DNA Polyplexes as Combinatory Drug Carriers of Doxorubicin and Cisplatin: An in Vitro Study

Abstract

Double helix nucleic acids were used as a combination drug carrier for doxorubicin (DOX), which physically intercalates with DNA double helices, and cisplatin (CDDP), which binds to DNA without an alkylation reaction. DNA interacting with DOX, CDDP, or both was complexed with positively charged, endosomolytic polymers. Compared with the free drug, the polyplexes (100 ~ 170 nm in size) delivered more drug into the cytosol and the nucleus and demonstrated similar or superior (up to a 7-fold increase) in vitro cell-killing activity. Additionally, the gene expression activities of most of the chemical drug-loaded plasmid DNA (pDNA) polyplexes were not impaired by the physical interactions between the nucleic acid and DOX/CDDP. When a model reporter pDNA (luciferase) was employed, it expressed luciferase protein at 0.7- ~ 1.4-fold the amount expressed by the polyplex with no bound drugs (a control), which indicated the fast translocation of the intercalated or bound drugs from the “carrier DNA” to the “nuclear DNA” of target cells. The proposed concept may offer the possibility of versatile combination therapies of genetic materials and small molecule drugs that bind to nucleic acids to treat various diseases.

Bioreducible Poly(ethylene glycol)–Triphenylphosphonium Conjugate as a Bioactivable Mitochondria-Targeting Nanocarrier

“…Second, although more drugs could be delivered into cells, the drugs must reach the subcellular compartments to exert therapeutic activity. However, the fluorescence intensity of DOX in DOX-intercalated DNA is approximately 10-fold lower than that of free DOX, 36 which thus indicates that DOX fluorescence in the mitochondria and the nucleus may be approximately 10-fold lower than that of the cytosolic DOX, although the same amount of DOX may be present in each of these three compartments. Therefore, we isolated the nuclei and the mitochondria for further analysis of the subcellular DOX fluorescence intensity in mPEG−(TPP) 2 /DOX NPs and mPEG−(ss-TPP) 2 /DOX NPs because the therapeutic action of DOX must be exerted in the nucleus and the mitochondria.…”

Nanomedicines for Malaria Chemotherapy: Encapsulation vs. Polymer Therapeutics

“…As in cancer, albumin has continued to attract interest as a carrier in conjugated drug delivery systems (204,205). These polymer therapeutics are molecular mimics of viruses and have been researched as gene delivery vehicles (221,222). While these constructs are non-covalently conjugated they could be seen as occupying the penumbra of conventional covalent polymer therapeutics.…”

Thermosensitive Polypeptide Hydrogels Co‐Loaded with Two Anti‐Tumor Agents to Reduce Multi‐Drug Resistance and Enhance Local Tumor Treatment

“…[ 10,11 ] Recently, use of nanomedicine‐based combination therapy for systemic cancer treatment to overcome MDR in cancer cells has received intensive investigation. [ 21–25 ]…”

“…[10,11] Recently, use of nanomedicine-based combination therapy for systemic cancer treatment to overcome MDR in cancer cells has received intensive investigation. [21][22][23][24][25] Besides systemically administered cancer chemotherapy, localized and long-acting delivery of anti-cancer agents to target tumor sites has emerged for enhanced cancer therapy. [26,27] In particular, locoregional combination therapy by the co-delivery of more than one therapeutics simultaneously is of increasing interest for both tumor treatment and tissue regeneration, due to its unique advantages including predictable and enhanced drug concentration at pathological sites, sustained drug release profiles, and reduced systemic toxicity.…”