Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.inhalation | antisense oligonucleotides | liposomes | orthotopic lung cancer model | pump and nonpump resistance L ung cancer is the leading cause of cancer-related death worldwide (1). Because of the size and distribution of lung cancer, cytoreductive surgery is not very effective for this disease, and therefore chemotherapy and/or radiation are the treatments of choice. However, despite the advances in cancer treatment and improvements in lifestyle and health care, death rates from lung cancer have not changed significantly over the last 50 years. In contrast, mortality from heart disease, the leading cause of death, declined almost 2.5-fold over the same period (2). The patient survival has been in a plateau for three decades (3), with a 5-year relative survival rate of less than 18% in most countries (4). The efficacy of chemotherapy in lung cancer is limited by the rapid development of cancer cell resistance during treatment. To overcome this resistance, higher doses of toxic anticancer drug(s) are administered, often producing adverse side effects in healthy organs. We hypothesize that a substantial enhancement in the efficiency of lung cancer treatment is possible by (i) local delivery of chemotherapeutic agent(s) by inhalation and (ii) simultaneous suppression of at least major mechanisms of lung cancer cell resistance. Local delivery of anticancer drugs directly into the lungs will increase their accumulation in tumor cells and will reduce adverse side effects on healthy organs by limiting drug concentration in the blood. Simultaneous suppression of cellular resistance in tumors will increase the intracellular concentration of the drug in cancer cells and enhance its cytolethality for cancerous cells.Patients with asthma and chronic obstructive pulmonary disease commonly use inhaled drugs (5). Although some chemotherapeutic agents can be delivered through the pulmonary or intratracheal route (6-9), most anticancer drugs cannot be inhaled in t...

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“…Previously described methods (19,20,30,31) were used for the analysis of these parameters (details in SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance

Garbuzenko¹,

Saad²,

Pozharov³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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167

149

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“…46 So, the sias can be used as part of drugs, their function is to increase the drug distributions specifically in metastatic foci and increase the efficacy of anticancer drugs.…”

Section: Experimental Therapeutic Studymentioning

confidence: 99%

Antimetastatic therapy targeting aberrant sialylation profiles in cancer cells

Lu¹,

Lü

Wu³

2011

Drugs Ther Studies

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Neoplasm metastases involve a fixed cascade of pathological processes, and are responsible for more than 60% cancer deaths worldwide and can only be controlled or inhibited by drugs now. Antimetastatic drugs targeting aberrantly sialylated in tumors have involved about a quarter of a century and might be a future therapeutic option apart from currently utilized antimetastatic drugs, such as antivascular and matrix metalloproteinase (MMP) inhibitors. Since neoplasm tissues often manifest high levels of sialic acids and sialyl antigens or glycoligands, and some types of sialic acid analogue, such as N-glycolylneuraminic acid (Nau5Gc) occurred in most tumor tissues, is absent in common humans, more attentions are needed to work with new therapeutic approaches to target these changes. Previously preliminary data have shown some compounds that inhibit some pathways of sialic acids can inhibit the tumor metastasis in vitro and tumor metastasis in experimental animal models. This type of pharmacological work can be helped by glycome investigations in order to deep understanding their mechanisms. As the central dogma of glycobiology is still unknown, some fundamental questions related to carbohydrate itself are even more welcoming and decisive to our understanding to nature of cancer. These types of work also need mathematical analysis of data. In this review, we will document and discuss the latest experimental therapeutic data and their clinical significance between cancer pathological profiles and therapeutics benefits.

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“…It involved from bioassays to anti-proliferative evaluation to anti-metastatic responses in murine tumor models (Lewis lung carcinoma and melanoma B16). The therapeutic studies of sias-related Antimetastatic drugs began at approximately 30 years ago [12,25,[36][37][38][39][40][41][42][43][44][45][46]. Since this type of anticancer drugs (especially targeting sias in tumors) has been seldom entering into clinical investigations, most experimental therapeutic studies have been collected here.…”

Section: Experimental Therapeutic Studymentioning

confidence: 99%

“…Moreover, sias-anticancer prodrug may increase its uptake and cytotoxicity against tumor cells ( Figure 3 and Table 3) [46].…”

Section: Experimental Therapeutic Studymentioning

confidence: 99%

Antimetastatic therapy at aberrant sialylation in cancer cells, a potential hotspot

Lu¹,

Lu²,

Xu³

et al. 2017

Clin Proteom Bioinform

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Neoplasm metastases involve a fixed cascade of pathological processes responsible for 90% cancer mortality worldwide. However, currently neoplasm metastases are poorly managed in humans for lack of good drug targets. To change this situation, new drug targets must be established. Aberrantly tumor sialylated study is one of potential drug targets, which has been involved for a half century. Many new discoveries show promising outcomes in experimental models. Since neoplasm tissues often contain higher levels of total sialic acids (sia), sialic acids-containing antigens, several types of sialic acid analogue, such as N-glycolylneuraminic acids, growing attentions of sia-related tumor diagnostics and therapeutics are needed to work with new cancer treatment approaches. Previously some compounds that inhibit pathologic pathways of sialic acids in tumor movements in vitro and tumor metastasis in animal tumor models were found. This type of pharmacological limitations of cancer metastasis treatments can be possibly solved by future glycome/metabolomics technology utilities. As the "central dogma" of glycobiology is still unknown to us, some fundamental questions related to carbohydrate itself are even more important comparing with individual experimental discoveries. In addition, mathematicor physics-majored talents in this topic might catalyze these new discoveries. In this review, we document these strings of lab biologic evidence, drug development updating and close relationships between cancer pathological profiles and therapeutic targets/benefits in clinics.

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Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

Abstract: Targeting of the conjugate to cancer cells by SA with increased copies of targeting moiety and anticancer drug enhanced prodrug uptake by cancer cells and cytotoxicity of the prodrug.

Cited by 62 publications

References 33 publications

Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance

Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance

Antimetastatic therapy targeting aberrant sialylation profiles in cancer cells

Antimetastatic therapy at aberrant sialylation in cancer cells, a potential hotspot

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