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A Tripeptide-Stabilized Nanoemulsion of Oleic Acid
Published on: February 27, 2019
Structural regression modelling of peptide based drug delivery vectors for targeted anti-cancer therapy
Yvonne Christian1, Amay Sanjay Redkar1, Naveen Kumar1
1Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
Abstract:
Drug resistance in cancer poses a serious challenge in finding an effective remedy for cancer patients, because of the multitude of contributing factors influencing this complex phenomenon. One way to counter this problem is using a more targeted and dose-limiting approach for drug delivery, rather than relying on conventional therapies that exhibit multiple pernicious side-effects. Stability and specificity have traditionally been the core issues of peptide-based delivery vectors. In this study, we employed a structural regression modelling approach in the design, synthesis and characterization of a series of peptides that belong to approximately same topological cluster, yet with different electrostatic signatures encoded as a result of their differential positioning of amino acids in a given sequence. The peptides tagged with the fluorophore 5(6)-carboxyfluorescein, showed higher uptake in cancer cells with some of them colocalizing in the lysosomes. The peptides tagged with the anti-cancer drug methotrexate have displayed enhanced cytotoxicity and inducing apoptosis in triple-negative breast cancer cells. They also showed comparable uptake in side-population cells of lung cancer with stem-cell like properties. The most-optimized peptide showed accumulation in the tumor resulting in significant reduction of tumor size, compared to the untreated mice in in-vivo studies. Our results point to the following directives; (i) peptides can be design engineered for targeted delivery (ii) stereochemical engineering of peptide main chain can resist proteolytic enzymes and (iii) cellular penetration of peptides into cancer cells can be modulated by varying their electrostatic signatures.
Insights
Engineered peptides show promise for targeted cancer drug delivery, overcoming resistance and reducing side-effects. These novel peptides enhance drug uptake and efficacy in cancer cells, leading to significant tumor reduction in vivo.
Area of Science:
- Biochemistry and Molecular Biology
- Drug Delivery Systems
- Cancer Research
Background:
- Drug resistance in cancer presents a significant challenge to effective treatment.
- Conventional therapies often cause adverse side effects due to their lack of specificity.
- Peptide-based drug delivery vectors face challenges in stability and specificity.
Purpose of the Study:
- To design, synthesize, and characterize peptides with modulated electrostatic signatures for targeted cancer therapy.
- To evaluate the efficacy of peptide-drug conjugates in enhancing cancer cell uptake and cytotoxicity.
- To investigate the in vivo performance of optimized peptides in reducing tumor growth.
Main Methods:
- Utilized structural regression modeling for peptide design.
- Synthesized and characterized peptides with varying amino acid positioning and electrostatic properties.
- Conjugated peptides with a fluorophore (5(6)-carboxyfluorescein) for cellular uptake studies and with methotrexate for cytotoxicity assays.
- Performed in vitro studies on cancer cell lines and in vivo studies on tumor-bearing mice.
Main Results:
- Peptides exhibited differential uptake in cancer cells, with some localizing in lysosomes.
- Methotrexate-conjugated peptides demonstrated enhanced cytotoxicity and induced apoptosis in triple-negative breast cancer cells.
- Peptides showed comparable uptake in lung cancer side-population cells with stem-cell-like properties.
- In vivo studies revealed significant tumor size reduction in mice treated with the most optimized peptide.
Conclusions:
- Peptides can be engineered for targeted drug delivery in cancer treatment.
- Stereochemical engineering of the peptide backbone can enhance resistance to proteolytic enzymes.
- Modulating peptide electrostatic signatures can control cellular penetration into cancer cells, offering a promising strategy for overcoming drug resistance.
