Table 2.

Biological properties of tumors that may disturb 3BP effects

Serial no.	Tumor biological criteria that may disturb 3BP effects	Suggested practical solutions	Rationale
1	Leaky nature of the tumor-associated blood vessels	Coating 3BP in liposomes, PEGylated liposomes, perillyl alcohol or other formulations	To increase the molecular size and prevent 3BP leakage outside the tumor tissues
2	Large-sized gaps between the endothelial cells lining the tumor capillaries (100–780 nm) depending on the cancer type	Coating 3BP in liposomes, PEGylated liposomes, perillyl alcohol or other formulations	To increase the molecular size and prevent 3BP leakage outside the tumor tissues vs normal endothelium (5–10 nm)24
3	Lacking adequate lymphatic drainage (in solid tumors)	Formulating 3BP in liposomes	To enhance 3BP trapping inside the tumors
4	Enhanced tumor permeability to chemotherapeutics (EPR effect causing 3BP efflux and wash out)	Formulating 3BP in liposomes, PEG or perillyl alcohol	To enhance 3BP trapping inside the tumors
5	Short retention time of low-molecular-weight drugs (eg, 3BP)25,26	Formulating 3BP in liposomes, PEG or perillyl alcohol	To enhance 3BP trapping inside the tumors
6	No accumulation of very small liposomes in the tumors	Formulating 3BP in liposomes (>200 nm), PEG or perillyl alcohol	To increase the molecular size of 3BP formulations and prevent 3BP leakage outside the tumor tissues
7	Extravasation of very small liposomes outside the tumors27	Formulating 3BP in liposomes, PEG or perillyl alcohol (>200 nm)	To increase the molecular size of 3BP formulations and prevent 3BP leakage outside the tumor tissues
8	Extensive angiogenesis	Formulating 3BP in liposomes coated with anti-VEGF monoclonal antibodies, PEG or perillyl alcohol	To facilitate 3BP-induced antiangiogenesis
9	Increased expression of mediators of cell surface permeability (may increase leakiness)	Formulating 3BP in liposomes, PEG or perillyl alcohol	Formulating 3BP in liposomes having tagged suitable ligands to facilitate tumor targeting and 3BP retention
10	Acidic tumor pH (neutralizes alkaline chemotherapeutics, eg, 3BP dissolved in alkaline medium)	Avoid dissolving 3BP in alkaline solutions	To preserve 3BP chemistry and prevent chemical neutralization of 3BP
11	High tumor GSH	Formulating 3BP in liposomes, PEG or perillyl alcohol	To mask 3BP from thiol groups in GSH and proteins
12	Attachment of crude 3BP to serum and tissue proteins	Formulating 3BP in liposomes, PEG or perillyl alcohol	To mask 3BP from thiol groups in serum and tissue proteins
13	Lack of effective tumor targeting	Formulating 3BP in liposomes, PEG or perillyl alcohol	To allow better 3BP retention inside the tumor tissues based on biological differences that distinguish the tumors from normal tissues

Abbreviations: 3BP, 3-Bromopyruvate; EPR, enhanced permeability and retention; GSH, glutathione; PEG, polyethylene glycol; VEGF, vascular endothelial growth factor.