Nanoconjugate Platforms Development Based in Poly(<i>β</i>,L‐Malic Acid)Methyl Esters for Tumor Drug Delivery

Portilla-Arias, José; Patil, Rameshwar; Hu, Jinwei; Black, Keith L.; García‐Alvarez, Montserrat; Muñoz‐Guerra, Sebastián; Ljubimova, Julia Y.; Holler, Eggehard

doi:10.1155/2010/825363

Cited by 19 publications

(19 citation statements)

References 27 publications

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“…Additionally, PMA has been characterized, 23,24 as it is a polymer with biomedical applications. 25 Here, we demonstrate that subjecting L-malic acid to repeated wet−dry conditions at varying temperatures supports the formation of oligoesters of steady-state concentrations and lengths. This system demonstrates the generation of far-from-equilibrium polymers via a condensation−dehydration process in a model environmental cycle.…”

Section: Introductionmentioning

confidence: 57%

Ester Formation and Hydrolysis during Wet–Dry Cycles: Generation of Far-from-Equilibrium Polymers in a Model Prebiotic Reaction

et al. 2014

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Biopolymers exist within living cells as far-fromequilibrium metastable polymers. Living systems must constantly invest energy for biopolymer synthesis. In the earliest stages of life on Earth, the complex molecular machinery that contemporary life employs for the synthesis and maintenance of polymers did not exist. Thus, a major question regarding the origin of life is how the first far-from-equilibrium polymers emerged from a prebiotic "pool" of monomers. Here, we describe a proof-of-principle system, in which L-malic acid monomers form far-from-equilibrium, metastable oligoesters via repeated, cyclic changes in hydration and temperature. Such cycles would have been associated with day−night and/or seasonal cycles on the early Earth. In our model system, sample heating, which promotes water evaporation and ester bond formation, drives polymerization. Even though periodic sample rehydration and heating in the hydrated state promotes ester bond hydrolysis, successive iterations of wet−dry cycles result in polymer yields and molecular weight distributions in excess of that observed after a single drying cycle. We term this phenomenon a "polymerization ratchet". We have quantitatively characterized the "ratchet" of our particular system. Ester bond formation rates and oligoester hydrolysis rates were determined for temperatures ranging from 60 to 95°C. Based on these rates, a mathematical model was developed using polycondensation kinetics, from which conditions were predicted for oligoester growth. This model was verified experimentally by the demonstration that L-malic acid monomers subjected to multiple wet−dry cycles form oligoesters, which reach a steady-state concentration and mean length after several cycles. The concentration of oligoesters that persist between subsequent steady-state cycles depends on the temperature and durations of the dry and wet phases of the cycle. These results provide insights regarding the potential for very simple systems to exhibit features that would have been necessary for initiation of polymer evolution, before the emergence of genomes or enzymes.

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Section: Introductionmentioning

confidence: 57%

Ester Formation and Hydrolysis during Wet–Dry Cycles: Generation of Far-from-Equilibrium Polymers in a Model Prebiotic Reaction

et al. 2014

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“…Toxicity caused by physical damage due to membrane disruption may be neglected since NPs effect on cell viability is not manifested in the time scale of 1 h. In a way similar to that observed for partial hydrolyzed PAALM‐1 derivatives,23 it is highly probable that the low toxicity observed was due to the effect of methanol that is released during polymer degradation. Both methanol and L ‐malic acid are generated in the hydrolysis of PAALM‐1 but whereas L ‐malic acid is converted into water and carbon dioxide in the tricarboxylic acid cycle, methanol is known to adversely affect the living cells.…”

Section: Resultsmentioning

confidence: 94%

Poly(methyl malate) Nanoparticles: Formation, Degradation, and Encapsulation of Anticancer Drugs

Lanz-Landázuri

García‐Alvarez

Portilla-Arias

et al. 2011

Macromolecular Bioscience

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PMLA nanoparticles with diameters of 150–250 nm are prepared, and their hydrolytic degradation is studied under physiological conditions. Degradation occurs by hydrolysis of the side chain methyl ester followed by cleavage of the main-chain ester group with methanol and L-malic acid as the final degradation products. No alteration of the cell viability is found after 1 h of incubation, but toxicity increases significantly after 3 d, probably due to the noxious effect of the released methanol. Anticancer drugs temozolomide and doxorubicin are encapsulated in the NPs with 20–40% efficiency, and their release is monitored using in vitro essays. Temozolomide is fully liberated within several hours, whereas doxorubicin is steadily released from the particles over a period of 1 month.

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“…Charge hydration and charge-charge repulsion between carboxylates of the same copolymer molecule restrain the formation of such hydrophobic clusters. Simple charge neutralization by methylation of pendant carboxylates rendered pH-independent membranolysis fo PMLA [34]. Similarly, permanent charge neutralization of copolymers P/LLL-NH 2 and P/LOEt evoked pH-independent liposome leakage.…”

Section: Discussionmentioning

confidence: 99%

The optimization of polymalic acid peptide copolymers for endosomolytic drug delivery

et al. 2011

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Membranolytic macromolecules are promising vehicles forcytoplasmic drug delivery, but their efficiency and safety remains primary concerns. To address those concerns, membranolytic properties of various poly(β-l-malic acid) (PMLA) copolymers were extensively investigated as a function of concentration and pH. PMLA, a naturally occurring biodegradable polymer, acquires membranolytic activities after substitution of pendant carboxylates with hydrophobic amino acid derivatives. Ruled by hydrophobization and charge neutralization, membranolysis of PMLA copolymers increased as a function of polymer molecular weight and demonstrated a maximum with 50% substitution of carboxylates. Charge neutralization was achieved either conditionally by pH-dependent protonation or permanently by masking carboxylates. Membranolysis of PMLA copolymers containing tripeptide ofleucine, tryptophan and phenylalanine were pH-dependent in contrast to pH-independent copolymers of Leucineethylester and Leu-Leu-Leu-NH2 with permanent charge neutralization. PMLA and tripeptides seemed a unique combination for pH-dependent membranolysis. In contrast to nontoxic pH-dependent PMLA copolymers, pH-independent copolymers were found toxic at high concentration, which is ascribed to their nonspecific disruption of plasma membrane at physiological pH.pH-dependent copolymers were membranolytically active only at acidic pH typical of maturating endosomes, and are thus devoid of cytotoxicity. The PMLA tripeptide copolymers are useful for safe and efficient cytoplasmic delivery routed through endosome.

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Nanoconjugate Platforms Development Based in Poly(β,L‐Malic Acid)Methyl Esters for Tumor Drug Delivery

Cited by 19 publications

References 27 publications

Ester Formation and Hydrolysis during Wet–Dry Cycles: Generation of Far-from-Equilibrium Polymers in a Model Prebiotic Reaction

Ester Formation and Hydrolysis during Wet–Dry Cycles: Generation of Far-from-Equilibrium Polymers in a Model Prebiotic Reaction

Poly(methyl malate) Nanoparticles: Formation, Degradation, and Encapsulation of Anticancer Drugs

The optimization of polymalic acid peptide copolymers for endosomolytic drug delivery

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