Journal of the National Cancer Institute Advance Access originally published online on June 27, 2007
JNCI Journal of the National Cancer Institute 2007 99(13):983-985; doi:10.1093/jnci/djm042
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Published by Oxford University Press 2007.
EDITORIALS |
Toward a Systems Engineering Approach to Cancer Drug Delivery
Affiliations of authors: Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Bethesda, MD (MRD); Department of Biomedical Engineering, Duke University, Durham, NC (AC)
Correspondence to: Ashutosh Chilkoti, PhD, Department of Biomedical Engineering, Duke University, Durham, NC 27708 (e-mail: chilkoti{at}duke.edu).
As illustrated by Tang et al. (1) in this issue of the Journal, the treatment of solid tumors may be improved by controlling the pharmacologic properties of anticancer therapeutics. In 1906, Paul Ehrlich established the concept of drug delivery (2) by proposing a carrier that would "bring therapeutically active groups to the organ in question." The objective of drug delivery in the treatment of solid tumors is to increase the concentration of a therapeutic agent in the tumor while limiting systemic exposure (3–5). Increasing the concentration of drugs in the tumor relative to normal tissues results in improved tumor control and reduced toxic side effects. Numerous drug delivery technologies have been developed to accomplish this objective, including liposomes (6), micelles (7), antibody-directed enzyme–prodrug therapy (8), photodynamic therapy (9), affinity targeting (10), and macromolecular drug carriers (11,12).
Many of these drug delivery technologies, including the one described by Tang et al., take advantage of the unique pathophysiology of tumor vasculature. As early as the 1920s, researchers using a transparent chamber and injectable dye techniques found that, in contrast to normal tissue, tumors contain a high density of abnormal blood vessels that are dilated and poorly differentiated, with chaotic architecture and aberrant branching (13–16). Subsequently, various parameters of tumor vasculature were found to be impaired: for example, tumor blood vessels were observed to have a higher permeability than normal ones. These impaired functions contribute to the higher concentration of plasma proteins detected in tumor tissues than in normal tissues (17–26). This phenomenon was elucidated by Maeda and colleagues (27–29) and reviewed by Seymour (30), who described it as the enhanced permeability and retention effect, which is a combination of the increased permeability of tumor blood vessels and the decreased rate of clearance. The enhanced permeability of tumor vessels is due in part to larger pores in the tumor vasculature (
100–2000 nm) (31–33) compared with those of normal healthy continuous vasculature (2–6 nm) (34). The decreased rate of clearance is due to the lack of functional lymphatic vessels within a tumor, although there are indications that lymphatic vessels may exist in the periphery of a tumor (35–37). Even though retention and cellular uptake in a tumor may be improved with a targeting moiety specific for tumor receptors, all macromolecules, including targeted ones, preferentially accumulate in solid tumors after intravenous administration because their longer plasma half-life compared with small molecules provides a sustained driving force for their migration across the leaky tumor vasculature into the tumor mass.
Despite the constant development of new drug delivery vehicles that focus on increasing the overall accumulation of anticancer drugs within a tumor, the penetration of these drug carriers––a factor that is equally important in determining efficacy––has received much less attention. The penetration of drugs and/or drug carriers in a tumor can be operationally defined at different length scales as 1) penetration from the surface of the tumor boundary into the tumor center (i.e., whole tissue scale), 2) penetration across the tumor blood vessel (i.e., vascular permeability), 3) penetration away from the blood vessels through the extracellular matrix (analogous to the effective diffusion coefficient), and 4) penetration into the tumor cell itself (cellular uptake). Optimizing penetration in a tumor is important at length scales that are relevant to the mode of action of the drug. Hence, for chemotherapeutic drugs such as doxorubicin that normally have an intranuclear mode of action, optimization of penetration from the macroscale down to the intracellular site of action is critical, whereas for radionuclides, homogeneous penetration through the tumor mass without substantial tumor cell uptake may suffice to elicit a therapeutic effect. In terms of the determinants of penetration, properties of the drug or drug carrier, such as molecular size and binding affinity, as well as properties of the tissue, including extracellular matrix constituents and pore interconnectedness, are important factors that will affect penetration at all length scales (38–44). Increasing molecular size limits penetration across the blood vessel (40) and through the tumor tissue (41). Although Tang et al. (1) used doxorubicin encapsulated in a polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelle with a diameter of 10–20 nm, which is larger than doxorubicin alone, they achieved sufficient tumor accumulation to elicit a therapeutic response that they claimed could be attributed to the improved penetration of doxorubicin within the tumor.
Tang et al. (1) used a multitude of analytic, in vitro, and in vivo techniques to raise many interesting questions and present some promising results. Most notably, cellular uptake of doxorubicin was improved when delivered with PEG-PE, and this increased uptake may have contributed to the lower IC50 observed for doxorubicin PEG-PE micelles. Furthermore, the doxorubicin encapsulated within PEG-PE micelles demonstrated a different intracellular distribution than the free drug, and, in the light of the lower IC50 compared with free doxorubicin, these data suggest that the encapsulated doxorubicin may well have a different mechanism of cytotoxicity (45,46), though the precise mechanism of both cellular uptake and cytotoxicity of doxorubicin PEG-PE micelles remains a mystery. These results are also intriguing because they are in stark contrast to other drug delivery systems, in which encapsulated or conjugate drugs are often less cytotoxic than free drug. Many drug delivery systems demonstrate impressive tumor targeting in vivo but fail to elicit tumor regression because the drug is less bioavailable than free drug once it is localized to the tumor due to the encapsulation or conjugation process. The combination of impressive tumor targeting and good bioavailability of doxorubicin PEG-PE micelles most likely caused the excellent tumor control and reduced toxic side effects at equivalent doxorubicin doses observed by Tang et al.
In our view, several aspects of this study are puzzling and deserve further scrutiny: first, it is surprising that the ability of PEG-PE to form micelles that can encapsulate doxorubicin has not been previously explored, as claimed by the authors, and, if this claim is correct, the authors deserve credit for examining the interaction of an old drug with a well-known formulation agent to create a potent drug delivery system. In this context, we note that the authors do not provide information on which of the many PEG-PE lipids they used, because the molecular weight of PEG will affect the self-assembly of PEG-PE into micelles versus liposomes, and, indeed, data on the formation of micelles are lacking. Furthermore, the absence of hard evidence on the degree of doxorubicin encapsulation within these micelles raises the question of whether apples were compared with apples when cytotoxicity and tumor regression of free drug and micelle-encapsulated drug were compared. Fluorescence is extremely sensitive to the microenvironment of the fluorophore, and it is unclear exactly how doxorubicin content was quantified. Any errors in estimation of drug loading would skew the results on efficacy. We also take issue with the authors’ claim that their flow cytometry data prove enhanced tumor penetration of the micelles compared with free drug. Although they cite our work on the penetration of macromolecules into tumors as a motivation for their approach (42), simple flow cytometry of cells retrieved from a tumor cannot yield quantitative information on the spatial penetration of the drug into the tumor at any of the length scales that define tumor penetration. Their flow cytometry results indicate that tumor cells as a whole experienced more drug, but penetration was never quantified. Techniques such as administering a perfusion marker before sacrifice to separate tumor cells into subpopulations that are proximal and distal to a blood vessel based on perfusion marker intensity (47) would have provided more conclusive results. Nevertheless, impressive preclinical results have been reported by Tang et al. with this deceptively simple drug delivery system, so further studies are clearly warranted.
The future of drug delivery will depend on the ability of material scientists, chemists, pharmaceutical scientists, pharmacologists, biologists, bioengineers, and clinicians to work in concert to develop and translate to the clinic the next generation of drug delivery systems that focus on what are, in our opinion, three critical aspects of delivery: "drug combinations/sequencing," "targeting," and "integration." Currently, most drug delivery systems are designed to deliver only a single agent; however, combination chemotherapy is the current standard of care, so that future delivery systems should focus on the combination of multiple drugs with optimized spatial and temporal distribution within a tumor. The combination and proper temporal sequencing of chemotherapy delivery systems with other anticancer therapies such as radiation or immunotherapy may prove to be a very effective approach. Dynamic drug delivery technologies also represent a fertile ground for future research, and here, we need to move beyond the intellectually seductive but constricting notion that the only worthwhile method to target drugs to tumors is one based on affinity interaction between a ligand and a tumor-associated receptor. That said, although affinity targeting has many intrinsic limitations (10,38–40), it is, and will remain, an important weapon in our armamentarium. Emerging technologies that exploit the ability of delivery vehicles to dynamically morph their properties within a tumor to selectively deliver their payload to a tumor while sparing normal tissue is a new and intriguing concept for drug delivery. Examples of such "morphing" carriers include thermally responsive elastin-like polypeptides that undergo a soluble–insoluble transition in heated tumors (46,48–50) and thermally sensitive liposomes that release their payload in tumors that are mildly heated to 42 °C (51,52). Another fruitful area of investigation is the design of carriers that, instead of changing their properties in response to an "extrinsic" signal, can exploit the physicochemical differences between tumors and normal tissues (53) as "intrinsic" triggers to selectively deliver drugs to tumors (54). Prototypical examples of this approach are drug-loaded micelles and liposomes that rupture in response to the lowered pH of the tumor microenvironment. We believe that affinity targeting and dynamically morphing carriers are orthogonal yet complementary approaches, so that a clever and judicious combination of the two is likely to improve the prospects of getting the payload to its desired site. Finally, using a somewhat inexact analogy, we believe that integration is key to getting all this to work on the therapeutic battlefield––integration of the warhead (drug) with the guidance system (targeting moiety) and with the rocket (the delivery vehicle). Therefore, a systems engineering approach is clearly necessary for the design of drug delivery systems. The study by Tang et al. is a simple but effective demonstration of the benefits of integration of a drug with an appropriate carrier to yield a striking gain in efficacy. If Werner Von Braun and company could get it right more than a half-century ago, it is time for us to do so as well. May the days of pharmacologic missiles that miss their target and friendly fire that kills patients soon be over!
NOTES
M. R. Dreher would like to acknowledge the Intramural Research Program of the National Institutes of Health for support during the preparation of this Editorial.
REFERENCES
(1) Tang N, Du G, Wang N, Liu C, Hang H, Liang W. Improving penetration in tumors with nanoassemblies of phospholipids and doxorubicin. J Natl Cancer Inst (2007) 99:1004–15.
(2) Ehrlich P. Collected studies on immunity (1906) 1st ed. New York (NY): John Wiley and Sons.
(3) Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science (2004) 303:1818–22.
(4) Jain RK. Delivery of molecular and cellular medicine to solid tumors. Adv Drug Deliv Rev (2001) 46:149–68.[CrossRef][ISI][Medline]
(5) Moses MA, Brem H, Langer R. Advancing the field of drug delivery: taking aim at cancer. Cancer Cell (2003) 4:337–41.[CrossRef][ISI][Medline]
(6) Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov (2005) 4:145–60.[CrossRef][ISI][Medline]
(7) Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev (2001) 47:113–31.[CrossRef][ISI][Medline]
(8) Senter PD, Springer CJ. Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates. Adv Drug Deliv Rev (2001) 53:247–64.[CrossRef][ISI][Medline]
(9) Vrouenraets MB, Visser GWM, Snow GB, van Dongen G. Basic principles, applications in oncology and improved selectivity of photodynamic therapy. Anticancer Res (2003) 23:505–22.[ISI][Medline]
(10) Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer (2002) 2:750–63.[CrossRef][ISI][Medline]
(11) Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov (2003) 2:347–60.[CrossRef][ISI][Medline]
(12) Kopecek J, Kopeckova P, Minko T, Lu Z. HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action. Eur J Pharm Biopharm (2000) 50:61–81.[CrossRef][ISI][Medline]
(13) Algire GH, Chalkley HW, Legallais FY, Park HD. Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst (1945) 6:73–85.[ISI]
(14) Ide AG, Baker NH, Warren SL. Vascularization of the brown-pearce rabbit epithelioma transplant as seen in the transparent ear chamber. AJR Am J Roentgenol (1939) 42:891–9.
(15) Lewis WH. The vascular pattern of tumors. Bull Johns Hopkins Hosp (1927) 41:156–62.[ISI]
(16) Sandison JC. Observations on the growth of blood vessels as seen in the transparent chamber introduced into the rabbit's ear. Am J Anat (1928) 41:475–96.[CrossRef][ISI]
(17) Babson AL, Winnick T. Protein transfer in tumor-bearing rats. Cancer Res (1954) 14:606–11.
(18) Busch H, Greene HSN. Studies on the metabolism of plasma proteins in tumor-bearing rats. Yale J Biol Med (1955) 27:339–49.[Medline]
(19) Dewey WC. Vascular-extravascular exchange of plasma proteins in the rat. Am J Physiol (1959) 197:423–31.
(20) Duran-Reynals F. Studies on the localization of dyes and foreign proteins in normal and malignant tissue. Am J Cancer (1939) 35:98–107.
(21) Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol (1988) 133:95–109.[Abstract]
(22) Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res (1986) 31:288–305.[CrossRef][ISI][Medline]
(23) Heuser LS, Miller FN. Differential macromolecular leakage from the vasculature of tumors. Cancer (1986) 57:461–4.[CrossRef][ISI][Medline]
(24) Peterson H-I, Appelgren KL. Experimental studies on the uptake and retention of labeled proteins in a rat tumor. Eur J Cancer (1973) 9:543–7.[ISI][Medline]
(25) Song CW, Levitt SH. Quantitative study of the vascularity in Walker carcinoma 256. Cancer Res (1971) 31:587–9.
(26) Underwood JCE, Carr I. The ultrastructure and permeability characteristics of the blood vessel of a transplantable rat sarcoma. J Pathol (1972) 107:157–66.[CrossRef][ISI][Medline]
(27) Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst (1989) 6:193–210.[ISI][Medline]
(28) Maeda H, Seymour LW, Miyamoto Y. Conjugates of anticancer agents and polymers—advantages of macromolecular therapeutics in vivo. Bioconjug Chem (1992) 3:351–62.[CrossRef][ISI][Medline]
(29) Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy—mechanism of tumoritropic accumulation of proteins and the antitumor agent Smancs. Cancer Res (1986) 46:6387–92.
(30) Seymour LW. Passive tumor targeting of soluble macromolecules and drug conjugates. Crit Rev Ther Drug Carrier Syst (1992) 9:135–87.[ISI][Medline]
(31) Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol (2000) 156:1363–80.
(32) Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A (1998) 95:4607–12.
(33) Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, et al. Vascular permeability in a human tumor xenograft—molecular size dependence and cutoff size. Cancer Res (1995) 55:3752–6.
(34) Takakura Y, Mahato RI, Hashida M. Extravasation of macromolecules. Adv Drug Deliv Rev (1998) 34:93–108.[CrossRef][ISI][Medline]
(35) Jain RK, Fenton BT. Intratumoral lymphatic vessels: A case of mistaken identity or malfunction? J Natl Cancer Inst (2002) 94:417–21.
(36) Jain RK, Padera TP. Lymphatics make the break. Science (2003) 299:209–10.
(37) Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science (2002) 296:1883–6.
(38) Fujimori K, Covell DG, Fletcher JE, Weinstein JN. A modeling analysis of monoclonal antibody percolation through tumors—a binding-site barrier. J Nucl Med (1990) 31:1191–8.
(39) Weinstein JN, Eger RR, Covell DG, Black CDV, Mulshine J, Carrasquillo JA, et al. The pharmacology of monoclonal antibodies. Ann N Y Acad Sci (1987) 507:199–210.[Medline]
(40) Juweid M, Neumann R, Paik C, Perezbacete MJ, Sato J, Vanosdol W, et al. Micropharmacology of monoclonal antibodies in solid tumors—direct experimental evidence for a binding site barrier. Cancer Res (1992) 52:5144–53.
(41) Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res (2000) 60:2497–503.
(42) Dreher MR, Liu WG, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst (2006) 98:335–44.
(43) Rihova B. Receptor-mediated targeted drug or toxin delivery. Adv Drug Deliv Rev (1998) 29:273–89.[CrossRef][ISI][Medline]
(44) Yuan F, Krol A, Tong S. Available space and extracellular transport of macromolecules: effects of pore size and connectedness. Ann Biomed Eng (2001) 29:1150–8.[CrossRef][ISI][Medline]
(45) Nishiyama N, Nori A, Malugin A, Kasuya Y, Kopeckova P, Kopecek J. Free and N-(2-hydroxypropyl)methacrylamide copolymer-bound geldanamycin derivative induce different stress responses in A2780 human ovarian carcinoma cells. Cancer Res (2003) 63:7876–82.
(46) Dreher MR, Raucher D, Balu N, Colvin OM, Ludeman SM, Chilkoti A. Evaluation of an elastin-like polypeptide-doxorubicin conjugate for cancer therapy. J Control Release (2003) 91:31–43.[CrossRef][ISI][Medline]
(47) Tanaka J, Holden SA, Herman TS, Teicher BA. Response of subpopulations of the FSall C fibrosarcoma to low-dose x-rays and various potential enhancing agents. Anticancer Res (1992) 12:1029–33.[ISI][Medline]
(48) Dreher MR, Liu W, Michelich CR, Dewhirst MW, Chilkoti A. Thermal cycling enhances the accumulation of a temperature-sensitive biopolymer in solid tumors. Cancer Res (2007) 67:4418–24.
(49) Liu W, Dreher MR, Furgeson DY, Peixoto KV, Yuan H, Zalutsky MR, et al. Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice. J Control Release (2006) 116:170–8.[CrossRef][ISI][Medline]
(50) Meyer DE, Kong GA, Dewhirst MW, Zalutsky MR, Chilkoti A. Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia. Cancer Res (2001) 61:1548–54.
(51) Kong G, Anyarambhatla G, Petros WP, Braun RD, Colvin OM, Needham D, et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res (2000) 60:6950–7.
(52) Needham D, Anyarambhatla G, Kong G, Dewhirst MW. A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res (2000) 60:1197–201.
(53) Cardone RA, Casavola V, Reshkin SJ. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer (2005) 5:786–95.[CrossRef][ISI][Medline]
(54) Lee ES, Na K, Bae YH. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor. J Control Release (2005) 103:405–18.[CrossRef][ISI][Medline]
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