![]() The drug then diffuses into the cytoplasm after spontaneous deprotonation of the galactosamine residue. In this nanoconjugate, the attachment of DOX via an acid-cleavable hydrazone linkage has been an effective way to enhance the delivery of DOX, because the hydrazone linkage is cleaved under the mild acidic conditions of late endosomes/lysosomes to yield free DOX molecules. Among nanoconjugates used to deliver DOX, the polymer platform N-(2-hydroxypropyl)methacrylamide (HPMA) showed promising results in animal models and also entered clinical trials. One such successful example is “DOXIL ®” a clinically approved nanodrug for the treatment of refractory ovarian cancer. ![]() The application of various nanodrugs such as liposome and polymer micelle systems in cancer treatment improved DOX therapeutic efficacy and reduced acute toxicity of the free drug. ![]() While improved delivery through targeting is a general property of various delivery devices, polymer-based delivery systems have also proven advantageous to circumvent multidrug resistance and to be less immunogenic than protein based e.g., viral vectors when antitumor treatment is repeated, avoiding acute or chronic host immune response. The effect of this targeting will be enhanced internalization of nanodrugs and increased treatment efficacy. Another important targeting is binding to surface antigens which are specific for tumor cells. In addition, an efficient tumor accumulation is achieved through active targeting by combining nanodrugs with specific antibodies that bind to receptors overexpressed on vascular tumor endothelium. Nanodrugs can selectively accumulate in tumor through a passive targeting mechanism known as enhanced permeability and retention (EPR) effect. Compared with chemotherapeutic molecules for cancer treatment, “nanodrugs” offer several advantages such as increased solubility, tumor targeting, enhanced accumulation in tumor tissue and tumor cells, decreased systemic toxicity and increased maximum tolerated dosages. In recent years, significant efforts have concentrated on nanoscale delivery systems of DOX. However, it has considerable toxicity, which limits its therapeutic use, preventing treatment at high dosages, and it has an acquired resistance excluding repeated treatment at tolerated dosages. The anticancer drug doxorubicin (DOX) is potent and therapeutically efficient for treatment of a variety of tumors. DOX-nanoconjugates were found stable under physiological conditions and shown to successfully inhibit in vitro cancer cell growth of several invasive breast carcinoma cell lines such as MDA-MB-231 and MDA-MB- 468 and of primary glioma cell lines such as U87MG and U251. For delivery into recipient cancer cells, DOX was conjugated via pH-sensitive hydrazone linkage along with polyethylene glycol (PEG) to a biodegradable, non-toxic and non-immunogenic nanoconjugate platform: poly(β- l-malic acid) (PMLA). This is why in our work we aimed to improve DOX delivery and reduce the toxicity by chemical conjugation with a new nanoplatform based on polymalic acid. However, a major drawback remains its toxicity to healthy tissue and the development of multi-drug resistance during prolonged treatment. Doxorubicin (DOX) is currently used in cancer chemotherapy to treat many tumors and shows improved delivery, reduced toxicity and higher treatment efficacy when being part of nanoscale delivery systems.
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