Many pharmaceutical agents, including various large molecules (proteins, enzymes, antibodies) and even drug-loaded pharmaceutical nanocarriers, need to be delivered intracellularly to exert their therapeutic action within the cytoplasm or specific organelles, such as nuclei, lysosomes, or mitochondria. So far, multiple and only partially successful attempts have been made to brings various low-molecular-weight and macromolecular drugs and drug-loaded pharmaceutical carriers directly into the cell cytoplasm or individual organelles bypassing the endocytic pathway and protecting drugs from lysosomal degradation. Since, various pharmaceutical nanocarriers are increasingly used to increase the efficacy and safety of drugs, the final goal of this application is to engineer a set of nanoparticulate drug carrier systems capable of targeted delivery of various pharmaceuticals to specific intracellular organelles. We hypothesize that the application of drug-loaded pharmaceutical nanocarriers, such as liposomes and micelles, modified with the specific ligands capable of targeting intracellular organelles, such as nuclei, mitochondria, and lysosomes, will significantly increase the efficacy of gene therapy, drug delivery into lysosomes, and apoptosis in cancer cells. To check this hypothesis, we will pursue the following specific aims: (1) Prepare formulations of pharmaceutical nanocarriers (liposomes and polymeric polyethylene glycol-phosphatidylethanolamine (PEG- PE) conjugate-based micelles) with various ligands for preferential binding with selected intracellular organelles. We will then study their interaction with both purified individual cell organelles and with normal and cancer murine and human cells as well as their intracellular distribution and fate;(2) Investigate, using in vitro cell culture systems, biological properties of drug-, model compound-, or DNA-loaded specific ligand-modified liposomes and micelles and their cargo delivery into nuclei, lysosomes, and mitochondria;(3) Investigate, using in vivo tumor models, biological and therapeutical properties of drug-, or DNA-loaded specific ligand- modified nanocarriers (liposomes and micelles). We expect this application to successfully develop a novel platform for targeted drug and gene delivery within cells to specific intracellular organelles enhanced therapeutic outcome.
The main goal of this application is to solve the extremely important and still challenging problem of intracellular organelle-specific drug delivery, thus dramatically increasing the efficacy of many therapies, including anti-cancer therapies.
We aim to engineer a platform for creating drug delivery systems capable of intracellular penetration and specific targeting of intracellular compartments and organelles, such as nuclei, lysosomes and mitochondria, for improved delivery of drugs and DNA. The algorithm for creating such systems should be applicable to a variety of diseases and treatment protocols. We will confirm the validity of the approach by testing with the mitochondria-targeted experimental cancer therapy using novel and promising proapoptotic anti-cancer drugs, and with experimental targeting of lysosomes and nuclei with model compounds and model plasmid.
|Apte, Anjali; Koren, Erez; Koshkaryev, Alexander et al. (2014) Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models. Cancer Biol Ther 15:69-80|
|Lukianova-Hleb, Ekaterina Y; Ren, Xiaoyang; Sawant, Rupa R et al. (2014) On-demand intracellular amplification of chemoradiation with cancer-specific plasmonic nanobubbles. Nat Med 20:778-784|
|Biswas, Swati; Torchilin, Vladimir P (2014) Nanopreparations for organelle-specific delivery in cancer. Adv Drug Deliv Rev 66:26-41|
|Thekkedath, Ritesh; Koshkaryev, Alexander; Torchilin, Vladimir P (2013) Lysosome-targeted octadecyl-rhodamine B-liposomes enhance lysosomal accumulation of glucocerebrosidase in Gaucher's cells in vitro. Nanomedicine (Lond) 8:1055-65|
|Deshpande, Pranali P; Biswas, Swati; Torchilin, Vladimir P (2013) Current trends in the use of liposomes for tumor targeting. Nanomedicine (Lond) 8:1509-28|
|Biswas, Swati; Dodwadkar, Namita S; Deshpande, Pranali P et al. (2013) Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity. Eur J Pharm Biopharm 84:517-25|
|Biswas, Swati; Deshpande, Pranali P; Perche, Federico et al. (2013) Octa-arginine-modified pegylated liposomal doxorubicin: an effective treatment strategy for non-small cell lung cancer. Cancer Lett 335:191-200|
|Biswas, Swati; Deshpande, Pranali P; Navarro, Gemma et al. (2013) Lipid modified triblock PAMAM-based nanocarriers for siRNA drug co-delivery. Biomaterials 34:1289-301|
|Biswas, Swati; Dodwadkar, Namita S; Piroyan, Aleksandr et al. (2012) Surface conjugation of triphenylphosphonium to target poly(amidoamine) dendrimers to mitochondria. Biomaterials 33:4773-82|
|Biswas, Swati; Dodwadkar, Namita S; Deshpande, Pranali P et al. (2012) Liposomes loaded with paclitaxel and modified with novel triphenylphosphonium-PEG-PE conjugate possess low toxicity, target mitochondria and demonstrate enhanced antitumor effects in vitro and in vivo. J Control Release 159:393-402|
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