From Design to Study of Liposome-Driven Drug Release Part 1: Impact of Temperature and pH on Environment

Abstract

The marketed drug Doxorubicin (DOX) and the promising anti-cancer agent 9-(N-piperazinyl)-5-methyl-12(H)-quino[3,4-b][1,4]benzothiazinium chloride (9-PBThACl) were used to prepare and compare a range of liposomal delivery systems based on dipalmitoylphosphatidylcholine (DPPC). Liposome-assisted drug release was examined using the spectrophotometric method. In order to provide in vitro release characteristics of liposomal conjugates (L_DPPC/drug vs. L_{DPPC/drug/drug}) as well as to evaluate the impact of temperature and pH buffering on the conformation/polarity of the phospholipid bilayer, the encapsulation efficiency of the liposomes entrapping 9-PBThACl and DOX was calculated. In fact, some competition between the investigated molecules was noticed during the entrapment process because relatively high values of the encapsulation efficiency were observed only for the liposomal complexes containing one trapped drug molecule. An averaged absorbance value enabled us to indicate the pH value of the environment (pH ≈ 6.8), at which the physicochemical property profiles of the liposomal complexes were noticeably changed. Moreover, the operational factors limiting the drug release kinetics from the produced liposomes were mathematically modeled. First-order and Bhaskas models ensured satisfactory compliance with the experimental data for the liposomal complexes buffered at pH values of 5.50, 6.00, and 7.40, respectively.

Keywords: drug release profile; encapsulation efficiency; liposomal delivery systems; nanocarriers.

Figure 1

Size distribution in L_DPPC/DOX, L_{DPPC/9-PBThACl}, and L_{DPPC/9-PBThACl/DOX} liposomes.

Figure 2

Drug release (R%) profiles of 9-PBThACl and DOX from DPPC/drug/drug and DPPC/drug complexes for different pH values: ((A1,A2): pH = 5.50); ((B1,B2): pH = 6.00); ((C1,C2): pH = 6.50); and ((D1,D2): pH = 7.40).

Figure 3

Liposomal location of 9-PBThACl and DOX.

Figure 4

Impact of 5 week incubation of liposomal complexes: L_{DPPC/9-PBThACl/DOX} and L_{DPPC/9-PBThACl} on absorbance A (A_{λmax 9-PBThACl} = 488 nm); ((A): pH = 5.50), ((B): pH = 6.00), ((C): pH = 6.50), and ((D): pH = 7.40).

Figure 5

Impact of 5 week incubation of liposomal complexes: L_{DPPC/9-PBThACl/DOX} and L_DPPC/DOX on absorbance A (A_{λmax DOX} = 233 nm); ((A): pH = 5.50), ((B): pH = 6.00), ((C): pH = 6.50), and ((D): pH = 7.40).

Figure 5

Impact of 5 week incubation of liposomal complexes: L_{DPPC/9-PBThACl/DOX} and L_DPPC/DOX on absorbance A (A_{λmax DOX} = 233 nm); ((A): pH = 5.50), ((B): pH = 6.00), ((C): pH = 6.50), and ((D): pH = 7.40).

Figure 6

Effect of surrounding pH on averaged value of absorbance ΔA ((A): L_{DPPC/9-PBThACl/DOX} − L_{DPPC/9-PBThACl}, A_λmax = 488 nm) and ((B): L_{DPPC/9-PBThACl/DOX} − L_DPPC/DOX, A_λmax = 233 nm).

Figure 7

Release kinetics of 9-PBThACl and DOX from L_{DPPC/9-PBThACl/DOX} liposomes. Red lines correspond to the fits of the best mathematical models; ((A1): pH = 5.50, 9-PBThACl, (A2): pH = 5.50, DOX); ((B1): pH = 6.00, 9-PBThACl, (B2): pH = 6.00, DOX); ((C1): pH = 6.50, 9-PBThACl, (C2): pH= 6.50, DOX); and ((D1): pH = 7.40, 9-PBThACl, (D2): pH = 7.40, DOX). Measurement temperature: 37 °C.

Figure 7

Release kinetics of 9-PBThACl and DOX from L_{DPPC/9-PBThACl/DOX} liposomes. Red lines correspond to the fits of the best mathematical models; ((A1): pH = 5.50, 9-PBThACl, (A2): pH = 5.50, DOX); ((B1): pH = 6.00, 9-PBThACl, (B2): pH = 6.00, DOX); ((C1): pH = 6.50, 9-PBThACl, (C2): pH= 6.50, DOX); and ((D1): pH = 7.40, 9-PBThACl, (D2): pH = 7.40, DOX). Measurement temperature: 37 °C.

Figure 8

Release kinetics of 9-PBThACl and DOX from the L_{DPPC/9-PBThACl/DOX} liposomes. Red lines correspond to the fits of the best mathematical models; ((A1): pH = 5.50, 9-PBThACl, (A2): pH = 5.50, DOX); ((B1): pH = 6.00, 9-PBThACl, (B2): pH = 6.00, DOX); ((C1): pH = 6.50, 9-PBThACl, (C2): pH 6.50, DOX); and ((D1): pH = 7.40, 9-PBThACl, (D2): pH = 7.40, DOX). Measurement temperature: 41 °C.

Figure 8

Release kinetics of 9-PBThACl and DOX from the L_{DPPC/9-PBThACl/DOX} liposomes. Red lines correspond to the fits of the best mathematical models; ((A1): pH = 5.50, 9-PBThACl, (A2): pH = 5.50, DOX); ((B1): pH = 6.00, 9-PBThACl, (B2): pH = 6.00, DOX); ((C1): pH = 6.50, 9-PBThACl, (C2): pH 6.50, DOX); and ((D1): pH = 7.40, 9-PBThACl, (D2): pH = 7.40, DOX). Measurement temperature: 41 °C.

Scheme 1

Synthesis of 9-(N-piperazinyl)-5-methyl-12(H)-quino[3,4-b][1,4]benzothiazinium chloride.