Bypassing P-Glycoprotein Drug Efflux Mechanisms: Possible Applications in Pharmacoresistant Schizophrenia Therapy

Table 4

Drug delivery system	Polymer	Drug	Application	References
Nanocarrier (nanospheres)	Polyethylene glycol; Polybutylcyanoacrylate, alginate, polyethylene glycol, polylactic –co-glycolic acid, and polylactic acid.	Doxorubicin, clozapine, methotrexate, saquinavir, and zidovudine	Drug molecule is delivered to the cell nucleus and thus avoids recognition by the BBB and intestinal P-gp efflux pump.	[83, 106–108]
Liposomes	Phospholipids and cholesterol	Epirubicin, cisplatin, methotrexate, and doxorubicin	It inhibits P-gp efflux transporter by interaction with phospholipids; the system may also incorporate P-gp inhibitors.	[95, 96]
Polymer nanoparticles	Acrylic polymers such as poly-butyl-cyanoacrylate (PBCA)	Loperamide and doxorubicin	It bypasses the P-gp due it its nanosize.	[106]
Dendrimers	Mannosylated poly(propyl eneimine) and polyethylene glycol-poly(amidoamine)	Vinblastine, doxorubicin, and propranolol (intestinal)	It inhibits P-gp efflux by bypassing the pump	[97–99]
Nanogels	Cationic and non-ionic polymers, NVP/NIPAM	Antisense phosphorothioate oligonucleotides (SODN) and 5-fluorouracil	It allows for the incorporation of P-gp inhibitors.; Polysorbate coating of nanogel increases brain accumulation from 0.18 to 0.52%.	[83, 109]
Micelles	Pluronics L61 and F127 and P85	Doxorubicin, digoxin, paclitaxel, ritonavir, and vinblastine	() It inhibits P-gp efflux and also involves intracellular drug transport modification thereby avoiding the P-gp efflux pump.; () Drug permeability in monolayered BBB model by P-gp substrates increased from 1.6- to 29-fold. No change in digoxin concentration in mdr1 knockout mice.	[83, 110, 111]
Hydrogels	(hydroxypropyl) Methacrylamide	Cyclosporine A and doxorubicin	It inhibits the P-gp efflux transporter by incorporation of drugs such as cyclosporine A that are P-gp inhibitors.	[112]
Lipid Nanocapsule	PEG-HS (polyethylene glycol-660 hydroxystearate), poly-methacrylate polymers, and HPMC	Etoposide and tacrolimus	() It inhibits P-gp efflux by incorporation of surfactant based P-gp inhibitors.	[83, 89]
	Triglycerides of capric and caprylic acids, Solutol	Paclitaxel	() Paclitaxel uptake increased in MDR1 expressing cells; the half-life in brain prolonged from 21 min to >5 h.
Self-emulsifying drug delivery systems	Poly-methacrylate polymers	Paclitaxel and yacrolimus	It inhibits P-gp efflux by incorporation of surfactant based P-gp inhibitors, for example, Tween.	[113, 114]
	Medium chain triglyceride, PEG 400, polysorbate 80, and cremophor EL	Penfluridol (schizophrenia therapeutic agent)	It enhances solubilization of drug and thus effective brain concentrations.
	Capmul MCM-C8, cremophor EL, and pluronic L-121	Irinotecan	It increased oral bioavailability by P-gp modulation.
Nanosuspension	Pluronic F68	Risperidone	P-gp efflux inhibition by employing polymers that inhibit the P-gp transporter, such as pluronic.	[101]