Drug Release from Liposomes: Role of Mechanism Based Models. Bradley D. Anderson University of Kentucky

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1 Drug Release from Liposomes: Role of Mechanism Based Models Bradley D. Anderson University of Kentucky

2 l i p o s o m e Why liposomes? Si OH N O N AR-67 O H O O Xiang and Anderson, Adv. Drug Delivery Rev. 58, (2006) Drug solubilization Tumor targeting EPR effect Controlled release potential Safety/reduction of drug toxicity Commercial products

3 EPR effect (enhanced permeability & retention) Particle size cut-off for extravasation Rakesh K. Jain et.al. Nature Reviews Cancer 2, (2002)

4 Pegylation and particle size effects on liposome clearance and tissue uptake Ishida et al., Int. J. Pharm., 190, (1999)

5 NCI Alliance for Nanotechnology in Cancer Tunable release kinetics? Nanoparticle accumulation in tumor may require up to12-24 hrs to reach optimum Free drug concentration profile in tumor determines efficacy What release rate is optimal? Can mechanistic models enable the design of optimal release rates?

6 NCI Alliance for Nanotechnology in Cancer Antitumor efficacy of CPT-11 in a colon cancer model depends on liposome release kinetics Vehicle CPT mg/kg Liposomal CPT mg/kg t 1/2 = 14 h t 1/2 = 57 h Drummond et al., Cancer Res., 66, 3271 (2006)

7 As long as the release process is still not fully understood it is difficult and speculative to make improvements to the existing formulation or devise new compounds.

8 Predictive Models Must Account for the Driving Force, Membrane Permeability and Environmental Factors Prediction of: Driving Force Contributions What species are transported? ph gradients and their role? Membrane binding Drug precipitation & self-association Role of environmental factors (ph, temperature, media composition) Membrane Permeability Barrier domain for lipid bilayer transport. What governs membrane selectivity to permeant structure? How do we predict chemical selectivity? How do we predict permeant size selectivity?\ Temperature effects

9 from the Doxil package insert 2 mg/ml doxorubicin HCl 16 mg/ml lipid 3.19 mg/ml cholesterol 9.58 mg/ml HSPC 3.19 mg/ml MPEG- DSPE ~0.6 mg/ml NH 4 SO 4 ph 6.5 buffer(histidine) sucrose for isotonicity

10 OCH 3 O O OH OH H O O OH OH Equilibria and kinetic processes governing DXR release rates from actively loaded liposomes using dynamic dialysis H 3 C O NH 3 OH Cl Doxorubicin (DXR) DXR actively-loaded - low intravesicular ph Extravesicular ph

11 Physical processes included in a mechanistic model for Doxil Acid-base dissociation equilibria (i.e., DXR pka) for DRX inside and outside the liposomes; Acid-base dissociation equilibria (i.e., pka) for Ammonia inside and outside the liposomes; Acid-base dissociation equilibria (pka) for sulfate inside and outside (if present) the liposomes; Precipitation equilibrium (i.e., Ksp) for DRX + and SO4 2- inside the liposomes; Binding equilibria for DRX and DRX + onto outer and inner bilayer leaflets; Forward/reverse rate constants for DRX bilayer and dialysis membrane transport Forward and reverse rate constants for ammonia bilayer and dialysis membrane transport Csuhai et al., J. Pharm. Sci., 104, 1087 (2015)

12 PD MiniTrap G25 Gel filtration columns Separation of drugloaded liposomes by gel filtration Dox conc( µg/ml) Unentrapped free drug Liposomal fraction ENCAP FREE Volume (ml) Encapsulated Dox ( ug/ml) ug/ml Dox 5 ug/ml Dox 10 ug/ml Dox 15 ug/ml Dox 20 ug/ml Dox Time (h) Representative blank liposomal uptake profiles (ph 5.5,3 mg/ml lipid w/250 mm (NH 4 ) 2 SO 4 ) Gel filtration: Dox spiked (90%) human plasma/ph 7.4 buffer (10%)

13 Which is the permeable DXR species? SA k f n = P n f n + P 1 f p ( n + = 1/(1 + [ H ]/ Ka ) ) pk a = 8.13 ± 0.20 Rate constant vs ph for DXR monomer uptake into blank liposomes containing 250 mm (NH 4 ) 2 SO4 at 37 C. Suspension concentration: 3 mg lipid/ml (HPLC with ELSD detection) P n = 8.5 x 10-4 cm/h P p ~ 0 Neutral form is the permeable species Csuhai et al., J. Pharm. Sci., 104, 1087 (2015)

14 DXR self-association Top view Anti parallel stacking Side view Agrawal et al., Eur. J. Med. Chem., 44, 1437 (2009) DXR uptake vs. time at varying DXR concentrations in 242 mm Na 2 SO 4 at ph 6.5 (10 mm phosphate), 37 ºC. Dotted lines represent simultaneous fits to the isodesmic self-association model. Csuhai et al., J. Pharm. Sci., 104, 1087 (2015)

15 Rate of liposomal uptake (- - -) and fraction of DXR monomer ( ) vs. DXR concentration (3 mg lipid/ml, 240 mm Na 2 SO 4 ph 6.5, 37 C) DXRmon = DXRTotal{2/[1 + (4KnDXRTotal + 1)0.5]}2 K n = 7030 ± 900 M -1 Csuhai et al., J. Pharm. Sci., 104, 1087 (2015)

16 Ksp determination for (DXR) 2 SO 4 DXR solubility vs ph and (NH 4 ) 2 SO 4 concentration at 37 ± 0 C. Error bars represent standard deviations. Pooled DXR solubility data at 5 ± 1 C, 25 ± 1 C, and 37 ± 0 C, in the presence of 250, 150, 100, or 50 mm (NH 4 ) 2 SO 4. DXR Solubility (mg/ml) * T ( C) 250 mm (NH 4 ) 2 SO mm (NH 4 ) 2 SO mm (NH 4 ) 2 SO 4 50 mm (NH 4 ) 2 SO 4 Apparent Ksp (M 3 ) (Eq. 7) 5 ± ± ± ± ± ± 0.2 x ± ± ± ± ± ± 0.3 x ± ± ± ± ± ± 0.2 x 10-7 *n=3; average values ± SD Csuhai et al., J. Pharm. Sci., 104, 1087 (2015)

17 Influence of membrane binding on liposomal uptake rate constant A: liposomal surface area per ml P 1 : neutral monomer permeability f n : fraction neutral monomer f ubo : fraction unbound c & d: aqueous & outer bilayer leaflet volume ratios Intravesicular membrane binding is amplified due to the high internal surface/volume ratio. DXR uptake versus lipid concentration at 10 µg/ml DXR, 37 C, ph 6.5, with 250 mm intraliposomal (NH4)2SO4. The model fit assumes only the monomeric, neutral species is membrane permeable.

18 O OH O OH OH Mechanistic model accounts for all equilibria and kinetic processes below Dynamic intravesicular ph calculation is critical. OCH 3 O OH H O Implicit eqn. for ph calculation (from charge balance H 3 C O NH 3 OH Cl Doxorubicin (DXR) DXR actively-loaded - low intravesicular ph Extravesicular ph Fugit et al., J. Control. Release, 217, 82 (2015)

19 Mechanistic model simulations in various release conditions (e.g., external ph and [NH 3 ]) Low internal ph driven by NH 3 release when [NH 3 ] = 0 in media Intravesicular ph governed by external [NH 3 ] Fugit et al., J. Control. Release, 217, 82 (2015)

20 Intravesicular ph modulates the driving force for DXR release model simulations ph mm NH 3 ph mm NH 3 ph mm NH 3 ph mm NH 3 Fugit et al., J. Control. Release, 217, 82 (2015)

21 NH mm x 2 x 3 DXR release vs time (expt. vs. prediction) ph x % DXR Remaining % DXR Remaining Time (hours) Time (hours) Experimental Fugit et al., J. Control. Release, 217, 82 (2015) Prediction

22 75 Observed Simulated 60 % DXR Released After 19 hr Calculated Intravesicular ph Superiority of the mechanistic model Empirical model Mechanistic model Fugit et al., J. Control. Release, 217, 82 (2015)

23 DXR Susp. Conc. entrapped (µg/ml) y = x y = x y = x Dox uptake vs. Temperature ph 6.0, 30 mm phosphate, 265 mm NaCl, 10 ug/ml Dox, 3 mg/ml lipid y = x y = x Time (h) 37 C 42 C 47 C 52 C 57 C Arrhenius plot uptake rate vs. 1/T Ea = 65.6 kcal/mol 10 => 24-fold in k (consistent with chain ordering effect on bilayer barrier properties & size selectivity) Xiang & Anderson, Biophys. J., 72, 223 (1997)

24 Historical Model for Structure- Transport Relationships Bulk Solubility-Diffusion theory Graham (1866); Overton s rule (1896, 1899, 1902) Permeability: P o = K mem D mem /h incorrect! K mem = PC membrane/water ~ PC octanol/water D mem = const/mw 1/2 log (P o ) = const log PC octanol/water /MW 1/2 Not for bilayer transport! Xiang & Anderson, Adv. Drug Delivery Revs., 58, 1357 (2006)

25 Bulk Solubility Diffusion Theory fails to account for phase transitions ln Perm (observed and predicted) Bulk permeability Formic Acid across DPPC DPPC phase transition /T x 1000 (K) Data plotted from Xiang and Anderson, Biophys. J

26 10-4 Bulk solubility-diffusion model fails to account for the amplified size selectivity log P m δ /K = const - n log V 10-5 P m δ / K or D Decane diffusion (n=0.8) Egg PC - liquid crystalline bilayers (n=1.48) DPPC - gel phase bilayers (n=6.2) V (A 3 )

27 Permeability theory - barrier domain model Xiang & Anderson, Adv. Drug Delivery Revs., 58, 1357 (2006) P m Kbarrier/ water Dbarrier = = f h barrier P o = from solubility-diffusion theory f = reflects chain ordering factor P o Lactone t 1/2 = 3 hr f = f o exp(-λa s /a f ) Bilayer free-surface area decreases with increase in chain-order Permeant cross-sectional area Joguparthi et al., J Pharm Sci 97: , 2008

28 Translation from in vitro to in vivo Release methods in blood or plasma Pitfalls of dynamic dialysis see Modi & Anderson, Mol. Pharmaceutics, 10, 3076 (2013) Non-sink release methods see Fugit & Anderson, Mol. Pharmaceutics, 11, 1314 (2014) Real-time spectroscopic methods see Fugit et al., J. Control. Release, 197, 10 (2015) Topotecan (TPT) Liposomal TPT release in human plasma monitored by fluorescence excitation spectra Dependence of TPT release t 1/2 on extravesicular ammonia concentration

29 Environmental factors in vivo may influence liposomal release rates Exchange of plasma lipid components with vesicle lipids Disruption of ph gradients by permeable (small molecule) plasma components see Joguparthi & Anderson, J. Pharm. Sci., 97, 433 (2008) accelerated silatecan release due to plasma CO 2 see Fugit et al., J. Control. Release, 197, 10 (2015) Liposomal TPT retention in PBS vs. human plasma NH 3 in human plasma (8 donors) as rec d from supplier Increase in NH 3 in human plasma vs storage time at various temps. Liu et al., Anticancer Drugs, 13, 709 (2002)

30 Acknowledgments Eva Csuhai Sogol Kangarlou Tian-Xiang Xiang Andre Ponta Kyle Fugit Duhyung Choi Paul Bummer Amar Jyoti Portions of the work presented were supported by Grant Number R25CA from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Instittute or the National Institutes of Health.

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