Multifunctional nanocarriers for enhanced tumor delivery
Permanent URL:
http://hdl.handle.net/2047/d20002948
Ohta, Akio (Committee member)
Gatley, Samuel J. (Committee member)
Giese, Roger W. (Committee member)
Carrier, Rebecca (Committee member)
Passive targeting of nanoparticles can be achieved by using polyethylene glycol-phosphatidylethanolamine (PEG-PE) coating to prevent uptake of the nanoparticles by macrophages and make the particle long-circulating. For active targeting, several moieties can be attached to the particle surface. Anti-nucleosome monoclonal antibody 2C5 recognizes a broad variety of tumor cells via the tumor cell surface-bound nucleosomes. It can recognize murine and human tumor cells, but not normal cells. Cell-penetrating peptides (CPPs) have shown enhanced transport of cargoes through the plasma membrane into the cells. Stimuli-sensitive PEG-hydrazone (Hz)-PE conjugate (with a low pH-sensitive hydrazone bond between PEG and PE) which is stable at normal pH and can shield the CPP function.
In this study, micelles and liposomes were modified with a CPP-PEG-PE conjugate to improve the transport of these nanocarriers into the cells. Since CPPs are susceptible to enzymatic degradation and non-specific cellular interactions, they were shielded by the PEG-Hz-PE conjugate. At normal pH (as found in circulation), the PEG-Hz-PE shielded the CPP and at low pH (as found in tumors), when this polymer underwent hydrolysis, PEG detached to expose the CPP and increased the internalization of the micelles and liposomes. CPP modified pH-sensitive micelles loaded with anticancer drug paclitaxel, improved tumor cell association and cytotoxicity in vitro. Intratumor injections of these micelles demonstrated apoptosis in tumors developed subcutaneously in mice and established this proof of concept.
Liposomes were further modified with mAb 2C5-PEG-PE. Recognition of the tumor cells during the first phase of delivery was imparted by the attached mAb 2C5. During the second phase of delivery, the exposure of the shielded TATp upon hydrolysis of pH-sensitive polymer at the slightly acidic pH of the tumor cell environment, improved the uptake of drug-loaded liposomes by tumor cells. Thus, tumor cell recognition and uptake of the liposomes was obtained in a controlled fashion. Moreover, the growth of subcutaneously developed drug-resistant and drug-sensitive tumors in nude mice was inhibited and substantial decrease in the mean tumor weights was obtained by intravenous injection of these drug-loaded multifunctional liposomes. In this way, nanoparticles can be modified with multiple functionalities to improve tumor targeting and enhance the effect of an anticancer agent.
liposomes and micelles
monoclonal antibody
multifunctional nanocarriers
pH-sensitive polymer
tumor drug delivery
Medicinal and Pharmaceutical Chemistry
Pharmaceutics and Drug Design
Pharmacy and Pharmaceutical Sciences
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