Rational Design of Translational Nanocarriers - Functional Polymers for Nanomedicine - page 42

showed low or even no anticancer activity. 77 The rate of drug release is also very
important because tumor cells have intrinsic and acquired drug-resistance
mechanisms to remove intracellular drugs, 78,79 e.g. as a result of cell-membrane-
associated multidrug resistance to efflux drugs 79,80 and cell-specific drug
metabolism or detoxification. 81 Tumor cells can also sequestrate some weakly
basic drugs in their lysosomes and use biomacromolecules to bind drugs to limit
their access to their targets. Thus, it is only the intracellular drug molecules free to
bind to their targets that are useful therapeutically. Such free drug concentration
in the cytosol, herein referred to as the effective cytosolic drug concentration [D]
(effective [D] for short) determines the overall therapeutic efficacy.
Drug carriers that reach tumor cells are generally internalized by endocy-
tosis 82,83 and routed to endosomes and then acidic lysosomes, as shown in
Figure 3.7. The internalized carrier can release the drug in one of two possible
ways or both: (1) within the lysosome, followed by drug diffusion, as illustrated
with the upper path in Figure 3.7, and (2) in the cytosol, following the carrier
escape from the lysosome, as illustrated in the lower path in Figure 3.7. For a
specific tumor cell, [D] is a function not only of the cellular uptake of the carrier
but also of its drug release rate (see Eq. 1 on the figure). If either ends up being
''too little, too late,'' it can prevent reaching an effective [D].

d n 4 y 3 n g | 2

(1) Intra-lysosome release
The intra-lysosome release mechanism (upper path in Figure 3.7) works for
most carriers that can be endocytosed into endosomes/lysosomes. The pH in
endosomes decreases progressively, typically near 6 in early endosomes, near 5
in late endosomes, and about 4-5 in lysosomes. 84 This acidic pH and the

Figure 3.7

Cytosolic drug accumulation by drug delivery: [D], effective drug
concentration in cytosol; R e , endocytosis rate of the carrier; R rL , drug
release rate of the carrier in lysosomes; R rC , drug release rate of the
carrier in cytosol; R LDr , lysosomal drug release rate; R LCr , lysosomal-
carrier escape rate; R R , the overall rate of drug removal by P-gp pumps
and drug consumption by other forms of drug resistance. Reprinted with
permission from ref. 8. Copyright 2012 Elsevier.