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Characterization of a clinical polymer-drug conjugate using multiscale modeling.

ABSTRACT: The molecular conformation of certain therapeutic agents has been shown to affect the ability to gain access to target cells, suggesting potential value in defining conformation of candidate molecules. This study explores how the shape and size of poly-?-glutamyl-glutamate paclitaxel (PGG-PTX), an amphiphilic polymer-drug with potential chemotherapeutic applications, can be systematically controlled by varying hydrophobic and hydrophilic entities. Eighteen different formulations of PGG-PTX varying in three PTX loading fractions (f(PTX)) of 0.18, 0.24, and 0.37 and six spatial arrangements of PTX ('clusters', 'ends', 'even', 'middle', 'random', and 'side') were explored. Molecular dynamics (MD) simulations of all-atom (AA) models of PGG-PTX were run until a statistical equilibrium was reached at 100 ns and then continued as coarse-grained (CG) models until a statistical equilibrium was reached at an effective time of 800 ns. Circular dichroism spectroscopy was used to suggest initial modeling configurations. Results show that a PGG-PTX molecule has a strong tendency to form coil shapes, regardless of the PTX loading fraction and spatial PTX arrangement, although globular shapes exist at f(PTX) = 0.24. Also, less uniform PTX arrangements such as 'ends', 'middle', and 'side' produce coil geometries with more curvature. The prominence of coil shapes over globules suggests that PGG-PTX may confer a long circulation half-life and high propensity for accumulation to tumor endothelia. This multiscale modeling approach may be advantageous for the design of cancer therapeutic delivery systems. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 936-951, 2010.

SUBMITTER: Peng LX

PROVIDER: S-EPMC3099131 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Characterization of a clinical polymer-drug conjugate using multiscale modeling.

Peng Lili X LX Ivetac Anthony A Chaudhari Akshay S AS Van Sang S Zhao Gang G Yu Lei L Howell Stephen B SB McCammon J Andrew JA Gough David A DA

Biopolymers 20101101 11

The molecular conformation of certain therapeutic agents has been shown to affect the ability to gain access to target cells, suggesting potential value in defining conformation of candidate molecules. This study explores how the shape and size of poly-γ-glutamyl-glutamate paclitaxel (PGG-PTX), an amphiphilic polymer-drug with potential chemotherapeutic applications, can be systematically controlled by varying hydrophobic and hydrophilic entities. Eighteen different formulations of PGG-PTX varyi ...[more]

PMID: 20564048

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Project description:A fully biodegradable zwitterionic polymer and the corresponding conjugate with paclitaxel (PTX) were synthesized as promising biomaterials. Allyl-functionalized polylactide (PLA) was employed as the precursor of polymer backbones. UV-induced thiol-ene reaction was conducted to conjugate thiol-functionalized sulfobetaine (SB) with the PLA-based backbone. The resulting zwitterionic polymer did not exhibit considerable cytotoxicity. A polymer-drug conjugate was also obtained by thiol-ene reaction of both thiol-functionalized SB and PTX with allyl-functionalized PLA. The conjugate could readily form narrowly-dispersed nanoparticles in aqueous solutions with a volume-average hydrodynamic diameter (Dh,V) of 19.3 ± 0.2 nm. Such a polymer-drug conjugate-based drug delivery system showed full degradability, well-suppressed non-specific interaction with biomolecules, and sustained drug release. In vitro assessments also confirmed the significant anti-cancer efficacy of the conjugate. After 72 h incubation with PLA-SB/PTX containing 10 µg/mL of PTX, the cell viabilities of A549, MCF7, and PaCa-2 cells were as low as 20.0 ± 2.5%, 1.7 ± 1.7%, and 14.8 ± 0.9%, respectively. Both flow cytometry and confocal microscopy suggested that the conjugates could be easily uptaken by A549 cells before the major release of PTX moieties. Overall, this work elucidates promising potentials of biodegradable zwitterionic polymer-based materials in biomedical applications.Statement of significanceThe applicability of FDA-approved biodegradable aliphatic polyesters has been significantly restricted because they are hydrophobic and lack functionalities. Recently zwitterionic polymers have emerged as promising hydrophilic biomaterials, but most of the reported zwitterionic polymers are non-biodegradable. This study reports a novel aliphatic polyester-based zwitterionic polymer and the corresponding polymer-drug conjugate. Their aliphatic polyester and zwitterionic components provide them with high enzymatic degradability and low nonspecific interactions with biomolecules, respectively. While the zwitterionic polymer did not show noticeable cytotoxicity, the corresponding polymer-anticancer drug conjugate exhibited acid-sensitive sustained drug release, remarkable effectiveness in killing cancer cells, as well as the ready cellular internalization. This work lays a foundation for the further development of synthetic biodegradable zwitterionic polymer-based materials which potentially may have broad and significant biomedical applications.

Project description:Owing to their potential applicability against multidrug-resistant bacteria, antimicrobial peptides (AMPs) or host defense peptides (HDPs) gain increased attention. Besides diverse immunomodulatory roles, their classical mechanism of action mostly involves membrane disruption of microbes. Notably, their unbalanced overexpression has also been associated with host cell cytotoxicity in various diseases. Relatedly, AMPs can be subject to aggregate formation, either via self-assembly or together with other compounds, which has demonstrated a modulation effect on their biological functions, thus highly relevant both for drug targeting projects and understanding their in vivo actions. However, the molecular aspects of the related assembly formation are not understood. Here, we focused in detail on an experimentally studied AMP-drug system, i.e., CM15-suramin, and performed all-atom and coarse-grain (CG) simulations. Results obtained for all systems were in close line with experimental observations and indicate that the CM15-suramin aggregation is an energetically favorable and dynamic process. In the presence of bilayers, the peptide-drug assembly formation was highly dependent on lipid composition, and peptide aggregates themselves were also capable of binding to the membranes. Interestingly, longer CG simulations with zwitterionic membranes indicated an intermediate state in the presence of both AMP-drug assemblies and monomeric peptides located on the membrane surface. In sharp contrast, larger AMP-drug aggregates could not be detected with a negatively charged membrane, rather the AMPs penetrated its surface in a monomeric form, in line with previous in vitro observations. Considering experimental and theoretical results, it is promoted that in biological systems, cationic AMPs may often form associates with anionic compounds in a reversible manner, resulting in lower bioactivity. This is only mildly affected by zwitterionic membranes; however, membranes with a negative charge strongly alter the energetic preference of AMP assemblies, resulting in the dissolution of the complexes into the membrane. The phenomenon observed here at a molecular level can be followed in several experimental systems studied recently, where peptides interact with food colors, drug molecules, or endogenous compounds, which strongly indicates that reversible associate formation is a general phenomenon for these complexes. These results are hoped to be exploited in novel therapeutic strategies aiming to use peptides as drug targets and control AMP bioactivity by directed assembly formation.

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Characterization of a clinical polymer-drug conjugate using multiscale modeling.

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Characterization of a clinical polymer-drug conjugate using multiscale modeling.

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