controlled release of the drug. In this study, mesoporous silica nanoparticles (MSNs) were employed for the first time to encapsulate PTM. PTM-S was first used for loading experiments into bare (MSN-OH) and aminopropyl, cyanopropyl and carboxypropyl-functionalized MSNs (MSN-NH2, MSN-CN and MSN-COOH respectively) but it was not adequately loaded in any MSNs. The free base of PTM (PTM-B) was then obtained from PTM-S and successfully loaded into MSNs. Specifically, MSN-COOH exhibited the highest loading capacity. In vitro evaluation of PTM-B kinetic release from the different MSNs was carried out. An influence of the functional groups in slowing the release of the drug, when compared to bare MSNs was observed. Altogether, these results demonstrate that MSN-COOH could be a promising system to achieve a controlled release of PTM.

The Nuclearity of the Active Site for Methane to Methanol Conversion in Cu-Mordenite: A Quantitative Assessment.

The direct conversion of methane to methanol (MTM) is a reaction that has the potential to disrupt a great part of the synthesis gas-derived chemical industry. However, despite many decades of research, active enough catalysts and suitable processes for industrial application are still not available. Recently, several copper-exchanged zeolites have shown considerable activity and selectivity in the direct MTM reaction. Understanding the nature of the active site in these materials is essential for any further development in the field. Herein, we apply multivariate curve resolution analysis of X-ray absorption spectroscopy data to accurately quantify the fraction of active Cu in Cu-MOR (MOR = mordenite), allowing an unambiguous determination of the active site nuclearity as a dicopper site. By rationalizing the compositional parameters and reaction conditions, we achieve the highest methanol yield per Cu yet reported for MTM over Cu-zeolites, of 0.47 mol/mol.

Investigating the Low Temperature Formation of CuII -(N,O) Species on Cu-CHA Zeolites for the Selective Catalytic Reduction of NOx.

In this work, we show the potentiality of operando FTIR spectroscopy to follow the formation of CuII -(N,O) species on Cu exchanged chabazite zeolites (Cu-CHA), active for the selective catalytic reduction of NOx with NH3 (NH3 -SCR). In particular, we investigated the reaction of NO and O2 at low temperature (200 and 50 °C) on a series of Cu-CHA zeolites with different composition (Si/Al and Cu/Al ratios), to investigate the nature of the formed copper nitrates, which have been proposed to be key intermediates in the oxidation part of the SCR cycle. Our results show that chelating bidentate nitrates are the main structures formed at 200 °C. At lower temperature a mixture of chelating and monodentate nitrates are formed, together with the nitrosonium ion NO+ , whose amount was found to be proportional to the zeolite Brønsted site concentration. Nitrates were found to mainly form with CuII ions stabilized by one negative framework charge (Z), Z-[Cu(OH]I or Z-[Cu(O2 ]I , without involvement of Z2 -CuII ones. This evidence, together with the absence of bridging nitrates in samples with high probability for Cu-Cu pairs, indicate that the nitrate ligands are not able to mobilize copper ions, at variance with what recently reported for NH3 . Finally, water was found to replace preformed chelating copper nitrates and deplete NO+ (though with different kinetics) at both temperatures, while favouring the presence of monodentate ones.

Hyaluronated mesoporous silica nanoparticles for active targeting: influence of conjugation method and hyaluronic acid molecular weight on the nanovector properties.

We have prepared and evaluated the physico-chemical and biological properties of four different hyaluronated mesoporous silica nanoparticles (MSNs) samples (MSN/HA). Hyaluronic acid (HA) with two different molecular weights (200 and 6.4 kDa) was used for the conjugation of aminopropyl-functionalized MSN (NH2-MSN), following two different procedures. Namely, samples HA200A and HA6.4A were prepared by reacting activated HA with NH2-MSN (method A), while samples HA200B and HA6.4B were obtained carrying out HA activation in the presence of the nanoparticles (method B). The four samples showed similar hydrophilicity, but clear differences in the HA loading, textural properties, surface charge and stability of the suspensions. More in detail, conjugation using low molecular weight HA with method A resulted in low HA loading, with consequent scarce effects on dispersity and stability in physiological media. The highest yield and corresponding best performances were obtained with method B using high molecular weight HA. HA loading and molecular weight also influenced in a concerted way the biological response towards the MSNs of CD44 target cancer cells (CD44+) and control cells (CD44-): MDA-MB-231 and A2780, respectively. The absence of cytotoxicity was assessed. Moreover, the targeting ability of the best performing MSN/HA was confirmed by cellular uptake studies.

Methane to Methanol: Structure-Activity Relationships for Cu-CHA.

Cu-exchanged zeolites possess active sites that are able to cleave the C-H bond of methane at temperatures ≤200 °C, enabling its selective partial oxidation to methanol. Herein we explore this process over Cu-SSZ-13 materials. We combine activity tests and X-ray absorption spectroscopy (XAS) to thoroughly investigate the influence of reaction parameters and material elemental composition on the productivity and Cu speciation during the key process steps. We find that the CuII moieties responsible for the conversion are formed in the presence of O2 and that high temperature together with prolonged activation time increases the population of such active sites. We evidence a linear correlation between the reducibility of the materials and their methanol productivity. By optimizing the process conditions and material composition, we are able to reach a methanol productivity as high as 0.2 mol CH3OH/mol Cu (125 µmol/g), the highest value reported to date for Cu-SSZ-13. Our results clearly demonstrate that high populations of 2Al Z2CuII sites in 6r, favored at low values of both Si:Al and Cu:Al ratios, inhibit the material performance by being inactive for the conversion. Z[CuIIOH] complexes, although shown to be inactive, are identified as the precursors to the methane-converting active sites. By critical examination of the reported catalytic and spectroscopic evidence, we propose different possible routes for active-site formation.

Metal-organic framework mixed-matrix disks: Versatile supports for automated solid-phase extraction prior to chromatographic separation.

We present for the first time the application of metal-organic framework (MOF) mixed-matrix disks (MMD) for the automated flow-through solid-phase extraction (SPE) of environmental pollutants. Zirconium terephthalate UiO-66 and UiO-66-NH2 MOFs with different size (90, 200 and 300nm) have been incorporated into mechanically stable polyvinylidene difluoride (PVDF) disks. The performance of the MOF-MMDs for automated SPE of seven substituted phenols prior to HPLC analysis has been evaluated using the sequential injection analysis technique. MOF-MMDs enabled the simultaneous extraction of phenols with the concomitant size exclusion of molecules of larger size. The best extraction performance was obtained using a MOF-MMD containing 90nm UiO-66-NH2 crystals. Using the selected MOF-MMD, detection limits ranging from 0.1 to 0.2µgL-1 were obtained. Relative standard deviations ranged from 3.9 to 5.3% intra-day, and 4.7-5.7% inter-day. Membrane batch-to-batch reproducibility was from 5.2 to 6.4%. Three different groundwater samples were analyzed with the proposed method using MOF-MMDs, obtaining recoveries ranging from 90 to 98% for all tested analytes.

Poly(NIPAM-co-MPS)-grafted multimodal porous silica nanoparticles as reverse thermoresponsive drug delivery system.

Hybrid drug delivery systems (DDS) have been prepared by grafting poly(NIPAM-co-MPS) chains on multimodal porous silica nanoparticles having an inner mesoporous structure and an outer thin layer of micropores. The hybrid thermoresponsive DDS were fully characterized and loaded with a model drug. The in vitro drug release tests are carried out at below and above the lower critical solution temperature (LCST) of the copolymer. The results have revealed that due to the presence of small diameter (~1.3 nm) micropores at the periphery of the particles, the collapsed globules of the thermoresponsive copolymer above its LCST hinders the complete release of the drug which resulted in a reverse thermoresponsive drug release profile by the hybrid DDS.