202 research outputs found
New polymeric receptors : microgels and RAFT copolymers, their synthesis and supramolecular binding to low-molecular-weight compunds and proteins
The aim of this thesis is to explore the use of microgels and linear copolymers as
supramolecular receptors for low molecular weight compounds and proteins. It was
postulated that the long-range interactions made possible by repeating units within a
polymer would be advantageous in creating high affinity supramolecular hosts in a
competitive aqueous environment.
Tetrazoles frequently replace carboxylic acids in pharmaceutical drugs, their binding to
amidines was investigated as a model system to determine their exact mode of
interaction with an arginine analogue, where there has been some ambiguity in the
literature regarding the preferred binding sites for tetrazolates. 1H NMR studies and
crystal structures of model complexes were used to investigate their interactions. A
preference for protonated amines over guanidine-like amidines was observed, it was
postulated that this would infer a degree of selectivity to microgels and linear
copolymers incorporating the tetrazolate functional group.
Microgels and linear copolymers were synthesised and investigated using 1H NMR,
UV-Vis and ITC titrations to determine their affinity for selected ligands, such as the
biologically significant polyamine spermine and proteins such as haemoglobin and
cytochrome C.
A living free radical polymerisation (RAFT) process was used to create linear
copolymers with defined molecular weights and low polydisperisties.
Evidence for the microgels and linear copolymers binding to the target molecules will
be discussed. Evidence for the structural manipulation of the polymers, via dynamic
combinatorial chemistry, to create highly specific hosts will be presented and discussed.Engineering and Physical Sciences Research Council (EPSRC
Synthesis, antimalarial evaluation, Ç-hematin inhibition, and in silico and in vitro ADMET profiling of 4-aminoquinoline-hydroxypyridinone hybrids
Includes abstract.With the aim of designing appropriate hybrid molecules as a strategy to fight drug resistant malaria parasites, 4-aminoquinoline-3,4-hydroxypyridinone hybrids were designed and synthesized. Their hypothesized mode of action was studied with respect to inhibition of hemozoin formation
Novel C11 amino derivatives of cryptolepine : synthesis and in vitro studies with DNA and haeme
Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2010Malaria is one of the most widespread infectious diseases of our time. The global malaria map
has been shrinking over the past 60 years, but today more people are at risk of suffering from malaria
than any other time in history. In the past few years malaria has once again attracted more attention,
partly because it is recognized that malaria spread in sub-Saharan Africa has increased in the recent
years, mainly due to the development of drug resistances.
Cryptolepine (1), is an indoloquinoline alkaloid, extracted from the West African climbing shrub
Cryptolepis sanguinolenta (Lindl.) Schltr, a traditional herb used in folk medicine for the treatment of
malaria. Several authors hypothesized that the mechanism of action of cryptolepine could be by
inhibition of haemozoin formation in the digestive vacuole (DV) of the parasite, however in a
microscopic fluorescence study, the indoloquinoline chromophore, was suggested to accumulate into
specific parasite structures that could correspond to the parasite nuclei, and thus justifying its activity
due to cytotoxic effects on DNA and topoisomerase II activity.
Cryptolepine derivatives (3) have been synthesized through the incorporation of basic side-chains
in the C-11 position of the 10H-indolo[3,2-b]quinoline scaffold and evaluated for their antiplasmodial
and cytotoxicity properties. The derivative containing a conformationally restricted piperidine sidechain
(3n) presented IC50 values of 23-44 nM against chloroquine resistant strains and a selectivity
index value of ca 1400, i.e. a 1000-fold improvement in selectivity when compared with 1. The
introduced side chains are weakly basic, with pKa values in the terminal amine functionality ranging
from 5.2 to 12.5, and are predicted to promote accumulation inside the DV to an extent similar to that of
chloroquine. All compounds within this series showed the ability to interact with monomeric haematin
(FPIX-OH), with a stoichiometry of 1:1 (3:FPIX-OH) and with association constants (Kass) values
between 0.062 and 0.41 x106 M-1, comparable to chloroquine (Kass = 0.085 x106 M-1). The complex
stabilization is assured by π-π stacking interactions modulated by the aromatic core, and H-bond
between the terminal amine side chain and haematin carboxylate anions, thus capable to inhibit
haemozoin formation in DV. However, localization studies of compound 3n inside parasite blood stages
suggest an additional mechanism of action, like interactions with DNA, besides inhibition of haemozoin
crystal growth. Cryptolepine derivatives (3) bind strongly to double-stranded d(GATCCTAGGATC)2
oligonucleotide with association constants ranging from 105 M-1 to 107 M-1. Furthermore, molecular
docking simulations showed that, in contrast with 1, compounds 3 are predicted to not intercalate into
DNA double helix, binding essentially to single- and double-stranded DNA, with a stoichiometry of 2:1
(3:DNA), through electrostatic and H-bonding interaction involving charged nitrogens.
In order to explore the indolo[3,2-b]quinolin-11-one (quindolone) scaffold (4), and get new
antimalarial chemotypes, we decided to synthesize a series of quindolones derivatives (5), targeting
malaria parasite digestive vacuole and haeme detoxification pathway, through the introduction of N,N diethylethanamine in the indolo[3,2-b]quinoline aromatic nucleus (N5,N10-alkylation). This reaction
gave N,O- (94), N,N- (5) and O-(95) alkylated products containing two or one basic side-chains, which
were evaluated for antiplasmodial activity against chloroquine-resistant P. falciparum W2 strain and
cytotoxicity for HepG2 A16 hepatic cells. By incorporating alkylamine side chains and chlorine atoms
in the quindolone nucleus we transformed the inactive tetracyclic parent quindolones (4, 91a and 91b)
into moderate or highly active and selective compounds to the resistant P. falciparum W2 strain, with
IC50 ranging from 51 to 2638 nM and with selectivity ratios up to 98. All the quindolone derivatives in
the series showed the ability to complex FPIX-OH (1:1 stoichiometry) with associations constants (Kass)
ranging from 0,074 to 0,14 x106 M-1, being the main intermolecular interactions due to π-π stacking
interactions and H-bond between derivatives and haematin.
Cryptolepine and the new antimalarial chemotype, quindolone, are suitable scaffolds for the
design of active and selective compounds targeting parasite haemozoin detoxification pathway, with
potential for development as antimalarial agents.A malária ou paludismo é uma doença infecciosa provocada por parasitas do género Plasmodium
e transmitida pela picada do mosquito fêmea do género Anopheles. A malária é uma das infecções mais
difundida por todo o mundo. Apesar propagação ter diminuído nos últimos 50 anos, nos dias de hoje há
mais pessoas em risco de contaminação com malária do que em qualquer outra época da história. Em
2008, a malária era endémica em 108 países, contando com cerca de 247 milhões de casos reportados,
3,3 mil milhões de pessoas em risco. Anualmente, entre 1 a 3 milhões de casos culminam em morte, dos
quais, muitos são crianças com idade inferior a 5 anos. A malária é a principal causa de morte infantil
em África, sendo que 60 % dos novos casos registados todos os anos ocorrem na África sub-Sahariana,
onde ocorrem 90 % dos casos fatais de malária. Para além de ser um grave problema de saúde pública, a
malária é também um problema sócio-económico, não só devido ao elevado investimento efectuado na
prevenção e tratamento, mas também devido a custos indirectos resultantes da perda de productividade
que advêm da elevada morbilidade e mortalidade. No entanto, recentemente a malária voltou a chamar a
atenção da comunidade, muito porque foi reconhecido que o número de casos reportados em África tem
aumentado nos últimos anos devido ao aumento de fenómenos de resistência nos parasitas aos fármacos
utilizados para tratamento da infecção.
Apesar da enorme variedade de compostos com actividade antimalárica, a sua eficácia contínua
no entanto a ser reduzida devido aos fenómenos de resistência associados. A cloroquina (2) é uma 4-
amionoquinolina sintetizada em 1934 e tem sido um dos pilares do tratamento da malária nos últimos 60
anos, sendo de consenso geral, que a sua actividade antimalárica se deva à inibição da formação do
cristal de hemozoína no vacúolo digestivo do parasita. No organismo humano, o parasita ingere
hemoglobina e digere-a, libertando os amino ácidos necessários para o seu desenvolvimento, e o heme,
tóxico para o parasita. Este heme é então biocristalizado pelo parasita a hemozoina, um cristal inerte e
não tóxico. A cloroquina, devido às suas propriedades básicas, apresenta a capacidade de se acumular
no interior do vacúolo digestivo acídico e formar complexos estáveis cloroquina:heme, através de
interacções π-π entre os anéis aromáticos, impedindo assim a formação da hemozoina e originando a
morte do parasita. Vários autores referem ainda que a cloroquina apresenta também a capacidade de
complexar com as faces em crescimento do cristal de hemozoina, inibindo assim o processo de
cristalização.
Nos últimos 30 anos, extractos de uma enorme variedade de espécies de plantas, incluindo muitas
utilizadas na medicinal tradicional, têm sido avaliadas in vitro quanto à sua actividade antimalárica. O
alcalóide criptolepina (1), constituinte maioritário da raíz da Cryptolepis sanguinolenta, um arbusto
trepador africano normalmente utilizado na medicina tradicional para tratamento da malária,
demonstrou possuir propriedades antiplasmodicas equivalentes à cloroquina. A criptolepina parece
exercer as propriedades antiplasmodicas devido à capacidade de inibir a formação da hemozoina, tal como a cloroquina, ligando-se ao heme e bloqueando assim o mecanismo de destoxificação do parasita.
No entanto, a criptolepina é também um agente intercalante de cadeias de ADN ricas em guanina (G) e
citosina (C), e tendo preferência por sequências CC não alternadas. Assim, a criptolepina apresenta
propriedades citotóxicas devido à inibição da topoisomerase II e da síntese do ADN. Estas propriedades
citotóxicas podem também estar na origem da actividade antiplasmódica uma vez que, um estudo de
localização intracelular em eritrócitos infectados com P. falciparum, revelou que o alcalóide se acumula
em estruturas no interior do parasita que poderão corresponder ao núcleo.
Neste trabalho foram sintetizados 25 análogos da criptolepina (3) com cadeias laterais diaminoalquílicas,
na posição C11 do núcleo aromático da indolo[3,2-b]quinolina e avaliados quanto as suas
propriedades antiplasmodicas e citotóxicas em linhas celulares de mamífero. O análogo com uma cadeia
lateral de piperidina (3n), apresentou uma actividade antiplasmódica (IC50) variando entre 23 e 44 nM,
contra diferentes estripes resistentes à cloroquina, e um índice de selectividade de aproximadamente
1400, representando um aumento de cerca de 1000 vezes quando comparado com 1. Os nossos estudos
sugerem que a introdução de cadeias laterais com aminas terminais basicas, apresentando valores de pKa
variando entre 5,2 e 12,5, promove a acumulação dos compostos no interior do vacúolo digestivo do
parasita, em níveis de concentração semelhantes aos da cloroquina. Todos os análogos da criptolepina
sintetizados apresentam a capacidade de formar complexos com o monómero da hematina (FPIX-OH),
com constantes de associação (Kass) variando entre 0,062 e 0,41 x106 M-1, semelhante à constante de
associação determinada para a cloroquina (Kass = 0,085 x106 M-1). Os complexos são estabilizados
maioritariamente através de interacções π-π entre o núcleo aromático da indolo[3,2-b]quinolina e o
núcleo porfirínico da hematina. Estudos de modelação molecular revelaram também que os azotos
protonados nas aminas terminais das cadeias laterais podem formar pontes de hidrogénio com os iões
carboxilato da hematina. Estes resultados demonstraram que os novos análogos da criptolepina
apresentam a capacidade de complexar com a FPIX-OH e inibir a formação da hemozoina. No entanto,
o estudo de localização intracelular realizado por microscopia de fluorescência em eritrócitos infectados
com P. falciparum, demonstrou que os análogos da criptolepina também apresentam a capacidade de se
acumularem no núcleo do parasita e assim, potenciar a actividade antiplasmódica. De modo a avaliar a
capacidade de 3 para interagir com estruturas de ADN, foram realizados estudos de interacção com um
oligonucleótido de cadeia única d(5’-GCCAAACACAGAATCG-3’) e de cadeia dupla
d(GATCCTAGGATC)2. Os compostos 3 apresentaram forte capacidade de complexação com ambas as
estruturas de DNA e valores de constante de associação (Kass) variando entre 105 M-1 e 107 M-1. Estudos
de modelação molecular com estruturas de ADN de hélice duplas semelhante à utilizada no ensaios in
vitro, demonstraram que os compostos não são agentes intercalantes, tal como verificado para a
criptolepina, mas ligam-se à fenda menor/maior, com uma estequiometria 2:1 (análogo da
criptolepina:ADN) e interagem preferencialmente com a cadeia de fosfatos através de interacções
electrostáticas e pontes de hidrogénio. Estes resultados demonstraram que a actividade antiplasmódica dos novos análogos da
criptolepina parece ser justificada por efeitos sinérgicos ou aditivos à inibição da formação da
hemozoina e citotoxicidade associada à interacção com estruturas de ADN.
Com o objectivo de aumentar a diversidade de esqueletos químicos com actividade antimalárica,
foram sintetizados novos análogos da indolo[3,2-b]quinolin-11-ona (11-quindolona), tendo como
propósito aumentar a retenção destes compostos no interior do vacúolo digestivo do parasita. Para tal,
foram introduzidas duas cadeias amino-alquílicas (N,N-dietiletanoamina) no núcleo aromático da
quindolona (alquilação em N5 e N10). A reacção originou no entanto padrões de alquilação adicionais,
N,O- (94) e O- (95), que foram também avaliados quanto ao seu potencial antiplasmódico e
citotoxicidade em células hepáticas HepG2 A16. Com introdução de uma ou duas cadeias aminoalquílicas
e átomos de cloro no núcleo aromático, as quindolonas (4, 91a e 91b), inicialmente inactivas,
deram origem a compostos com actividade moderada a forte contra a estirpe W2 do P. falciparum
resistente à cloroquina, apresentando valores de IC50 entre 51 e 2638 nM, e com maior selectividade
para o parasita. Todos os análogos da quindolona sintetizados apresentam também a capacidade de
formar complexos com a hematina, com uma estequiometria 1:1 (análogo:FPIX-OH) e constantes de
associação (Kass) que variam entre 0,074 e 0,14 x106 M-1. A estabilidade do complexo é assegurada pela
formação de interacções π-π entre o núcleo aromático e o anel de porfírina da hematina e estudos de
modelação molecular confirmaram a possibilidade de formação de pontes de hidrogénio entre a amina
terminal da cadeia lateral e os aniões carboxilato do dimero da hematina. Estes resultados demonstraram
que a introdução de cadeias amino-alquílicas no núcleo da quindolona origina compostos com boa
actividade antiplasmódica, com aparente capacidade de inibição da formação da hemozoína e
possivelmente com maior capacidade de acumulação no vacúolo digestivo do parasita.
As indolo[3,2-b]quinolinas demonstraram assim serem bons esqueletos para o desenho e
desenvolvimento de compostos para tratamento da malária, obtendo-se compostos mais activos e
selectivos para o parasita.Fundação para a Ciência e Tecnologia (SFRH/BD/29202/2006); Faculdade de Farmácia, Universidade de Lisboa, Portugal;
Scholl of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK(material and equipment necessary to the development of the study)
Self-Assembled Molecules – New Kind of Protein Ligands: Supramolecular Ligands
immunotargeting techniques; ligands; intramolecular immunological signals; congo red amyloid
Haematin-Quinoline interactions and structure-activity relationships in the antimalarial chloroquine and related compounds
Includes bibliographical references.The nature of the ferriprotoporphyrin IX (Fe(III)PPIX) antimalarial drug target and its interactions with aminoquinolines was investigated spectrophotometrically. The antiquity of malaria, which is caused by protozoan parasites of the genus Plasmodium, is demonstrated by the host specificity of over 100 parasite species found in reptiles, birds and mammals. The four species of plasmodia that infect man are P. vivax, P. malariae, P. ovale and P. falciparum; of which P. falciparum is the most deadly (Bruce-Chwatt 1981 )
Biomimetic models for redox enzyme systems
Supramolecular chemistry involves the study of noncovalent interactions that take place between molecules. A supramolecule or host-guest complex is formed when a noncovalent binding or complexation event occurs between two such molecules. Hydrogen bonds, electrostatics, pi-stacking, hydrophobic effects, solvatophobic effects and van der Waals forces are all types of noncovalent interactions. Biological systems have provided much of the inspiration for the development of supramolecular chemistry, and many synthetic supramolecular systems have been designed to mimic biological and enzymatic processes. Biomimetic modelling involves the synthesis of compounds containing similar functional groups to that of the specific enzyme’s protein and cofactor. Subsequent analysis using chemical, physical or computational techniques can be used to gain a better understanding of the interactions taking place.
This study involves the investigation of various biomimetic redox enzyme systems. Firstly, model systems containing the 1- and 5-deazaflavin cofactor have been synthesised and studied to probe how their redox behaviour compares to that of riboflavin in a supramolecular environment using physical, electrochemical and computational techniques. Secondly, this study has focussed on the flavin cofactor but has expanded upon what factors influence its redox behaviour, and ability to noncovalently interact with other molecules, by examining how the presence of different dendritic architectures can affect its redox properties and noncovalent behaviour. A series of dendrons have been synthesised and studied that have a water-soluble dendron architecture attached to the flavin moiety, as well as a series of dendrons with branching designed to encapsulate the flavin unit. Finally, a biomimetic model of the pyrroloquinoline quinone cofactor has also been synthesised and studies carried out to investigate its redox behaviour in a supramolecular environment, and ability to noncovalently interact with other molecules.
The results of this study will hopefully contribute significantly to the body of chemical research in the area of supramolecular chemistry and biomimetics. Of particular interest will be the results from the flavin-based dendron research, as the prospect of purpose-built synthetic enzymes, designed and synthesised for whatever role is required, would surely be of great significance
Protein Structure and Interactions Studied by Electrospray Mass Spectrometry
Since the emergence of electrospray ionization (ESI) mass spectrometry (MS) as a tool for protein structural studies, this area has experienced tremendous growth. ESI-MS is highly sensitive, and it allows the analysis of biological systems ranging in size from a few atoms to large multi-protein complexes. This work aims to solve questions in protein structural biology by using ESI-MS in conjunction with other techniques.
We initially apply ESI-MS for studying the monomeric protein cytochrome c (Chapter 2). The physical reasons underlying the irreversible thermal denaturation of this protein remain controversial. By utilizing deconvoluted charge state distributions, oxidative modifications were found to be the major reason underlying the observed behavior. The positions of individual oxidation sites were identified by LC-MS/MS-based tryptic peptide mapping.
Chapter 3 and 4 focus on noncovalent protein complexes. ESI allows the transfer of multi-protein complexes into the gas phase, thereby providing a simple approach for monitoring the stoichiometry of these assemblies by MS. It remains somewhat unclear, however, in how far this approach is suitable for measuring binding affinities. We demonstrate that the settings used for rf-only quadrupoles in the ion path are a key factor for ensuring uniform transmission behavior, which is a prerequisite for meaningful Kd measurements. Overall, our data support the viability of the direct ESI-MS approach for determining binding affinities of protein–protein complexes in solution.
Having established suitable conditions for the analysis of noncovalent protein complexes, ESI-MS is applied for monitoring the folding and assembly of hemoglobin (Hb). The native structure of this protein comprises four heme-bound subunits. Hb represents an important model system for exploring coupled folding/binding reactions, an area that remains difficult to tackle experimentally. We demonstrate that efficient Hb refolding depends on the heme ligation status. Only under properly optimized conditions is it possible to return denatured Hb to its tetrameric native state with high yield. ESI-MS allows the observation of on-pathway and off-pathway intermediates that become populated during this highly complex self-assembly process. In summary, this work demonstrates that ESI-MS is a highly versatile tool for addressing questions at the interface of chemistry and structural biology
The PRE-Derived NMR Model of the 38.8-kDa Tri-Domain IsdH Protein from Staphylococcus aureus Suggests That It Adaptively Recognizes Human Hemoglobin
Staphylococcus aureus is a medically important bacterial pathogen that, during infections, acquires iron from human hemoglobin (Hb). It uses two closely related iron-regulated surface determinant (Isd) proteins to capture and extract the oxidized form of heme (hemin) from Hb, IsdH and IsdB. Both receptors rapidly extract hemin using a conserved tri-domain unit consisting of two NEAT (near iron transporter) domains connected by a helical linker domain. To gain insight into the mechanism of extraction, we used NMR to investigate the structure and dynamics of the 38.8-kDa tri-domain IsdH protein (IsdHN2N3, A326–D660 with a Y642A mutation that prevents hemin binding). The structure was modeled using long-range paramagnetic relaxation enhancement (PRE) distance restraints, dihedral angle, small-angle X-ray scattering, residual dipolar coupling and inter-domain NOE nuclear Overhauser effect data. The receptor adopts an extended conformation wherein the linker and N3 domains pack against each other via a hydrophobic interface. In contrast, the N2 domain contacts the linker domain via a hydrophilic interface and, based on NMR relaxation data, undergoes inter-domain motions enabling it to reorient with respect to the body of the protein. Ensemble calculations were used to estimate the range of N2 domain positions compatible with the PRE data. A comparison of the Hb-free and Hb-bound forms reveals that Hb binding alters the positioning of the N2 domain. We propose that binding occurs through a combination of conformational selection and induced-fit mechanisms that may promote hemin release from Hb by altering the position of its F helix
Investigating Hemoglobin Capture and Heme Acquisition by the Pathogen Staphylococcus aureus
Staphylococcus aureus is a medically important Gram-positive bacterial pathogen that actively procures heme from human hemoglobin (Hb) using the iron-regulated surface determinant (Isd) system. Research described in this dissertation investigated how the Isd system uses the IsdH receptor protein to capture Hb and extract its hemin (the oxidized form of heme). To rapidly extract Hb’s hemin, IsdH employs a conserved tri-domain unit that contains two NEAr iron Transporter (NEAT) domains that are connected by a helical linker domain. The work described in chapter 2 used UV-Vis spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and electrospray ionization mass spectrometry (ESI-MS) methods to define the importance of the conserved linker domain in hemin extraction and revealed that this domain enables the NEAT domains within the tri-domain unit to work together to synergistically extract hemin. Chapter 3 of this thesis describes the structure and dynamics of the tri-domain unit (IsdHN2N3). The solution structure of the apo-receptor was defined using small angle X-ray scattering, and advanced NMR methods such as paramagnetic relaxation enhancement (PRE), residual dipolar coupling (RDC), and selective methyl labeling approaches. The structure and inter-domain dynamics of IsdHN2N3 in the absence of Hb were further defined using ensemble modeling calculations. The results of these studies illustrated that the receptor adaptively recognizes Hb using a combination of conformational selection and induced fit mechanisms, and suggests that the linker domain may facilitate hemin transfer by destabilizing the iron-coordinating F-helix in Hb. Chapter 4 describes studies that investigated the kinetic and thermodynamic basis of hemin transfer using stopped-flow UV-Vis spectroscopy, analytical ultracentrifugation sedimentation equilibrium, and isothermal titration methods. The results of this work provide insight into the kinetic and thermodynamic determinants that facilitate receptor-mediated hemin release from Hb. Lastly, Chapter 5 describes the methods that were used to site-specifically label proteins with nitroxide spin-label probes and the subsequent derivation of paramagnetic NMR distance restraints. Altogether, the results of the work described in this dissertation have advanced our knowledge of Hb recognition and hemin acquisition by the pathogen S. aureus
Non-Covalent and Macromolecular Approaches to Study Protein Binding, Drug Delivery and Artificial Blood
To begin with, macromolecules consisting of poly(amido)amine dendrimers(PAMAM),polyglycidol,hyperbranched poly(amido)amine (HYPAM) were synthesized and characterized
extensively. Porphyrins were also synthesized, characterized and modified in line with
respective studies. Hereafter, surface modified TRIS PAMAM dendrimers and its analogs
(hyperbranched polymers, hyperbranched PAMAMs) as potential drug delivery systems were
studied with the use of model drugs (Ibuprofen and Porphyrin). Analogs of the model drugs
were used to investigate the role of secondary interactions for high drug loading(s). UV-Vis
Spectroscopy was utilized for studying and determining the maximum loading of the
macromolecules under investigation. Further ahead, non-covalent approaches to improve
dendrimer-protein binding were used by introducing amino acid chains as targeting groups on
the dendrimer surface. Surface modified carboxylate PAMAM dendrimers were studied for
their ability to bind with zinc metallated porphyrin. UV-Vis and Fluorescence Spectroscopy
were used for protein binding studies. Lastly, Surface Crosslinked Micelles were synthesized
and utilized as artificial blood mimics with an attempt to increase the half-life of encapsulated
iron porphyrin acting as the heme mimic with the help of UV-Vis Spectroscopy
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