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The Oncologist, Vol. 13, No. 3, 248-260, March 2008; doi:10.1634/theoncologist.2007-0180
© 2008 AlphaMed Press

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Clinical Pharmacology

Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents

William C. Zamboni

Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA; UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; GLP Analytical Facility, UNC Lineberger Comprehensive Cancer Center and School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA; Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina, USA; Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, North Carolina, USA

Key Words. Carrier-mediated anticancer agents • Nanoparticles • Nanosomes • Conjugates • Efficacy • Toxicity

Correspondence: William C. Zamboni, Pharm.D., Ph.D., Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, 3308 Kerr Hall CB 7360, 311 Pharmacy Lane, Chapel Hill, North Carolina 27599-7360, USA. Telephone: 919-843-6665; Fax: 919-962-0644; e-mail: zamboniwc{at}upmc.edu

Received September 27, 2007; accepted for publication January 9, 2008.

Disclosure: The article discusses several investigational anticancer agents; all agents included are investigational except Doxil® and Abraxane®. W.C.Z. has acted as a consultant/investigator to Alza, Hana Biosci, IDM, Insertt, Labopharm, Mersana, Yakult, Neopharm, SuperGen, and Sanofi-Aventis.


   ABSTRACT
Top
 Abstract
Introduction
 Nanosomal Formulations
 Nanoparticles
 Conjugates and Polymers
 Summary
 References
 
Major advances in the use of carrier vehicles delivering pharmacologic agents and enzymes to sites of disease have occurred over the past 10 years. This review focuses on the concepts and clinical evaluation of carrier-mediated anticancer agents that are administered i.v. or orally. The primary types of carrier-mediated anticancer agents are nanoparticles, nanosomes, which are nanoparticle-sized liposomes, and conjugated agents. Nanosomes are further subdivided into stabilized and nonstabilized or conventional nanosomes. Nanospheres and dendrimers are subclasses of nanoparticles. Conjugated agents consist of polymer-linked and pegylated agents. The theoretical advantages of carrier-mediated drugs are greater solubility, longer duration of exposure, selective delivery of entrapped drug to the site of action, superior therapeutic index, and the potential to overcome resistance associated with the regular anticancer agent. The pharmacokinetic disposition of carrier-mediated agents depends on the physiochemical characteristics of the carrier, such as size, surface charge, membrane lipid packing, steric stabilization, dose, and route of administration. The primary sites of accumulation of carrier-mediated agents are the tumor, liver, and spleen, compared with noncarrier formulations. The drug that remains encapsulated in or linked to the carrier (e.g., the nanosome or nanoparticle) is an inactive prodrug, and thus the drug must be released from the carrier to be active. The factors affecting the pharmacokinetic and pharmacodynamic variability of these agents remain unclear, but most likely include the reticuloendothelial system, which has also been called the mononuclear phagocyte system. Future studies need to evaluate the mechanism of clearance of carrier-mediated agents and identify the factors associated with the pharmacokinetic and pharmacodynamic variability of carrier agents in patients and specifically in tumors.


   INTRODUCTION
Top
 Abstract
 Introduction
Nanosomal Formulations
 Nanoparticles
 Conjugates and Polymers
 Summary
 References
 
Major advances in the use of carrier vehicles delivering pharmacologic agents and enzymes to sites of disease have occurred over the past 10 years [1–5]. This review focuses on the concepts and clinical evaluation of carrier-mediated anticancer agents that are administered i.v. or orally. A second review is being generated that will focus on the factors affecting the pharmacokinetic and pharmacodynamic disposition of carrier-mediated anticancer agents. Implantable nanoparticle devices or formulations of anticancer agents are not covered in this review [6, 7]. The primary types of carrier-mediated anticancer agents are nanoparticles, nanosomes, which are nanoparticle-sized liposomes, and conjugated agents (Table 1) [1–5]. Nanosomes are further subdivided into stabilized and nonstabilized or conventional nanosomes. Nanospheres and dendrimers are subclasses of nanoparticles. Conjugated agents consist of polymer-linked and pegylated agents. The theoretical advantages of carrier-mediated drugs are greater solubility, longer duration of exposure, selective delivery of entrapped drug to the site of action, superior therapeutic index, and the potential to overcome resistance associated with the regular anticancer agent [2, 3]. The process by which these agents preferentially accumulate in tumor and tissues is called the enhanced permeation and retention effect [8]. Pegylated STEALTH® (Alza Pharmaceuticals, Mountain View, CA) liposomal doxorubicin (Doxil®, Alza Pharmaceuticals; and Caelyx®, Schering-Plough Corporation, Kenilworth, NJ) and paclitaxel albumin-bound particles [1, 9] are the only two members of this relatively new class of agents that are administered i.v. and are U.S. Food and Drug Administration (FDA) approved [9–11]. Pegylated liposomal doxorubicin is approved for the treatment of refractory ovarian cancer and Kaposi's sarcoma (KS) [10–12]. Nonpegylated liposomal formulations of doxorubicin (Myocet®, Cephalon Europe, Maisons Alfort, France) and daunorubicin (DaunoXome®, Diatos, Paris, France) are approved in Europe for the treatment of breast cancer and KS, respectively [13]. Abraxane® (Abraxis BioScience, Inc., Los Angeles, CA) is approved for the treatment of refractory breast cancer [9]. There are also >100 nanosomal, nanoparticle, and conjugated anticancer agents that are in preclinical and clinical development. Newer generations of carrier-mediated agents containing two anticancer agents within a single nanosome or nanoparticle and antibody-targeted nanosomes and nanoparticles that may improve selective cytotoxicity are in preclinical and clinical development [14–16]. In addition, nanosomes, nanospheres, conjugates, and dendrimers provide a unique method to provide tumor-selective delivery of anticancer agents to tumors [17].


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  		Table 1. Summary of carrier-mediated chemotherapeutic agents

 
The pharmacokinetic disposition of these agents is dependent upon the carrier and not the parent drug until the drug is released from the carrier [15]. The drug that remains encapsulated in nanosomes or nanoparticles or linked to a conjugate or polymer is an inactive prodrug, and thus the drug must be released from the carrier to be active [17, 18]. Whether the drug needs to be released outside the cell in the tumor extracellular fluid (ECF) or within the cell depends on the formulation of the carrier and the mechanism of release [17, 19, 20]. After the drug is released from the carrier, the pharmacokinetic disposition of the drug is the same as after administration of the noncarrier form of the drug [17, 21]. Thus, the pharmacology and pharmacokinetics of these agents are complex, and detailed studies must be performed to evaluate the disposition of the encapsulated or conjugated form of the drug and the released active drug in plasma and tumors [18].

The nomenclature used to describe the pharmacokinetic disposition of carrier-mediated drugs is encapsulated or conjugated (drug within or bound to the carrier), released (active drug released from the carrier), and sum total (encapsulated or conjugated drug plus released drug) [17, 21] (Table 2). The released drug has also been called the legacy drug, regular drug, or warhead [17, 20, 21]. The released drug consists of drug that is protein bound and unbound or free drug. The ability to evaluate the various forms (encapsulated, released, unbound) of the drug after administration of a nanosome or nanoparticle formulation is dependent upon specific sample processing methods [21]. The factors affecting the pharmacokinetic and pharmacodynamic variability of these agents remain unclear, but most likely include the reticuloendothelial system (RES), which has also been called the mononuclear phagocyte system [17, 22–24].


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  		Table 2. Nomenclature describing the pharmacologic forms of carrier-mediated drugs

 

   NANOSOMAL FORMULATIONS
Top
 Abstract
 Introduction
 Nanosomal Formulations
Nanoparticles
 Conjugates and Polymers
 Summary
 References
 
Characteristics of Nanosomes
Nanosomes, also called liposomes, are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating the active drug. Conventional nanosomes are opsonized by plasma proteins, quickly recognized as foreign bodies, and rapidly removed by the RES [2, 25, 26]. Depending on the size and composition of the nanosome, RES uptake can occur within minutes after administration and remove the nanosomes from the circulation. Studies evaluating the disposition and tumor penetration of nanosomal and non-nanosomal anticancer agents suggest nanosomal agents have an extended systemic half-life (t1/2) and extravasate selectively into solid tumors through the capillaries of the tumor neovasculature [2, 26]. The exact mechanism of nanosomal clearance is currently unclear. The mechanisms by which nanosomes enter tissue and tumors and release drug are also not completely understood. In addition, nanosomes can be engineered to produce a complete spectrum of drug release rates that needs to be evaluated in in vivo systems [27, 28].

STEALTH® nanosomes are a specific type of pegylated nanosome [3, 24–26]. The development of STEALTH® nanosomes, which contain lipids conjugated to polyethylene glycol (PEG), was based on the theory that incorporation of PEG-lipids into nanosomes would allow the nanosome to evade the immune system and prolong the duration of exposure (Fig. 1) [3, 24–26]. STEALTH® nanosomes have a lipid bilayer membrane like conventional nanosomes, but the surface contains surface-grafted linear segments of PEG extending 5 nm from the surface [3, 24]. STEALTH® nanosomes are relatively small, with an average diameter of approximately 100 nm. The size optimally balances the drug-carrying capacity and circulation time, and allows extravasation through the endothelial gaps in the capillary bed of target tumors. Whether the drug is encapsulated in the core or in the bilayer of the nanosome is dependent upon the characteristics of the drug and the encapsulation process. In general, water-soluble drugs are encapsulated within the central aqueous core, whereas lipid-soluble drugs are incorporated directly into the lipid membrane.


Figure 1
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  		Figure 1. Clearance of stabilized and nonstabilized nanosomes via the reticuloendothelial system (RES) in the liver and spleen.

Abbreviation: HDL, high-density lipoprotein.

 
Systemic and Tissue Disposition of Nanosomes
Nanosomes can alter both the tissue distribution and the rate of clearance of the drug by making the drug take on the pharmacokinetic characteristics of the carrier [2, 3, 24]. The pharmacokinetic parameters of the nanosomes depend on their physiochemical characteristics, such as size, surface charge, membrane lipid packing, steric stabilization, dose, and route of administration [2]. The primary sites of accumulation of conventional nanosomes are the tumor, liver, and spleen, compared with non-nanosomal formulations [2, 22, 23, 25, 26, 29, 30]. The development of STEALTH® nanosomes was based on the discovery that incorporation of PEG-lipids into nanosomes yields preparations with superior tumor delivery to that of conventional nanosomes composed of natural phospholipids [2, 25, 26]. Incorporation of PEG-lipids causes the nanosome to remain in the blood circulation for an extended period of time (i.e., t1/2 >40 hours) and distribute through an organism relatively evenly, with most of the dose remaining in the central compartment (i.e., the blood) and only 10%–15% of the dose being delivered to the liver [25, 26, 29, 30]. This is a significant improvement over conventional nanosomes where typically 80%–90% of the nanosome deposits in the liver.

The clearance of conventional nanosomes has been proposed to occur by uptake of the nanosomes by the RES (Fig. 1) [2, 26]. The RES uptake of nanosomes results in their rapid removal from the blood and accumulation in tissues involved in the RES, such as the liver and spleen. Uptake by the RES usually results in irreversible sequestering of the encapsulated drug in the RES, where it can be degraded. In addition, uptake of the nanosomes by the RES may result in acute impairment of the RES and toxicity. The presence of the PEG coating on the outside of the nanosome does not prevent uptake by the RES, but simply reduces the rate of uptake (Fig. 1) [3, 24, 26]. The exact mechanism by which steric stabilization of nanosomes decreases the rate of uptake by the RES is unclear [2, 3, 30, 31].

There is significant interpatient variability in the pharmacokinetic disposition of nanosomal-encapsulated agents [17, 32–34]. It appears that the pharmacokinetic variability of the carrier formulation of a drug is several-fold higher than with the non-nanosomal formulation of the drug [17, 33, 34]. Thus, there is a need to identify factors associated with the significant pharmacokinetic variability. The potential factors affecting the pharmacokinetic and pharmacodynamic variability of nanosomal agents are the patient's age, body composition, and monocyte function [17, 21, 33–35]. There may be a reduction in the clearance of liposomes over time and thus dose reductions may be needed in subsequent cycles to minimize the risk for toxicity [36]. In addition, cisplatin has been shown to increase the clearance of pegylated liposomal doxorubicin; however, the mechanism of this interaction is unclear [37].

Tumor Delivery of Nanosomal Agents
The development of effective chemotherapeutic agents for the treatment of solid tumors depends, in part, on the ability of those agents to achieve cytotoxic drug exposure within the tumor [38, 39]. Solid tumors have several potential barriers to drug delivery that may limit drug penetration and provide inherent mechanisms of resistance [38]. Moreover, factors affecting drug exposure in tissue, such as alteration in the distribution of blood vessels, blood flow, capillary permeability, interstitial pressure, and lymphatic drainage, may be different in tumors than in the surrounding normal tissue [38].

The accumulation of nanosomes or large macromolecules in tumors is a result of the extended duration of exposure in the systemic circulation and the leaky microvasculature and impaired lymphatics supporting the tumor area [2, 29, 30, 38]. In addition, studies suggest that the cells of the RES also play a role in the tumor disposition of nanosomal agents and in the sensitivity of the tumors to nanosomal agents [32, 35, 40]. Once in the tumor, the nontargeted STEALTH® nanosomes are localized in the ECF surrounding the tumor cell, but do not enter the cell [41, 42]. Thus, for the nanosomes to deliver the active form of the anticancer agent, such as doxorubicin, the drug must be released from the nanosome into the ECF and then diffuse into the cell [18]. As a result, the abilities of the nanosome to carry the anticancer agent to the tumor and release it into the ECF are equally important factors in determining the antitumor effect of nanosomal-encapsulated anticancer agents. In general, the kinetics of this local release are unknown because it is difficult to differentiate between the nanosomal-encapsulated and released forms of the drug in solid tissue, although with the development of microdialysis this is becoming easier [18].

Modification of Toxicity with Nanosomal Agents
Nanosomal formulations can also modify the toxicity profile of a drug (e.g., Ambisome®; Astellas Pharma US, Inc., Deerfield, IL) [43]. This effect may be a result of the alteration in tissue distribution associated with nanosomal formulations [18, 26, 29, 30]. Anthracyclines, such as doxorubicin, are active against many tumor types, but cardiotoxicity related to the cumulative dose may limit their use [44]. Preclinical studies determined that nanosomal anthracyclines reduced the incidence and severity of cumulative dose–related cardiomyopathy while preserving antitumor activity [44]. There is also clinical evidence suggesting that pegylated liposomal doxorubicin is less cardiotoxic than conventional doxorubicin [44, 45]. Direct comparisons between pegylated liposomal doxorubicin and conventional doxorubicin showed comparable efficacies but a significantly lower risk for cardiotoxicity with the STEALTH® liposomal formulations of doxorubicin [44]. In addition, histologic examination of cardiac biopsies from patients who received cumulative doses of pegylated liposomal doxorubicin from 440–840 mg/m2, and had no prior exposure to anthracyclines, revealed significantly less cardiac toxicity than in matched doxorubicin controls (p < .001) [46]. Administration of a drug in a nanosomal formulation may also result in new toxicities [12, 47, 48]. The most common adverse events associated with pegylated liposomal doxorubicin are hand–foot syndrome, also known as palmar–plantar erythrodysesthesia (PPE), and stomatitis, which have not been reported with conventional doxorubicin [12]. The exact mechanisms associated with these toxicities are unknown, but these toxicities are schedule and dose dependent. Pegylated liposomal doxorubicin is generally well tolerated, and its side-effect profile compares favorably with those of other chemotherapies used in the treatment of refractory ovarian cancer. Proper dosing and monitoring may further enhance tolerability while preserving efficacy; however, there is still a need to identify factors associated with PPE, which can be dose limiting in some patients [12].

Nanosomal Agents
Stabilized and conventional nanosomes are the two primary subclasses of nanosomes. Nanosomes have been stabilized by coating the surface of the nanosome with PEG or proteins or incorporating PEG or proteins into the bilayer of the nanosome [13, 17, 21, 49, 50]. STEALTH® (Doxil®/Caelyx®) and conventional (Myocet®) are nanosomal formulations of doxorubicin that are approved in the U.S. and Europe, respectively [10–13]. Conventional nanosomal formulations of doxorubicin do not appear to have a pharmacologic or cytotoxic advantage over pegylated liposomal doxorubicin [44, 45, 51]. Pegylated STEALTH® nanosomal CKD-602 (S-CKD602), a camptothecin analogue, is in clinical development [32, 33, 40]. In addition, novel pegylated-nanosomal formulations of anticancer agents such as irinotecan (IHL-305 and nanoliposomal CPT-11) are in clinical development [52–55]. OptisomeTM nanoparticle technology using a novel sphingomyelin/cholesterol formulation has been used to stabilize nanosomes [49]. Optisomal vincristine, vinorelbine, and topotecan (topotecan liposome injection [TLI]) are in clinical development [49, 50, 56]. Protein stabilized nanoparticle (PSN) technology produces a lipid matrix that is stabilized by proteins for the encapsulation of drugs [57]. A PSN- stabilized nanosomal formulation of docetaxel (ATI-1123) is currently in development [57]. Conventional nanosomal paclitaxel (liposome-entrapped paclitaxel–easy to use [LEP-ETU]) is currently in phase III studies in breast cancer [58]. Compared with stabilized nanosomes, conventional nanosomal formulations of anticancer agents may result in the rapid release of the drug from the nanosome in blood and thus act more as an i.v. formulation than a tumor-targeting agent [59–64]. However, few studies have been performed to evaluate nanosomal-encapsulated and released drug in plasma and tumor [18, 21, 65].

Nanosomal encapsulation of camptothecins is an attractive formulation because of the solubility issues associated with most camptothecin analogues, maintenance of the drug in the active lactone form, and the potential for prolonged exposure after administration of a single dose [59, 61, 66]. Some of the nanosomal formulations of camptothecin analogues that are currently in development are liposome encapsulated SN-38 (LE-SN38) [61–64], lurtotecan (OSI-211) [59, 60, 67, 68], 9-nitrocamptothecin (9NC) [69–71], pegylated (IHL-305 and nanoliposomal CPT-11) and nonpegylated irinotecan [2, 52–54, 72], S-CKD602 [32, 33], and TLI [56]. A randomized phase II trial of OSI-211 in patients with relapsed ovarian cancer comparing OSI-211 i.v. on days 1, 2, and 3 repeated every 3 weeks with OSI-211 i.v. on days 1 and 8 repeated every 3 weeks was performed [59]. OSI-211 daily for 3 days was declared the winner in terms of objective response. A phase I study of LE-SN38 was performed in which patients were prospectively assigned to cohorts based on uridine diphosphate-glucuronosyltransferase 1A1 genotype [61]. The pharmacokinetic disposition of SN-38 was similar in the wild type (WT)/WT and WT/*28 cohorts. Interestingly, there were no reports of acute or delayed diarrhea even though the exposures of SN-38 were several-fold higher after administration of LE-SN38 than after irinotecan. The results of a phase I study of S-CKD602 administered i.v. over 1 hour every 21 days reported that the t1/2 was four- to eightfold higher and the plasma exposure was approximately 50-fold higher after administration S-CKD602 compared with non-nanosomal CKD-602 [32]. The results of that study suggest that S-CKD602 exhibits characteristics that are consistent with other STEALTH® nanosomes and thus may have pharmacologic advantages over other nanosomal formulations of camptothecin analogues [66]. In addition, S-CKD602 has produced responses in patients with platinum-refractory ovarian cancer [32]. Aerosolized administration of nanosomal 9NC was found to be feasible and safe in patients with advanced pulmonary malignancies, and 9NC was detected in plasma shortly after the start of treatment [69–71]. Novel pegylated (IHL-305 and nanoliposomal CPT-11) and nonpegylated nanosomal formulations of irinotecan are currently in preclinical and clinical development, and in theory may provide targeted delivery of irinotecan to the tumor with subsequent conversion to SN-38 via tumor carboxyl esterase [2, 52–55, 72]. The pegylated nanosomal formulations of irinotecan vary in the amount and type of PEG coated on the nanosome. IHL-305 is being developed for i.v. administration, whereas nanoliposomal CPT-11 is being developed for both systemic and convection-enhanced delivery to the brain [52–55, 72]. It appears that pegylated nanosomal formulations of irinotecan are pharmacologically superior to nonpegylated nanosomal formulations. Optisomal TLI produced a higher and longer exposure of topotecan in the plasma of rats compared with non-nanosomal topotecan. These results are consistent with prior optisomal formulations and provide pharmacokinetic advantages over non-nanosomal formulations of camptothecin analogues [49, 56].

Because of solubility issues, taxane analogues such as paclitaxel and docetaxel are also a class of anticancer agents that may be improved via the use of nanosomal carriers. In a phase I study, the pharmacokinetic profile of paclitaxel was similar after administration of LEP-ETU and non-nanosomal paclitaxel, suggesting that paclitaxel is immediately released from the liposome after LEP-ETU administration [58]. In addition, it is unclear if LEP-ETU has pharmacologic or cytotoxic advantages over ABI-007 [9, 58]. ATI-1123, is a PSN-stabilized nanosomal formulation of docetaxel that has shown greater antitumor activity in docetaxel-sensitive and docetaxel-resistant tumor models [57].

Liposomal formulations of vinca alkaloids and platinum analogues are also in development. Optisomal vincristine (vincristine sulfate liposome injection, Marqibo®; Hana Biosciences, South San Francisco, CA) has been evaluated in relapsed non-Hodgkin's lymphoma as a way to overcome the toxicity limitations and required dose reductions associated with the use of vincristine in this setting [49, 73]. Optisomal vincristine has a long t1/2 and achieves higher exposures in tumors and lymph nodes than in nerves. When administered at full doses, nanosomal vincristine appears to be less neurotoxic and more active than non-nanosomal vincristine in preclinical models and in patients. Optisomal vinorelbine (vinorelbine liposome injection, Alocrest®; Hana Biosciences) is also in clinical development for solid tumors and lymphoma [50]. MBP-426, a novel liposomal formulation of oxaliplatin, is currently in phase I studies [74]. Diaminocyclohexane (DACH) platinum L-NDDP, cis-bis-neodecanoato-trans-R,R-1,2 DACH platinum (AR-726, a structural analogue of oxaliplatin), has completed phase II trials in patients with advanced colorectal cancer [74].

The future generations of nanosomes will contain immunonanosomes, single nanosomes that contain two anticancer agents, and nanosomes that are thermosensitive [14–16, 51]. Immunonanosomes combine antibody-mediated tumor recognition with nanosomal delivery, and are designed for target cell internalization and intracellular drug release [16]. There are several nanosomal formulations that contain fixed ratios of two anticancer agents, such as doxorubicin:vincristine, daunorubicin:cytarabine, cisplatin:irinotecan, and floxuridine:irinotecan, that are currently in clinical development [14, 75]. Thermosensitive nanosomes may provide a means of improving the tumor-specific delivery of anticancer agents by rapidly releasing drug from the nanosome when hypothermia is applied to the tumor area [51].


   NANOPARTICLES
Top
 Abstract
 Introduction
 Nanosomal Formulations
 Nanoparticles
Conjugates and Polymers
 Summary
 References
 
ABI-007 is the first protein-stabilized nanoparticle approved by the FDA [1, 9, 76]. ABI-007 is an albumin-stabilized nanoparticle formulation of paclitaxel designed to overcome the solubility issues associated with paclitaxel that require the need for surfactants such as polyethoxylated castor oil (Cremophor EL®; BASF, Ludwigshafen, Germany) [1, 76, 77].

Albumin's central role in the delivery of hydrophobic molecules, such as paclitaxel, to target tissues is based on properties related to protein binding, receptor binding, and cellular accumulation [78] (Fig. 2). Albumin binds to paclitaxel reversibly (noncovalently), which allows the drug to be transported in the body and readily released at the cell surface. Through receptor binding, albumin initiates transcytosis of albumin-bound drug across the endothelial cell into the interstitial space. The albumin receptor–mediated transport on the endothelial cell wall within blood vessels facilitates the passage of ABI-007 from the bloodstream into the underlying tumor tissue [1, 76, 78] (Fig. 2). Consistent with this mechanism, ABI-007 differs from polyethoxylated castor oil–based paclitaxel with a higher plasma clearance and a larger volume of distribution [77]. Albumin accumulates in tumors, possibly in part as a result of the secretion of the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine, also called BM-40), which may result in intratumoral accumulation of albumin-bound paclitaxel [78, 79] (Fig. 2). The tumor retention times of non-nanoparticle paclitaxel and docetaxel are also longer, and thus the exact mechanisms associated with tumor retention of ABI-007 are unclear [77, 80, 81]. In addition, the mechanism by which the albumin-stabilized nanoparticle is catabolized and the extent to which paclitaxel is released are unclear. Based on in vitro studies, it appears that ABI-007 particles disperse into the individual albumin molecules bound to paclitaxel immediately after introduction into an aqueous solution, as would occur after i.v. administration into the bloodstream [78]. Thus, the albumin in ABI-007 may act more as a repackaging or formulation vehicle than as a nanoparticle-sized carrier of paclitaxel [17, 77, 78].


Figure 2
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  		Figure 2. Mechanism of albumin-bound paclitaxel transcytosis across blood vessels and accumulation of paclitaxel in tumor tissue via interactions with SPARC after administration of ABI-007.

Abbreviation: SPARC, secreted protein, acidic and rich in cysteine.

 
Similar to nanosomal agents, the dosage of ABI-007 is determined by the paclitaxel content of the formulation [1, 76]. The approved regimen for ABI-007 is 260 mg/m2 i.v. over 30 minutes every 3 weeks, which is higher than the usual dose range for paclitaxel (i.e., 135–200 mg/m2) [1, 9]. In addition, there was a lower incidence of myelosuppression after administration of ABI-007 than previously seen with similar doses of paclitaxel [76]. The other toxicities associated with ABI-007 were similar to those with high-dose, short-infusion paclitaxel, including sensory neuropathy and mucositis. Keratopathy, a relatively unique toxicity, was also associated with ABI-007 [76]. Thus, as with nanosomal formulations, administration of a drug in a nanoparticle formulation can alter the pharmacokinetic, tissue and tumor distribution, and toxicity pattern.

There are several nanosphere formulations of taxane and camptothecin analogues currently in development. Patients with primary brain tumors or brain metastases have a very poor prognosis that is primarily attributed to the impermeability of the blood–brain barrier (BBB) to cytotoxic agents [82]. Paclitaxel has shown activity against gliomas and other brain metastases; however, its use in the treatment of brain tumors is limited because of low BBB penetration and the side effects associated with i.v. administration. The lack of BBB penetration is believed to be associated with the P-glycoprotein (P-gp) efflux transporter. To overcome these issues, a formulation of paclitaxel entrapped in novel cetyl alcohol/polysorbate nanoparticles (PX-NP) was developed [82]. PX-NP had lower efflux by P-gp, greater brain exposure, and less toxicity than with paclitaxel, and thus may have potential in the treatment of brain tumors.

Tocosol® (Sonus Pharmaceuticals, Inc., Bothell, WA) paclitaxel is a proprietary drug emulsion delivery technology that uses vitamin E and its derivatives to create very small particles with high drug-loading capability [83]. Proposed benefits of the new formulation include its ready-to-use formulation (no reconstitution, dilution, or pharmacy preparation required) and its comparatively short 15-minute infusion administration time (conventional paclitaxel requires a 3-hour infusion). Tocosol® paclitaxel is also currently being evaluated in clinical trials for use in breast, ovarian, and lung cancer. Paclimer® (Guilford, Baltimore, MD), a nanosphere formulation of paclitaxel, is currently in preclinical development [84]. Paclimer® microspheres contain paclitaxel in a polilactofate polymer microsphere and are designed to continuously deliver low-dose paclitaxel. NK105 is a new polymeric micelle carrier system of paclitaxel that is in clinical development [85]. NK-012 is a micellar nanoparticle formulation of SN-38 that gradually releases SN-38 in an enzyme-independent manner at physiologic pH levels [86]. CNF1010 and ANX-514 are nanoemulsion formulations of 17-(allylamino)-17-demethoxygeldanamycin and docetaxel, respectively.


   CONJUGATES AND POLYMERS
Top
 Abstract
 Introduction
 Nanosomal Formulations
 Nanoparticles
 Conjugates and Polymers
Summary
 References
 
As an alternative to encapsulating anticancer agents in nanosomes or micelles, conjugates or polymers have been linked to drugs to act as a carrier to enhance drug delivery to tumor [20, 87, 88]. During the past 10 years, there has been a renaissance in the field of PEG-conjugated anticancer agents [89]. This new development has been attributed to the use of higher molecular weight PEGs (>20,000) and especially the use of PEG 40,000, which has an extended t1/2 in plasma and potential selective distribution to solid tumors [89]. Various PEG conjugates of anticancer agents, such as doxorubicin [90], methotrexate [91], and interferon [92], are currently in development. In addition, PEG conjugates of camptothecin analogues, including camptothecin, irinotecan, and SN-38, are currently in development [90–97]. PEG and 20-carbonate conjugates of camptothecin analogues are especially interesting because the conjugated prodrug forms highly water soluble agents and significantly extends the duration of exposure after a single dose [94, 95, 98].

There are several alternatives to PEG-conjugated anticancer agents. Paclitaxel poliglumex (PPX, Xyotax®, Cell Therapeutics, Seattle, WA), a macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-L-glutamic acid, has completed phase I studies [99]. PPX is a water-soluble formulation that also eliminates the need for polyethoxylated castor oil in the formulation. Previous conjugates of paclitaxel have been stopped in clinical development and have been associated with potential pharmacologic and pharmacokinetic problems [100, 101]. Docosahexaenoic acid (DHA)–paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation [100]. At the maximum-tolerated dose of DHA–paclitaxel (1,100 mg/m2), paclitaxel represented only 0.06% of the DHA–paclitaxel plasma exposure [101]. However, the paclitaxel concentrations remained >0.01 µM for an average of 6–7 days and the paclitaxel area under the concentration–time curve was correlated with neutropenia. The results of that study suggest that most of the drug remained in the inactive prodrug-conjugated form and that significant toxicity only occurred when released paclitaxel reached clinically relevant exposures. This depicts the need to perform detailed pharmacokinetic studies of conjugated and released drug in plasma and tumor.

MER-1001 is a novel polymeric prodrug of camptothecin that has produced greater antitumor activity in preclinical models and is currently in phase I development [20]. MER-1001 involves a dual-phase release of the prodrug camptothecin from the fleximer and then the release of the active camptothecin from the intermediate prodrug. The potential advantages of the dual-phase release system are that the intermediate prodrug is activated within the tumor rather than in the liver (e.g., irinotecan) so that tumor targeting is possible and camptothecin is released from the intermediate prodrug in a lipophilic, lactone-stabilized form within the tumor.

IT-101 is a camptothecin–polymer conjugate prepared by linking camptothecin to a hydrophilic, cyclodextrin-based, linear polymer through ester bonds [87, 88]. Preclinical studies indicate that IT-101 achieved longer plasma exposure and greater distribution to tumor than non-nanosomal camptothecin [87]. In addition, camptothecin is released from the conjugate within the tumor for an extended period of time. These pharmacologic characteristics likely play a role in the greater antitumor activity of IT-101 when compared with camptothecin or irinotecan [88]. IT-101 is currently in phase I development. CT-2106 is a biodegradable polyglutamated formulation of camptothecin that is current in clinical development [102].

Polymers of platinum analogues are also in clinical development. AP-5346 is a prodrug comprising a DACH platinum, a structural analogue of oxaliplatin, bound to hydroxypropyl methacrylate (HPMA), a water soluble biocompatible nanoparticle copolymer [103]. AP-5280 consists of a cisplatin-like platinum analogue linked to the copolymer HPMA [104]. Hyaluronic acid conjugates of anticancer agents are also in development [105]. Carrier-mediated conjugates of anticancer agents also have the same pharmacologic issues (the need to evaluate the pharmacokinetics of the prodrug conjugate and released drug) as nanosomal and nanoparticle formulations and the overall clinical benefit of these agents remains unclear.

Conjugated agents have also been developed to improve the oral bioavailability of drugs [106]. Synthetic phospholipid conjugates of cytosine arabinoside (ara-C) and gemcitabine have been developed [107, 108]. The novel ara-C and gemcitabine conjugates have systemic and cellular pharmacologic characteristics that are different from those of the parent drug, such as lower catabolism by cytidine deaminase, greater plasma t1/2, penetration of the BBB, and release of nucleoside monophosphate, a reaction that bypasses the rate-limiting initial nucleoside phosphorylation [107]. These phospholipid nucleoside conjugates possess the potential to have superior antineoplastic cytotoxicity profiles with less toxicity than the parent compound.


   SUMMARY
Top
 Abstract
 Introduction
 Nanosomal Formulations
 Nanoparticles
 Conjugates and Polymers
 Summary
References
 
Nanosomes, nanoparticles, polymers, and conjugates may be effective carriers to deliver anticancer agents to tumors [2–5, 18, 25, 26]. However, for anticancer agents encapsulated in nanosomes or nanoparticles or linked to conjugates to be an effective treatment in patients with solid tumors, the active form of the anticancer agent must be released from the nanosome into the tumor ECF or inside the cell [18]. As a result of this delivery process, new carrier-mediated anticancer agents should be evaluated in preclinical models and early clinical trials to insure that adequate release of drug occurs at its site of action. Future immunonanosomes and immunonanoparticles that contain an antibody conjugated to the carrier are being developed to provide targeted delivery to cancer cells expressing specific proteins [14, 109]. For example, anti–human epidermal growth factor receptor (HER)-2 immunonanosomes are being developed with the PEG nanosomes linked to an anti–HER-2 monoclonal antibody [109]. This technique may allow the entire nanosome to be taken up by the cell and possibly avoid potential problems with the release of active drug into the tumor ECF [14, 109]. It is unclear if drug conjugated to PEG or other carriers, or drugs encapsulated in microspheres or protein-stabilized nanoparticles, must be released from the carrier in order to achieve cytotoxic effects. A dendrimer is a nanoparticle of unimolecular micelles with a hydrophobic interior and hydrophilic exterior that acts as a drug carrier [4]. Dendrimers are a class of different fractal polymers prepared by a set of iterative reactions attached to a central core. The interior host sites can shield the drug from the exterior biologic milieu and stabilize the drug. The exterior of the dendrimer can also be labeled with tumor-specific ligands, such as folate, to provide tumor-selective delivery of anticancer agents [110]. In addition, novel methods for the fabrication of polymeric particles on the order of tens of nanometers to several microns using the technique particle replication in nonwetting templates (PRINT) allow the production of monodisperse, shape- and size-specific nanoparticles from an extensive array of organic precursors [19, 111]. The PRINT nature of particle production has a number of advantages over the construction of traditional nanoparticles such as nanosomes, dendrimers, and colloidal precipitates.

As more existing anticancer agents go off patent, these agents will most likely be evaluated in some type of carrier-mediated formulation. Antiangiogenic agents, antisense oligonucleotides, and enzymes represent rational candidates for nanosomal and nanoparticle formulations [16]. Anticancer agents that require continuous oral administration, such as tyrosine kinase inhibitors (e.g., imatinib, dasatinib, lapatinib, and sunitinib) may be candidates for nanoparticle carrier formulations that would provide prolonged drug exposure after administration of a single dose [112–114].

Future studies need to evaluate the mechanism of clearance of nanosomes, nanoparticles, and conjugated agents and identify the factors associated with pharmacokinetic and pharmacodynamic variability of nanosomes and nanoparticle anticancer agents in patients and specifically in tumors [30, 59–61, 66, 109]. In addition, future studies need to develop phenotypic probes that can be used to predict this variability and individualize therapy with nanosomal agents.


   REFERENCES
Top
 Abstract
 Introduction
 Nanosomal Formulations
 Nanoparticles
 Conjugates and Polymers
 Summary
 References
 

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