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Drug Delivery

Drug Delivery - Poster Session E

Poster X11 - Rationale design of denatured collagen binding PTX micelles for tumor targeted drug delivery

Saturday, October 26, 2024
10:00 AM – 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  

Background:
Active tumor-targeted approaches have been promising but often face regulatory hurdles due to complex designs and target selectivity issues within heterogeneous tumors. Denatured collagen in the tumor microenvironment can be used as a potential universal targeting entity for different subtypes of cancer. Thus, the objective of the current study is to develop a denatured collagen binding (CBP) heptapeptide decorated micellar (MC) system (PEG-b-PPS) to deliver model drug paclitaxel (PTX) to study its effect on a breast cancer model.
Hypothesis:
We hypothesize that the surface display of denatured collagen-binding peptide (CBP) TLTYTWS on PTX-loaded PEG-b-PPS MCs will have improved tumor microenvironment targeting for efficient drug delivery to inhibit tumor progression.

Materials and

Methods:  

Methods:
PTX-loaded PEG-b-PPS MCs were synthesized using the cosolvent evaporation method and their sizes, stability, zeta potential, and polydispersity index were characterized using Dynamic Light Scattering (DLS). Micelles surface-displaying 3% and 5% of CBP were synthesized by overnight rotation of blank micelles with DMSO solubilized CBP. The loading efficiency of PTX and its release from the PEG-b-PPS micelles within the period of 96 hours were evaluated using a UV-visible nano spectrophotometer. To evaluate the binding of CBP to the denatured collagen, MMP2-mediated denaturation of type IV collagen was carried out in a time-dependent reaction and assayed by silver staining. With the time optimized, 10µg/ml denatured collagen samples were coated on a 96-well plate to study the binding affinity of bare FITC-CBP and 5% CBP-PEG-b-PPS micelles. The cytotoxic evaluation of PTX-loaded micelles by MTT assay was carried out in MCF-7 cells.

Results, Conclusions, and Discussions: 

Results:
The sizes of the blank micelles and PTX-loaded micelles were 50.0 ± 6.09 nm and 61.8 nm ±12.6 with a polydispersity index (PI) of 0.4235 ± 0.00 nm and 0.271 ±0.09 nm respectively. 3% and 5% CBP-bound micelles displayed sizes of 46.9 ± 3.8nm and 42.4 ± 3.28nm with zeta potential -0.0497 mV and -0.0849 mV respectively. The PTX-loaded micelles stored at 4°C were stable from day 1 to day 7 in their optimum size range of 26 nm. The % encapsulation efficiency of PTX in MCs was obtained to be 50.1% to 95%. PTX displayed a slow and sustained release from MCs at pH 7.4 with 4% released by 3hrs, 18.3% by 6hrs, 44.65% by 24hrs, 61.8% by 48hrs, and remained steady at 61.8% by 72hrs. At pH 6.5, a slower release was observed at 48hrs of about 26.1%, 64.1% release at 72hrs remaining steady till 96hrs. There was a time-dependent increase in the denaturation indicating cleaved products at 200kDa, 169kDa, and 92kDa from 150 mins-1320 mins for MMP2-mediated denaturation of type IV collagen. 5% CBP-PEG-b-PPS displayed a 90% increase in binding as compared to 50µM CBP to denatured collagen. PTX-loaded PEG-b-PPS micelles of 50µg/ml, 100µg/ml, and 200µg/ml in MCF-7 cells resulted in an 86% decrease in cell viability at 72 hours.

Conclusion:
A peptide specific to denatured collagen was identified and bound to PEG-b-PPS micelles which was found to have slow and sustained release.

Acknowledgements (Optional):  Acknowledgements:
NIH R03EB032602-01 (Bijukumar), Blazer Foundation, MBT Program at UIC.