The preclinical development of peptidyl drugs for cancer treatment is
hampered by their poor pharmacological properties and cell penetrative
capabilities in vivo. In this study, we report a nanoparticle-based formulation
that overcomes these limitations, illustrating their utility in studies of the
anti-cancer peptide NuBCP-9 which converts BCL-2 from a cell protector to a cell
killer. NuBCP-9 was encapsulated in polymeric nanoparticles (NPs) comprised of a
polyethylene glycol (PEG)-modified polylactic acid diblock copolymer
(NuBCP-9/PLA-PEG), or PEG-polypropylene glycol-PEG-modified PLA - tetrablock
copolymer (NuBCP-9/PLA-PEG-PPG-PEG). We found that peptide encapsulation was
enhanced by increasing the PEG chain length in the block copolymers. NuBCP-9
release from the NPs was controlled by both PEG chain length and the PLA
molecular weight, permitting time-release over sustained periods. Treatment of
human cancer cells with these NPs in vitro triggered apoptosis by
NuBCP-9-mediated mechanism, with a potency similar to NuBCP-9 linked to a
cell-penetrating poly-Arg peptide. Strikingly, in vivo administration of
NuBCP-9/NPs triggered complete regressions in the Ehrlich syngeneic mouse model
of solid tumor. Our results illustrate an effective method for sustained
delivery of anticancer peptides, highlighting the superior qualities of the
novel PLA-PEG-PPG-PEG tetrablock copolymer formulation as a tool to target
intracellular proteins.
CdSe/CdS/ZnS and CdTe quantum dots (QDs) were synthesized by successive ion layer adsorption and reaction (SILAR) technique and direct aqueous synthesis respectively using thiol stabilizers. Synthesized CdSe/CdS/ZnS and CdTe QDs stabilized with 3-mercaptopropionic acid (MPA) and mercaptosuccinic acid (MSA) were used as fluorescent labels after conjugation with folic acid (FA) and anti-HER2 antibodies. Photoluminescence quantum yield of folated CdSe/CdS/ZnS-MPA and CdTe-MSA QDs was 59% and 77% than that of non-folated hydrophilic QDs. The folate receptor-mediated delivery of folic acid-conjugated CdTe-MSA and CdSe/CdS/ZnS-MPA QDs showed higher cellular internalization as observed by confocal laser scanning microscopic studies. Folated and non-folated CdTe-MSA QDs were highly toxic and exhibited only 10% cell viability as compared to > 80% cell viability with CdSe/CdS/ZnS-MPA QDs over the concentration ranging from 3.38 to 50 pmoles. Immunohistochemistry (IHC) results of human breast cancer tissue samples showed positive results with anti-HER2 antibody conjugated CdSe/CdS/ZnS-MPA QDs with better sensitivity and specificity as compared to conventional IHC analysis using diaminobenzedene staining.
CdSe/CdS/ZnS and CdTe quantum dots (QDs) were synthesized by successive ion layer adsorption and reaction (SILAR) technique and direct aqueous synthesis respectively using thiol stabilizers. Synthesized CdSe/CdS/ZnS and CdTe QDs stabilized with 3-mercaptopropionic acid (MPA) and mercaptosuccinic acid (MSA) were used as fluorescent labels after conjugation with folic acid (FA) and anti-HER2 antibodies. Photoluminescence quantum yield of folated CdSe/CdS/ZnS-MPA and CdTe-MSA QDs was 59% and 77% than that of non-folated hydrophilic QDs. The folate receptor-mediated delivery of folic acid-conjugated CdTe-MSA and CdSe/CdS/ZnS-MPA QDs showed higher cellular internalization as observed by confocal laser scanning microscopic studies. Folated and non-folated CdTe-MSA QDs were highly toxic and exhibited only 10% cell viability as compared to > 80% cell viability with CdSe/CdS/ZnS-MPA QDs over the concentration ranging from 3.38 to 50 pmoles. Immunohistochemistry (IHC) results of human breast cancer tissue samples showed positive results with anti-HER2 antibody conjugated CdSe/CdS/ZnS-MPA QDs with better sensitivity and specificity as compared to conventional IHC analysis using diaminobenzedene staining.
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