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Design of Silk-Vaterite Microsphere Systems as Drug Carriers with pH-responsive Release Behavior.

ABSTRACT: Improving the therapeutic efficacy of chemotherapy remains a key goal for cancer therapy. Various passive and active targeting strategies have been developed to facilitate drug release targeted to cancer lesions, but actively designing tunable drug release behavior for these needs remains a challenge. As a step towards this need, silk-vaterite microspheres were fabricated and utilized as carriers to tune drug release. Doxorubicin (DOX) was loaded on the microspheres with high efficiency and the release behavior was regulated by tuning the microspheres via thermal processing. In vitro cell inhibition results showed that the drug-loaded microspheres had different cytotoxic efficiencies depending on the DOX release rates. Better efficacy at lower drug doses suggests options to optimize anticancer effects while minimizing toxic side effects. The tunable drug release capacity combined with the inherent passive targeting property of vaterite-based carriers based on pH sensitivity suggests a promising system for enhanced efficacy of chemotherapy.

SUBMITTER: Liu SS

PROVIDER: S-EPMC4675348 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Design of Silk-Vaterite Microsphere Systems as Drug Carriers with pH-responsive Release Behavior.

Liu S S SS Liu L J LJ Xiao L Y LY Lu Q Q Zhu H S HS Kaplan D L DL

Journal of materials chemistry. B 20150911 42

Improving the therapeutic efficacy of chemotherapy remains a key goal for cancer therapy. Various passive and active targeting strategies have been developed to facilitate drug release targeted to cancer lesions, but actively designing tunable drug release behavior for these needs remains a challenge. As a step towards this need, silk-vaterite microspheres were fabricated and utilized as carriers to tune drug release. Doxorubicin (DOX) was loaded on the microspheres with high efficiency and the ...[more]

PMID: 26693020

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Project description:The ability of small interfering RNA (siRNA) to efficiently silence the expression of specific genes provides the basis for exciting new therapies based on RNA interference (RNAi). The efficient intracellular delivery of siRNA from cell uptake through the endosomal trafficking pathways into the cytoplasm remains a significant challenge. Previously we described the synthesis of a new family of diblock copolymer siRNA carriers using controlled reversible addition-fragmentation chain transfer (RAFT) polymerization. The carriers were composed of a positively charged block of dimethylaminoethyl methacrylate (DMAEMA) to mediate siRNA binding and a second pH-responsive endosome releasing block composed of DMAEMA and propylacrylic acid (PAA) in roughly equimolar ratios and butyl methacylate (BMA). Here we describe the development of a new generation of siRNA delivery polymers based on this design that exhibit enhanced transfection efficiency and low cytotoxicity. This design incorporates a longer endosomolytic block with increased hydrophobic content to induce micelle formation. These polymers spontaneously form spherical micelles in the size range of 40 nm with CMC (critical micelle concentration) values of approximately 2 μg/mL based on dynamic light scattering (DLS), (1)H NMR, electron microscopy, and selective partitioning of the small molecule pyrene into the hydrophobic micelle core. The siRNA binding to the cationic shell block did not perturb micelle stability or significantly increase particle size. The self-assembly of the diblock copolymers into particles was shown to provide a significant enhancement in mRNA knockdown at siRNA concentrations as low as 12.5 nM. Under these conditions, the micelle-based systems showed an 89% reduction in GAPDH mRNA levels as compared to only 23% (10 nM siRNA) for the nonmicelle system. The reduction in mRNA levels becomes nearly quantitative as the siRNA concentration is increased to 25 nM and higher. Flow cytometry analysis of fluorescent-labeled siRNA showed uptake in 90% of cells and a 3-fold increase in siRNA per cell compared to a standard lipid transfection agent. These results demonstrate the potential utility of this carrier design for siRNA drug delivery.

Project description:Doxorubicin is a chemotherapeutic drug typically administered systemically which frequently leads to cardiac and hepatic toxicities. Local delivery to a tumor has a chance to mitigate some of these toxicities and can further be mitigated by including a means of tumor-specific drug release. Our laboratory has explored the use of molecular interactions to control the rate of drug release beyond that capable of diffusion alone. To this system, we added an additional affinity group (adamantane) to doxorubicin through a pH-sensitive hydrazone bond. The result was a modified doxorubicin which had an even higher affinity to our drug delivery polymer, and virtually no release in normal conditions, but showed accelerated release of drug in tumor-like low pH. Further, we show that adamantane-modified doxorubicin (adamantane-doxorubicin) and cleaved adamantane-doxorubicin showed equivalent capacity to kill human U-87 glioblastoma cells in vitro as unmodified doxorubicin. Taken together, these data demonstrate our ability to load high levels of modified chemotherapeutic drugs into our affinity-based delivery platform and deliver these drugs almost exclusively in the acidic microenvironments, such as those surrounding the tumor tissue via pH-cleavable bond while minimizing drug delivery in neutral pH tissue, with the ultimate goal of reducing systemic through better local delivery. Impact statement Doxorubicin (DOX) is especially cytotoxic to the heart, liver, kidneys, and healthy tissues surrounding the tumor microenvironment. This systemic toxicity can be partially addressed by local, tumor-specific drug delivery systems. While pH-sensitive DOX delivery systems have been developed by several other groups, many lack a prolonged and consistent release profile required to successfully treat heterogeneous tumors. Our system of a chemically modified form of DOX combined with an affinity-based cyclodextrin delivery system is capable of delivering DOX for 87 days while maintaining its the drug cytotoxicity. This finding is particularly relevant to improving cancer treatments because it enables regulated local delivery of DOX specifically to tumor tissue and allows the drug to be continuously delivered over a therapeutically relevant amount of time.

Dataset Information

Design of Silk-Vaterite Microsphere Systems as Drug Carriers with pH-responsive Release Behavior.

Publications

Design of Silk-Vaterite Microsphere Systems as Drug Carriers with pH-responsive Release Behavior.

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