Since the discovery of nitrogen mustard and folate antagonists in 1940’s, chemotherapy has become one of the main arsenals against the war on cancer [1
]. Although the discovery of novel chemotherapeutic agents has led to significant excitement, one of the major challenges of cancer chemotherapy is the lack of specificity of the drugs against tumor cells. Majority of chemotherapeutic agents inhibit cellular proliferation and, as such, do not discriminate between healthy and neoplastic cells. In addition to the toxicity, poor bioavailability and short residence of systemic chemotherapy is also associated with the development of multidrug resistance (MDR) in cancer. Systemic delivery of anticancer agents that can achieve tumor specificity is highly desirable.
In an attempt to circumvent these limitations and improve systemic anticancer therapy, tremendous research efforts have been concentrated on the development of drug delivery systems, such as nanoparticles [2
]. Polymeric materials, in particular, play a significant role as drug carriers and therapeutic agents can either be either physically incorporated into a polymeric matrix or covalently bound to the polymer backbone [3
]. The drug carrier systems, such as encapsulated polymeric nanoparticles [4
], emulsions [5
], micelles [3
], liposomes [6
], have emerged as promising approaches in anticancer treatment with major advantages. The preferential drug localization at target sites through the “enhanced permeability and retention (EPR)
” effect and lower distribution in healthy tissues and capacity to deliver hydrophobic drugs, high drug loading, and control drug release rate [7
] are among these advantages. With the United States Food and Drug Administration approval of albumin-taxol nanoparticles (Abraxane®
], doxorubicin long-circulating liposomes (Doxil®
], and a formulation of rapamycin encapsulated in microemulsion system (Rapamune®
], the development of nanoscale delivery systems for other drugs with the aim of targeting drug more onto the cancer cells and less onto healthy tissues is needed.
Synthetic and natural polymeric materials used for preparing drug delivery systems should be biocompatible such as poly(epsilon-caprolactone), poly(D,L-lactide-co-glycolide), polysaccharides, and proteins. Because of their biocompatibility, biodegradability, and cell surface recognition sites, polysaccharides are a popular class of material among them [12
]. Also polysaccharides, such as dextran, chitosan and cellulose, have a large number of reactive hydroxyl groups and variable molecular weight, contributing to their structural diversity and property for intended applications. Dextran is composed of α-(1→6) and partly α-(1→3) linked D-glucose units with varying branches depending on the dextran-producing bacterial strain and it has been used clinically for more than five decades as plasma volume expansion, peripheral flow promotion, and antithrombolytic agents [13
]. Dextran has no surface charge, providing additional advantage for a drug delivery system as the systems without surface charge could reduce plasma protein adsorption and increase the rate of nonspecific cellular uptake [14
]. Due to the presence of high amount of hydroxyl groups facilitating the introduction of drugs into the polymer backbone, Dextran has been functionalized with various pharmaceutical agents, like naproxen [15
], daunorubicin [16
], mitomycin C [17
], and cisplatin [18
] as efficient prodrugs. Dextran is fully water-soluble and hydrophobically modified dextran forms micelles which can be used to entrap drug. Recently, Susa, et al.
] reported the use of a lipid-modified dextran-based polymeric nanosystem for doxorubicin loading and small interfering RNA delivery in tumor cells [20
]. This nanosystem showed pronounced antiproliferative effects against osteosarcoma cell lines and had potential for reversing MDR in osteosarcoma.
However, due to the fact that many newer generations of anticancer agents have varying degrees of physicochemical properties, such as molecular weight, charge, hydrophobicity, and intracellular target, there is a need to develop a versatile platform of nanoparticles that can encapsulate variety of different types of payloads. In this study, we report the development of a comprehensive and flexible dextran-based polymeric nanoparticle platform that can be customized to encapsulate therapeutic drugs with varying physicochemical properties. Individual functional blocks having (1) lipid chains (C2 to C12) for self-assembly in aqueous solution, (2) thiol groups for intermolecular disulfide crosslinking, and (3) poly(ethylene glycol) (PEG, Mw. 2kDa) for surface functionalization were synthesized from dextran (40 kDa) with controlled functionalization by “click” chemical conjugation method. With the use of combinatorial-design principles, representative anticancer drugs from the class of anthracyclines, topoisomerase inhibitors, and taxanes having different physicochemical properties were encapsulated using different combination of functional blocks utilizing different encapsulation techniques to develop a library of nanoparticle formulations. The optimized nanoparticle formulations were characterized and evaluated for preliminary cellular delivery and cytotoxic effects in SKOV3 human ovarian adenocarcinoma cells.