Cancer has dethroned heart disease as the top killer among Americans under the age of 85 despite the significant progress in cancer detection and treatment in the past decades. It was estimated that there would be more than 1.4 million new cancer cases and about half a million cancer deaths in 2006 alone [1]. Chemotherapy is one of the several available arsenals to fight cancer, but it often has life-threatening side effects. For example, cisplatin, a widely used potent anticancer drug [2–4], has significant acute and chronic nephrotoxicity [5]. Common side effects of anticancer drugs include the decrease in the number of white blood cells, red blood cells, and platelets, nausea, vomiting, and hair loss.
An increased resistance to drug treatment is another serious challenge. Most of the cancer patients, although initially responsive, eventually develop and succumb to drug-resistant metastasis. For example, the success of typical postsurgical regi- mens for ovarian cancer, usually a platinum/taxane combination, is limited either by primary tumors being intrinsically refractory to treatment or by initially respon- sive tumors becoming refractory to treatment [6]. As a result, the first-line treat- ment of ovarian cancer yields about 30% pathologic remission and an overall response rate of 75%, but the disease usually recurs within 2 years of the initial treatment, ultimately causing death [7–9].
The intrinsic and acquired drug resistance mechanisms that mitigate the cyto- toxic effects of anticancer drugs [6, 10–14] include the loss of surface receptors and transporters to slow drug influx, cell-membrane-associated multidrug resistance to remove drugs [12], specific drug metabolism or detoxification [15], intracellular drug sequestration [16], overexpression of Src tyrosine kinase [17] and splicing factor SPF45 [18], increased DNA-repair activity [19], altered expression of oncogenes and regulatory proteins [20, 21], and increased expression of antiapoptotic genes and mutations to resist apoptosis [14, 22]. For instance, melanoma cells are
drug-resistant to a variety of chemotherapeutic drugs by exploiting their intrinsic resistance to apoptosis and by reprogramming their proliferation and survival path- ways during melanoma progression [23]. Some mechanisms of drug resistance in cancer are shown in Fig. 10.1.
An important mechanism of multidrug resistance is that cancer cells overexpress ATP Binding Cassette (ABC) transporters in their plasma membranes [24], mainly the classical P-glycoprotein (PGP or MDR1, ABCB1), the multidrug resistance associated proteins (MRPs, in the ABCC subfamily), and the ABCG2 protein [25], all of which can very efficiently transport a variety of anticancer drugs out of the cells. [6, 10, 12, 13, 26–29] Therefore, as a consequence of the slowed drug entry but efficient drug removal by the P-gp pumps and the intracellular drug consump- tion (Eq. 1), the drug concentration in the cytoplasm is below the cell-killing thresh- old, resulting in a limited therapeutic efficacy.
d[D]/dt = Rd + Re + Rt − Rp - gp − Ri drug resistance (1) where [D] is the cytosolic drug concentration, Rd, Re, and Rt are the rates of drug entry by diffusion, endocytosis, and transport, respectively, RP-gp is the rate of drug
Fig. 10.1 Sketch of cancer cell’s drug internalization (a–c) and forms of drug resistance (d–k).
(modified from [12], with permission from Annual Reviews)
removal by the P-gp pumps, and Ri is the rate of drug consumption by other forms of drug resistance.
The drug toxicity to healthy tissues and the cell resistance to treatments described earlier pose a twofold challenge for drug delivery technology—to improve the delivery selectivity and to overcome the cell resistance—to simultane- ously maximize the therapeutic efficacy and minimize the side effects.
One approach toward this goal is to exploit the enhanced permeability and reten- tion effect (EPR) of cancerous tissues [30–36], which have unique pathophysiologi- cal characteristics, including the extensive angiogenesis and hence hypervasculature, defective vascular architecture, impaired lymphatic drainage/recovery system, and greatly increased production of permeability mediators. [30–36] The cutoff size for the permeation through the cancer blood capillaries was measured to be between 380 and 780 nm [34–37]. Thus, nanosized drug carriers for example, polymer–drug conjugates [38–41], dendrimers [42–44], liposomes [45, 46], and polymer micelles or nanoparticles [47–54], can easily extravasate from the bloodstream and are trapped in tumor tissues, but not from the tight blood capillaries in healthy tissues [55], and thus preferentially deliver drugs to cancerous tissues. Furthermore, active tumor-targeting is also achieved by equipping the drug carriers with tumor-targeting groups such as folic acid [42, 56–73] and luteinizing-hormone-releasing hormone (LHRH) peptide [74–78]. These ligands can also induce receptor-mediated endocy- tosis for efficient cellular internalization of the drug carriers by cells overexpressing their receptors [79]. Therefore, by increasing bioavailability of drugs at sites of action, drugs in these carriers have shown enhanced efficacy against resistant tumors and fewer side effects.
Among the drug carriers mentioned earlier, polymeric nanoparticles are attract- ing much attention. [48, 51–53, 80–82] Their sizes can be easily optimized for penetrating through fine capillaries, crossing the fenestration into interstitial space, and efficient cellular uptake via endocytosis/phagocytosis. Furthermore, they can be equipped with a hydrophilic surface, for example, with a layer of poly(ethylene glycol) (PEG), to evade the recognition and subsequent uptake by the reticuloen- dothelial system (RES), and thus to have a circulation time that is long enough for passive accumulation in cancer tissues via the EPR effect [47, 50, 83–88].
Such stealthy nanoparticles with long circulation times can be fabricated from core-shell micelles formed by self-assembly of amphiphilic block copolymers (Fig. 10.2) [51–53, 89–92]. The hydrophobic inner core can carry drugs. The tight hydrophilic shell (e.g., PEG chains) prevents the protein adsorption and cellular adhesion, and thus protects the drug from degradation. The PEG chains also prevent the recognition by the RES [52, 87], which leads to an increased blood circulation time and enhanced drug accumulation in tumor tissues [52, 87]. Such nanoparticles have been used as drug carriers for cisplatin [93–98], doxorubicin [99–103], camp- tothecin [104–110], and paclitaxel [111–115]. These drugs were found to have a higher accumulation in tumors and lower toxicity. For example, in C26 tumor-bearing mice, the administration of doxorubicin (20 mg/kg) resulted in toxic deaths, while the administration of doxorubicin in PEO-P(Asp) micelles permitted doses as high as 50 mg/kg with no toxic deaths [116].