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.
Purpose
The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell penetrating capabilities.
Experimental Design
Encapsulation of the MUC1-C inhibitor, GO-203, in novel polymeric nanoparticles (NPs) was studied for effects on intracellular targeting of MUC1-C signaling and function.
Results
Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. Additionally, we found that release of GO-203 from these NPs is controllable over at least 7 days. GO-203/NP treatment of MUC1-C-positive breast and lung cancer cells in vitro was more active with less frequent dosing than that achieved with non-encapsulated GO-203. Moreover, treatment with GO-203/NPs blocked MUC1-C homodimerization, consistent with on-target effects. GO-203/NP treatment was also effective in downregulating TIGAR, disrupting redox balance and inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/NPs to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable to those found when dosing on a daily basis with GO-203.
Conclusions
These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA-(PEG-PPG-PEG) NPs to target MUC1-C in cancer cells and (ii) the potential delivery of other anti-cancer peptide drugs.
Analyzing the long-term outcome in females with congenital adrenal hyperplasia (CAH) is crucial to evaluate effectiveness of treatment strategies. The aim of the study was to evaluate the long-term results in patients with CAH after feminizing surgery from the pediatric intersex clinic. Of 163 patients of CAH being followed (1980-2005), 50 responded for review. The patients had undergone feminizing genitoplasty and hormonal therapy. Evaluation included filling a detailed questionnaire along with physical examination and a structured interview in privacy. Assessment was performed for cosmetic results (50), psychosocial adjustment (42) above 5-year age, and functional outcome in 19 cases above 14-year age. Mean age at clitoroplasty was 3.6 years (1-16 years) and at time of the study was 14.6 years (4-23 years), with a mean post-op follow up of 6 years after the final surgery (6 months-17 years). The cosmetic outcome of clitoroplasty was excellent in 37, satisfactory in 10, and poor in 3. Gender identity was female, male, and mixed in 45, 4, and 1, respectively. The attitude to self and life was positive in 36 and negative in 6. The functional outcome of vaginoplasty was satisfactory, unsatisfactory, and undetermined in 11, 4, and 4, respectively. Endocrine control was satisfactory in 36/50. A novel assessment system has been adopted for analyzing the results of clitoroplasty and vaginoplasty. Endocrine control and surgical treatment are complimentary to each other to achieve satisfactory results in majority of CAH patients.
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