Targeting trastuzumab-resistant HER2+ breast cancer with a HER3-targeting nanoparticle
Disclosed herein are methods of treating cancer in a patient, the method comprising identifying a patient who is resistant to treatment with an anti-HER2 therapy; and administering to the patient a drug delivery molecule, comprising a polypeptide molecule adapted to target and/or penetrate a type of cell; a nucleic acid molecule bound to the polypeptide sequence via electrostatic interactions; and a chemical agent non-covalently linked to the nucleic acid sequence. Also disclosed are methods of inducing apoptosis in an anti-HER2 therapy resistant HER2+ breast cancer cell, the method comprising contacting the anti-HER2 therapy resistant HER2+ breast cancer cell with the drug delivery molecule. Further disclosed herein are methods of treating cancer in a patient, the method comprising identifying a patient who is resistant to anti-HER2 therapy; and administering to the patient a therapeutically effective amount of a drug delivery molecule, comprising a polypeptide molecule adapted to target and/or penetrate a type of cell; and a sulfonated corrole molecule bound to the polypeptide sequence. Finally disclosed herein are methods of inducing apoptosis in an anti-HER2 therapy resistant HER2+ breast cancer cell, the method comprising contacting the anti-HER2 therapy resistant HER2+ breast cancer cell with a drug delivery molecule, comprising a polypeptide molecule adapted to target and/or penetrate a type of cell; and a sulfonated corrole molecule bound to the polypeptide sequence.
1. A method of treating a triple-negative breast cancer in a patient comprising:
administering to the patient a therapeutically effective amount of a drug delivery molecule comprising:
(a) a polypeptide comprising a receptor binding domain of human heregulin-α; an adenovirus penton base protein; and a positively charged domain comprising a plurality of positively-charged amino acid residues that provide a net positive charge to the positively charged domain;
(b) a double-stranded nucleic acid molecule bound to the positively charged domain via electrostatic interactions; and
(c) a chemotherapeutic agent non-covalently linked to the double-stranded nucleic acid molecule;
wherein the triple-negative breast cancer expresses HER3.
2. The method of claim 1 , wherein the positively charged domain comprises a polylysine motif, and wherein the polylysine motif comprises a plurality of contiguous lysines.
3. The method of claim 2 , wherein the polylysine motif is a decalysine.
4. The method of claim 1 , wherein the double-stranded nucleic acid molecule comprises a nucleic acid molecule with the sequence of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.
5. The method of claim 1 , wherein the polypeptide comprises from N-terminus to C-terminus:
a heregulin-a binding domain comprising a sequence according to SEQ ID NO: 13;
a penton base segment comprising a sequence according to SEQ ID NO: 10; and
a decalysine.
6. The method of claim 1 , wherein the chemotherapeutic agent is doxorubicin.
7. The method of claim 1 , wherein the chemotherapeutic agent is intercalated with the double-stranded nucleic acid molecule.
8. The method of claim 1 , wherein the patient is a human.
9. A method of inducing apoptosis in a triple-negative breast cancer cell comprising:
contacting the triple-negative breast cancer cell with a drug delivery molecule comprising:
(a) a polypeptide comprising a receptor binding domain of human heregulin-α; an adenovirus penton base protein; and a positively charged domain comprising a plurality of positively-charged amino acid residues that provide a net positive charge to the positively charged domain;
(b) a double-stranded nucleic acid molecule bound to the positively charged domain via electrostatic interactions; and
(c) a chemotherapeutic agent non-covalently linked to the double-stranded nucleic acid molecule, wherein the chemotherapeutic agent is effective to induce apoptosis of the triple-negative breast cancer cell;
wherein the triple-negative breast cancer cell expresses HER3.
10. The method of claim 9 , wherein the contacting is in vitro.
11. The method of claim 9 , wherein the contacting is in vivo.
12. The method of claim 9 , wherein the breast cancer cell is a human breast cancer cell.
13. The method of claim 9 , wherein the double-stranded nucleic acid molecule comprises a nucleic acid molecule with the sequence of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.
14. A method of killing a triple-negative breast cancer cell comprising:
contacting the triple-negative breast cancer cell with a drug delivery molecule comprising:
(a) a polypeptide comprising a receptor binding domain of human heregulin-a; an adenovirus penton base protein; and a positively charged domain comprising a plurality of positively-charged amino acid residues that provide a net positive charge to the positively charged domain;
(b) a double-stranded nucleic acid molecule bound to the positively charged domain via electrostatic interactions; and
(c) a chemotherapeutic agent non-covalently linked to the double-stranded nucleic acid molecule;
wherein the triple-negative breast cancer cell expresses HER3.