Polymeric implants for cancer chemotherapy

Advanced Drug Delivery Reviews 26 (1997) 209–230

L

Polymeric implants for cancer chemotherapy Lawrence K. Fung, W. Mark Saltzman* 120 Olin Hall, School of Chemical Engineering, Cornell University, Ithaca, NY 14853, USA Received 22 October 1996; accepted 7 March 1997

Abstract Cancer chemotherapy is not always effective. Difficulties in drug delivery to the tumor, drug toxicity to normal tissues, and drug stability in the body contribute to this problem. Polymeric materials provide an alternate means for delivering chemotherapeutic agents. When anticancer drugs are encapsulated in polymers, they can be protected from degradation. Implanted polymeric pellets or injected microspheres localize therapy to specific anatomic sites, providing a continuous sustained release of anticancer drugs while minimizing systemic exposure. In certain cases, polymeric microspheres delivered intravascularly can be targeted to specific organs or tumors. This article reviews the principles of chemotherapy using polymer implants and injectable microspheres, and summarizes recent preclinical and clinical studies of this new technology for treating cancer.  1997 Elsevier Science B.V. Keywords: Polymers; Biodegradable polymers; Polymer pellets; Microspheres; Chemotherapeutic agents; Local delivery; Sustained delivery; Intratumoral delivery; Polymeric chemotherapy

Contents 1. Introduction ............................................................................................................................................................................ 2. Polymeric drug delivery systems .............................................................................................................................................. 2.1. Non-degradable polymeric reservoirs and matrices ............................................................................................................. 2.2. Biodegradable polymeric devices ...................................................................................................................................... 3. Applications of polymeric chemotherapy .................................................................................................................................. 3.1. Polymeric microparticles for sustained chemotherapy ......................................................................................................... 3.2. Polymeric implants for sustained interstitial chemotherapy.................................................................................................. 3.3. Polymeric microparticles for chemoembolization................................................................................................................ 4. Other emerging applications..................................................................................................................................................... Acknowledgments ....................................................................................................................................................................... References ..................................................................................................................................................................................

1. Introduction Systemically administered chemotherapy can be curative for some tumors [1], but it is not particularly effective in treating many solid malignant tumors, *Corresponding author. Tel: (607)255-2657; Fax: (607)2551136.

209 211 211 213 214 214 217 223 224 225 225

such as tumors in the brain [2] or liver [3]. The complex biology of tumors often limits the effectiveness of chemotherapy; cell type and doubling time [1], as well as tumor size, heterogeneity, location and vascularization [4], influence the outcome of a course of chemotherapy. In some cases, chemotherapy is enhanced by identifying drug analogs with different physical properties, such as lipophilicity or

0169-409X / 97 / $32.00  1997 Elsevier Science B.V. All rights reserved PII S0169-409X( 97 )00036-7

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ability to permeate membranes, or by synthesizing analogs that require activation within host tissues, or by administering multiple drugs [5]. New chemotherapeutic agents with novel mechanisms of action, higher antitumor activity or reduced toxicity can produce a better outcome for some patients. Antitumor activity can often be enhanced by improvements in the method of drug administration, particularly methods that focus therapy at the tumor

site. For example, intrathecal administration of methotrexate is often useful for treating meningeal neoplasia. In this article, we describe new methods for drug administration that may prove particularly valuable in the treatment of cancer. Over the past few decades, techniques for encapsulating a variety of drugs into polymer pellets (Fig. 1a) or microparticles (Fig. 1b) have been produced by physical entrapment of active agents in solid polymer

Fig. 1. Typical controlled drug delivery systems. (a) Solid particles of dopamine were dispersed within an EVAc matrix and coated with a rate-limiting EVAc membrane. The polymer pellets release dopamine at a constant rate for many months following implantation (see [103,104]). The ruler is scaled in cm; each pellet diameter is |0.3 cm. (b) Scanning electron micrograph of PLGA microspheres containing dispersed antibody particles. The antibodies are released at a constant rate from these small spheres for over one month (see [105]). The scale bar indicates 0.01 cm.

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Table 1 Examples of polymers used in polymeric drug delivery Polymers

Class of polymers

Examples

References

Natural, biodegradable

Proteins Polysaccharides

Albumin Cellulose Chondroitin sulfate Starch

[88,113,122] [110] [99,102] [87,91]

Synthetic, biodegradable

Polyesters

Poly(lactic acid) Poly(lactic–co-glycolic acid) Poly[bis( p-carboxyphenoxy)propane– co-sebacic acid] Poly(fatty acid dimer–co-sebacic acid)

[64,66,138–141] [42,111,114,117] [46–48,50–54,60,63,142]

Polyanhydrides

Poly(ortho esters) Synthetic, non-degradable

Silicone elastomers Poly(ethylene–co-vinyl acetate) Polyacrylates

Polyisobutylcyanoacrylate Polyisohexylcyanoacrylate Poly(methyl methacrylate)

[58,67,78,81,107,108] [143] [21] [24,49,61,62,106,144,145] [146] [115] [68,147]

materials 1 . These polymeric delivery systems slowly release the encapsulated agent during incubation in water or after implantation into tissues, providing clinicians with an opportunity to introduce large quantities of an anticancer agent directly at a tumor site for a prolonged period. Since drugs are administered locally, systemic toxicity can potentially be minimized. In the following sections, we review the general principles for the use of polymer implants for delivery of chemotherapy, and summarize the preclinical and clinical trials performed using polymeric controlled drug delivery. Interested readers may want to explore other related reviews that describe drug delivery systems for treating tumors of the brain [8–12], microspheres for drug delivery [13–16] and delivery systems for proteins and other macromolecules [17–20].

fashion using polymers as delivery vehicles. Since the discovery of the first controlled-release polymer systems in the 1960s, new drug delivery systems have become available for clinical use, including steroid-releasing reservoirs for contraception (Norplant and Progestasert), pilocarpine-releasing devices for glaucoma therapy (Ocusert) and a host of new delivery systems for the treatment of cancer (see references in Tables 2–8). Drug delivery systems are based on biocompatible polymers, a subset of polymer materials with sufficient biocompatibility and appropriate physical properties to provide controlled delivery (Table 1). A delivery system for a specific agent is usually produced by selecting a polymer with the correct physical properties, and designing a composite delivery system that provides the desired rate and pattern of drug release; these designs exploit various mechanisms of drug transport through polymer materials.

2. Polymeric drug delivery systems

2.1. Non-degradable polymeric reservoirs and matrices

The production of drug-loaded polymeric pellets and microspheres (Fig. 1) introduced a new concept in drug administration: Drugs can be delivered to tissues in a sustained, continuous and predictable 1

An alternate approach that is not covered here uses chemical coupling of anticancer agents to water-soluble polymers in an effort to produce drugs with enhanced stability, controlled bioavailability or tumor targeting [6,7].

The first polymeric controlled-release devices were based on non-degradable polymers, principally silicone elastomers. In 1964, researchers recognized that certain dye molecules could penetrate through the walls of silicone tubing [21,22], an observation that lead to the development of reservoir drug delivery systems, which are hollow polymer tubes

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filled with a drug suspension (Fig. 2a). The drug is released by dissolution into the polymer and then diffusion through the polymer wall, a mechanism that works for any agent that can dissolve and diffuse through either silicone or poly(ethylene–co-vinyl acetate) (EVAc), the two most commonly used nondegradable polymers. The Norplant 5-year contraceptive delivery system, approved for use by women in the United States since 1990, is based on this technology. Anticancer drugs can also be delivered by this same approach, as in the case of carmustine release from silicone-encased drug reservoirs, which provides reasonably constant release for | 30 h (Fig. 3a, data from [23]). Solid matrices of non-degradable polymers can

also be used for long-term drug release (Fig. 2b). In comparison to reservoir systems, these devices are simpler (since they are homogeneous and, hence, easier to produce) and potentially safer (since a mechanical defect in a reservoir device, but not a matrix, can lead to dose dumping). On the other hand, it is more difficult to achieve constant rates of drug release with non-degradable matrix systems; for example, the rate of release of carmustine from an EVAc matrix device drops continuously during incubation in buffered water (Fig. 3b) [24]. Constant release can sometimes be achieved by adding rate limiting membranes to homogeneous matrices, yielding devices in which a core of polymer / drug matrix serves as the reservoir. In other cases, water-soluble,

Fig. 2. Mechanisms of drug release from polymer delivery systems. Non-degradable polymers release drugs by diffusion or swelling: (a) In diffusion-controlled reservoir systems, a drug core is surrounded by a polymer coating; (b) in diffusion-controlled matrix systems, drug particles are dispersed in a polymer matrix; (e) swelling-controlled systems are produced from water-soluble, cross-linked polymers. Biodegradable polymers can release drugs by diffusion, erosion or both: (c) If the erosion front moves into the polymer relatively slowly, then the drug release may be controlled by surface erosion; (d) in most polymers, however, erosion occurs throughout the entire material (a process called bulk erosion) so that both diffusion and erosion contribute to the observed pattern of release.

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Fig. 3. Rates of release of carmustine from non-degradable and degradable devices. (a) Carmustine (45 mg) was encapsulated in a non-degradable silicone reservoir device, which was subsequently immersed in stirred water [23]. Constant carmustine release (h) occurred from |4 to |30 h. Matrices of (b) EVAc [24] and (c) PCPP-SA [28] loaded with carmustine (6 and 2 mg, respectively) were immersed in phosphate-buffered water. The in vitro rates of release (G) for both devices were similar. [(a) and (b) are redrawn from previous publications, permission granted by American Association for Cancer Research, Inc. and John Wiley & Sons, Inc.].

crosslinked polymers can be used as matrices [25]; release is then activated by swelling of the polymer matrix after exposure to water (Fig. 2e).

2.2. Biodegradable polymeric devices Polymeric devices formed from biodegradable polymers dissolve after implantation and drug release (Fig. 2c–d). The most commonly used biodegradable polymer is poly(lactide–co-glycolide) (PLGA), which was first developed as a material for absorbable sutures [26,27]. Polymer degradation occurs by hydrolysis for the most commonly used polymers, such as PLGA and polyanhydrides. Dissolution of an implant or microsphere occurs by a complex sequence of steps, including water penetration into the polymer, hydrolytic degradation of the polymer molecules and dissolution / release of monomers and oligomers, which leads to physical erosion of the material. By careful selection of the polymer prop-

erties, certain aspects of device erosion can be controlled (Fig. 2c–d). Biodegradable polymers are generally used to form drug delivery devices by physically entrapping drug molecules into matrices or microspheres. When carmustine-loaded pellets, formed from a polyanhydride polymer–poly( p-carboxyphenoxypropane–co-sebacic acid) (PCPP-SA), are incubated in phosphate-buffered water, the pattern of release is similar to that observed from non-degradable EVAc matrices (Fig. 3c) [28]. When these same pellets are implanted into the brains of laboratory animals, release appears to occur at a slower rate over a much longer period [28]. Correlating the rate of drug release measured in common laboratory assays with the rate of drug release into tissues is a difficult problem in the development of new drug delivery systems; for biodegradable polymers, observed differences appear to be due to local transport and metabolism of drugs in tissues [28], as well as to

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differences in the rate of polymer degradation after implantation [29].

3. Applications of polymeric chemotherapy When anticancer agents are delivered systemically, they must cross several barriers to reach their site of action within tumor cells [4,30]: Drug molecules must permeate through capillary walls, diffuse through the extracellular space, traverse the tumor cell membrane and reach the proper intracellular target. Unstable agents may be subject to spontaneous or metabolic elimination during this process; consequently, drug concentrations at the target may be low. Higher systemic doses could provide additional antitumor activity at the target, but may also result in undesirable toxic effects. Polymeric delivery systems can be used to provide better or safer chemotherapy by either prolonging the duration of systemic therapy (Fig. 4a) or focusing drug therapy in a particular tissue region (Fig. 4b–c).

3.1. Polymeric microparticles for sustained chemotherapy Conventional treatments for hormone-responsive cancers, such as carcinomas of the breast, prostate and endometrium, require frequent injections of hormone agonists [31]. For example, injections of synthetic agonistic analogs of luteinizing hormonereleasing hormone (LH-RH) inhibit tumor growth in the prostate by lowering plasma testosterone levels [32–34]. Since the plasma half-life of LH-RH analogs in humans is short (e.g. 3.6 h after subcutaneous injection and 2.9 h after intravenous injection [35]), daily injections are necessary to maintain concentrations that are sufficient to suppress testosterone production. Unfortunately, daily injection is inconvenient and often produces an undesirable testosterone release response in patients [36]. To lower the frequency of injections, (LH-RH analog)-loaded PLGA microspheres (Lupron Depot [37]) and cylindrical implants (Zoladex [38]) were produced (Table 2). Following injection

Fig. 4. Compartmental representation of transport of drugs released from polymers into the body: (a) represents intramuscular or subcutaneous injection of microspheres; (b) represents intratumoral pellet implantation or microsphere injection; (c) represents targeted intraarterial or intravenous injection of microspheres (chemoembolization). All boxes symbolize compartments where drug molecules can be present. Boxes with thickened boundaries represent polymeric devices: pellets or microspheres. Arrows between two compartments symbolize the transfer of drug molecules from one compartment to the next.

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Table 2 Commercially available devices for polymeric chemotherapy Device name

Drug encapsulated

Polymer

Disease treated

References

Decapeptyl Lupron Depot Zoladex Gliadel

( D-Trp 6 )LH-RH Leuprolide ( D-Ser(Bu t )6 ,AzGly 10 -GnRH Carmustine

PLGA PLGA PLGA PCPP-SA

Prostate cancer Prostate cancer Prostate cancer Recurrent malignant glioma

[109] [37] [38] [56]

of the microspheres, for example, serum testosterone levels are reduced for 4 weeks [39]. When the microspheres are injected subcutaneously or intramuscularly, they are immobilized at the injection site. The drug molecules are released from the immobilized spheres, diffuse locally in the tissue, then enter the vascular system, which distributes the drug throughout the body (Fig. 4a). Unlike free drug injection, the effective half-life for therapeutics administered by microspheres is much longer (Fig.

5) and the total amount of administered agent is reduced. Even longer periods of drug release are potentially achievable using this approach [40]. Prolonged systemic delivery appears particularly useful for hormonal anticancer therapies. For example, medroxyprogesterone acetate (MPA) is an androgenic steroid often used in the hormonal therapy of breast cancer in women [41]. A single subcutaneous injection of MPA-loaded PLGA microspheres inhibits both growth [42] and initiation [43] of

Fig. 5. Drug concentration in plasma following intramuscular injection of drug-loaded microspheres (solid lines) or daily subcutaneous injections of unencapsulated drug (dotted line). When the drug is administered via microspheres, therapeutic concentrations are maintained for over 4 weeks. In contrast, following an injection of unencapsulated agent, most of the drug is eliminated in 1 day, so repeated injections are necessary. Concentrations in blood following injection of free drug (dotted line) were calculated based on previously measured pharmacokinetic parameters for leuprolide in humans [35]. Plasma levels after microsphere injection matched the results of a simple pharmacokinetic model [106], similar to the one outlined in Fig. 4a, to data obtained following intramuscular injection of Lupron Depot in humans [39].

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Table 3 Partial list of animal studies for interstitial polymeric chemotherapy using microspheres, nanospheres, microcapsules and nanocapsules Device

Encapsulated agent

Study

Delivery method

Tumor

Reference

Cellulose, PLA microcapsules

5-Fluorouridine

Histology, radiology, pharmacokinetics

Intraarterial injection

Various

[110]

PLGA microcapsules

Luteinizing hormonereleasing hormone

Pharmacokinetics

Subcutaneous or intramuscular injection

Prostate cancer

[111]

Ion-exchange resin microspheres

Adriamycin

Pharmacokinetics, tumor growth

Aortic injection

Salivary adenocarcinoma in limbs

[93]

Gelatin microspheres

Human interferon a A/D

Tumor growth inhibition, efficacy

Intravenous injection

Pulmonary metastasis of B16 melanoma

[100]

PLGA microcapsules and microspheres

( D-Trp 6 )-LH-RH and SB-75

Histology, distribution

Intramuscular injection

Various LH-RHdependent tumors

[112]

Albumin microspheres

Adriamycin

Tumor regression

Intratumoral injection

Non-metastasizing sarcoma

[113]

PLGA microspheres

Leuprolide acetate

Pharmacokinetics

Intramuscular and subcutaneous injection

Prostate cancer

[114]

Polyisohexylcyanoacrylate nanoparticles

Doxorubicin

Histology, distribution

Intravenous injection

Metastatic retinosarcoma

[115]

Ion-exchange microspheres

Doxorubicin

Tumor growth

Intratumoral injection

Liver cancer

[116]

Albumin microspheres

Cisplatin

Tumor growth, pharmacokinetics

Injection in hepatic artery

VX 2 hepatocellular carcinoma

[88]

PLGA microspheres

Medroxyprogesterone acetate

Pharmacokinetics

Subcutaneous injection

Breast cancer

[42]

PLGA microspheres

Cisplatin

Toxicity, distribution

Venoportal injection

Colon carcinoma liver metastasis

[117]

Gelatin–chondroitin 4-sulfate microspheres

g-Interferon, GM-CSF

Histology, immunity

Subcutaneous injection

Intracranial B16/F10 melanoma

[99]

Ion-exchange resin microspheres

Doxorubicin

Tumor growth

Intrahepatic injection

Colorectal adenocarcinoma in liver

[118]

Magnetic chitosan microspheres

Oxantrazole

Pharmacokinetics

Intraarterial injection

Brain tumors

[119]

PLGA microspheres

Dimethylbenz(a)anthracene

Pharmacokinetics

Subcutaneous injection

Breast cancer

[43]

PLGA microspheres

N/A

Biodegradation, biocompatibility

Intracranial injection

Brain tumors

[120]

Starch microspheres

Doxorubicin

Distribution

Intrahepatic injection

Liver cancer

[91]

Starch microspheres

N/A

Toxicity

Intraarterial injection

Liver carcinoma

[87]

PIBCA nanocapsules

Indomethacin, MDP-Lalanyl-cholesterol

Inhibition of metastasis

Intravenous injection

Liver metastasis

[121]

Albumin microspheres

Epirubicin

Tumor growth

Intratumoral injection

Breast cancer

[122]

PCPP-SA microspheres

Methotrexate

Pharmacokinetics

Subcutaneous injection

Lymphoblastic leukemia

[123]

Magnetic microspheres

Methotrexate

Distribution

Intraarterial infusion

Brain tumors

[124]

Ethylcellulose microspheres

Cisplatin

Distribution

Maxillofacial arterial chemoembolization

Various cancers

[125]

Gelatin/chondroitin sulfate microspheres

GM-CSF

Distribution, immunity

Subcutaneous injection

B16 melanoma

[102]

PLGA: poly(lactic–co-glycolic acid); PIBCA: polyisobutylcyanoacrylate; GM-CSF: granulocyte-macrophage colony-stimulating factor; PIBCA: polyisobutylcyanoacrylate; 5-FU: 5-fluorouracil.

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chemically induced mammary tumor in rats, suggesting that long-term, low-dose delivery systems may be useful for the treatment and prevention of breast cancer. Sustained delivery of other anticancer agents by microspheres can be used to treat cancer (Tables 3 and 4).

3.2. Polymeric implants for sustained interstitial chemotherapy The most common tumors are solid tumors of the lung, breast, colon and prostate [44]. Generally, these tumors do not respond well to conventional systemic chemotherapy or radiotherapy, especially when the tumors are large [30] or poorly vascularized [4]. Solid tumors of the brain occur less frequently, but are among the most difficult to treat because the blood–brain barrier (BBB) prevents the entry of most intravascular agents into the brain. If the tumor is operable, surgical removal is the preferred therapy, but many brain tumors, such as malignant glioma, can recur; recurrence is usually within a 2-cm margin of the excision site [45]. Local chemotherapy, provided directly at the site of tumor resection, is a reasonable approach for preventing recurrence. Polymer drug delivery systems provide an opportunity to deliver high, localized doses of chemotherapy for a prolonged period after tumor resection [12]. The most extensively characterized local delivery system is carmustine-loaded PCPP-SA polymer pellets, which have been tested for biocompatibility [46–48], efficacy [49,50], dose escalation [51] and pharmacokinetics [52–54] in animals (Table 5). Clinical trials in the United States [55–57] and

217

Europe have demonstrated the safety and efficacy of this approach in humans (Table 6). Delivery systems based on other polymers are also potentially useful for chemotherapy delivery to brain tumors (Table 5). Certain chemotherapeutic agents that do not cross the BBB, such as carboplatin, 4-hydroperoxycyclophosphamide (4-HC) and taxol, are effective when directly delivered by polymer implants to animals with experimental tumors [58–60]. This approach appears to be useful for novel chemotherapy agents as well, including camptothecan (a topoisomerase I inhibitor) [61], angiogenesis inhibitors (minocycline and heparin / cortisone) [62,63]. While direct delivery to solid tumors by implanted polymers has been studied most extensively in the brain, polymeric pellets can potentially deliver chemotherapeutic agents locally to extracranial tumors as well (Tables 6 and 7). Polylactide needles were used to deliver 5-fluorouracil for the treatment of hepatomas in rats [64]; similar materials were used to deliver adriamycin intratumorally in animals with mammary carcinoma [65]. Bleomycin-loaded PLA cylinders were implanted in the mediastinum of dogs for targeted chemotherapy for esophageal cancer [66]. Cisplatin has been delivered by a variety of polymers: In polyanhydrides, for the local treatment of squamous cell carcinoma of the head and neck [67], and also in poly(methylmethacrylate), fibrin glue and EVAc, for the local treatment of osteosarcoma [68]. In all of these studies, intratumoral administration of anticancer agents by polymers resulted in higher drug activity in the tumors, when compared to more conventional delivery strategies. Some tumors are not resectable and implantation

Table 4 Clinical reports of polymeric chemotherapy using microparticles Device used

Function of device

Drug used / encapsulated

Indication

Number of patients

Reference

Starch microspheres

Chemotherapy

Mitomycin C

24

[126]

Starch microspheres Starch microspheres

Chemotherapy Chemotherapy

5-Fluorouracil 5-Fluorouridine

18 14

[127] [128]

PLGA microspheres PLGA microspheres Albumin microspheres Gelatin microspheres Starch microspheres Albumin microspheres

Hormonal therapy Hormonal therapy Embolization Embolization Chemo-occlusion Chemotherapy

Goserelin acetate Leuprolide acetate None None Mitomycin C Adriamycin

Incurable metastatic liver cancer Gastric cancer Hepatic metastasis of colorectal carcinoma Prostate cancer Prostate cancer Colorectal liver metastasis Inoperable hepatic carcinoma Irresectable liver metastasis Breast cancer

38 53 7 9 39 1

[129] [39] [130] [131] [132] [133]

Methotrexate Carmustine Dexamethasone Dexamethasone Carmustine Micocycline Camptothecin sodium No drug Carmustine Carmustine Carmustine Carmustine

PMMA

EVAc (60:40)

PCPP-SA (20:80)

Carboplatin N /A 4-Hydroperoxycyclophosphamide Methotrexate Methotrexate–dextran conjugate 4-Hydroperoxycyclophosphamide 4-Hydroperoxycyclophosphamide Carmustine Methotrexate Nimustine chloride

PFAD-SA (50:50)

PLA

Tumor volume Distribution

Efficacy Biocompatibility Efficacy Efficacy Efficacy Efficacy Toxicity, dose escalation Distribution

Biocompatibility Tumor growth inhibition Toxicity, dose escalation

Biocompatibility Distribution Efficacy Safety Metabolic disposition and elimination Excretion Efficacy Toxicity, dose Escalation Distribution, toxicity, dose escalation Distribution Distribution Distribution Distribution

Distribution Distribution Brain water determination Efficacy Efficacy Efficacy

Efficacy, tumor volume

Study

Human GM in rat flanks Normal rat brains

9L gliosarcoma in rat brains Normal rat brains F98 and 9L gliomas in rat brains 9L gliosarcoma in rat brains 9L gliosarcoma in rat brains 9L gliosarcoma in rat brains 9L gliosarcoma in rat brains Normal rat brains

Normal rabbit brains 9L gliosarcoma in rat brains 9L gliosarcoma in rat brains

9L gliosarcoma in rat brains Normal rat brains Normal monkey brains Normal monkey brains Normal monkey brains

Normal rabbit brains 9L gliosarcoma in rat brains 9L gliosarcoma in rat brains

Normal rat brains Normal rabbit brains 9L gliosarcoma in rat flanks and brains Normal monkey brains Normal rat brains

Peritoneum and brain of normal rats Normal rat brains 9L gliosarcoma in rat brains 9L gliosarcoma in rat flanks and brains 9L gliosarcoma in rat brains 9L gliosarcoma in rat brains

Glioma in rat brains

Animal model

[138] [139]

[58] [107] [108] [81] [81] [50] [59] [78]

[47] [63] [51]

[60] [53] [80] [80] [80]

[145] [50] [51]

[46] [52] [49] [48] [142]

[24] [106] [144] [49] [62] [61]

[144]

Reference

PMMA: Polymethacrylic methyl acid; EVAc: Poly(ethyl–co-vinyl) acetate; PCPP-SA: Poly[bis( p-carboxyphenoxy)propane–co-sebacic acid]; PFAD-SA: poly(fatty acid dimer–co-sebacic acid); PLA: poly(lactic acid); GM: glioblastoma multiforme.

N /A Heparin:cortisone acetate Carmustine

PCPP-SA (50:50)

Taxol Carmustine Carmustine 4-Hydroperoxycyclophosphamide Taxol

Carmustine Carmustine Carmustine

Chemotherapeutic agent

Polymer (formulation)

Table 5 Animal studies using interstitial polymeric chemotherapy for treating brain tumors

218 L.K. Fung, W. .M. Saltzman / Advanced Drug Delivery Reviews 26 (1997) 209 – 230

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Table 6 Clinical reports on the use of implantable, polymeric devices for interstitial chemotherapy Device used

Drug used / encapsulated

Disease treated

Number of patients

Vinyl polymer PMMA

Prostate cancer Malignant brain tumors

Polymer needles

Leuprolide acetate Mitomycin, adriamycin, ACNU, 5-fluorouracil Mitomycin C

PCPP-SA PCPP-SA PLA

Carmustine Carmustine Nimustine chloride

PCPP-SA

Carmustine

Non-resectable cancers of pancreas, biliary duct, liver Recurrent malignant glioma Recurrent malignant glioma Non-resectable or recurrent glioblastoma Malignant glioma (as initial treatment)

of a large polymer pellet is not possible. For example, even small tumor masses in the brain stem, pons and medulla oblongata cause significant deficits, but resection is not possible and access to the tumor is limited [69]. An alternate approach is to inject chemotherapeutic agent-encapsulated polymeric microspheres stereotactically into the tumor. This procedure is relatively non-invasive and provides local delivery of large quantities of chemotherapy. Drug-loaded microspheres are potentially useful for local chemotherapy at any anatomical site that can be reached with a needle or catheter. Pharmacokinetic models, often based on compartmental descriptions of drug distribution (as in Fig. 4) [70], have been used extensively to examine cancer chemotherapy. To evaluate the dynamics of local interstitial chemotherapy, we developed mathematical models that describe the transport of drugs into the tissue near the implant. This approach builds on previous studies of transport in the tissue interstitium [71–76] and, while we have applied it only to drug delivery in the central nervous system (consider Fig. 4b where the tumor is in the brain), it could be extended to include alternate delivery scenarios, such as those shown in Fig. 4a and c. When a drug-loaded polymer is implanted, the drug is released at a localized site (Fig. 4b). The released drug migrates away from the polymer / tissue interface, principally via the extracellular space (ECS) (Fig. 6). Drug molecules move in the ECS by diffusion and fluid convection; they may also be internalized by cells to react with subcellular components; the drug molecules can also enter the vascular system, be transported to the rest of the

References

5 55

[136] [147]

220

[137]

21 222 11

[55] [56] [139]

22

[57]

body, or be eliminated systemically. If the drug is sufficiently lipophilic, it may penetrate cell membranes rapidly enough to move by a transcellular path. Therefore, the fate of drug molecules delivered to the tissue depends on the rates of transport (via diffusion and fluid convection), elimination (by degradation, metabolism and transcapillary permeation) and internalization. In our model, the tissue adjacent to the polymer implant is treated as a material consisting of three phases; intracellular space (ICS), cellular membrane (CM) and ECS. Therefore, the molar concentration of drug per total tissue volume, C, can be expressed as [75]: 0 0 C 5 a ? C 0ECS 1 b ? C ICS 1 (1 2 a 2 b ) ? C CM

(1)

where a and b are the volume fractions of ECS and 0 0 0 ICS, respectively; C ECS , C ICS and C CM indicate the moles of drug per phase volume. If we assume that the tissue is isotropic, the local concentration of drug molecules in the tissue can be described by the following partial differential equation, which quantifies transport and elimination in the tissue [53]: ≠C ] 5 2=? (2a ? D ECS =C 0ECS 1 a ? v¯ r C 0ECS ) ≠t 2 (a ? k ECS ? C 0ECS 1 b ? k ICS ? C 0ICS ≠B 1 (1 2 a 2 b) ? k m ? C 0CM ) 2 ] ≠t

(2)

where t is the time following polymer implantation, DECS is the diffusion coefficient of the drug in the ECS, v¯ r is a vector describing the fluid velocity, and k ECS , k ICS and k m are the first-order elimination

In vivo polymer degradation, distribution Tumor growth

In vivo polymer degradation, distribution Distribution Pharmacokinetics, toxicity, histology, tumor growth Histology, tumor growth

LH-RH agonist

Adriamycin hydrochloride

LH-RH agonist

Bleomycin Cisplatin

Cisplatin

Cisplatin

PLA

EVAc, PLA, EVAc–HPMC, PLA–HPMC PLA, PHBA, PHIVA, PHICA PLA PFAD-SA

PMMA

EVAc

Intratumoral or subcutaneous in rats Intratumoral or subcutaneous in rats

Under mediastinum in dogs Subcutaneous in mice

Back of rats

Brain of rats

Intratumoral, intrahepatic in rats Back of rats

Implantation site(s)

Osteosarcoma

Esophageal cancer Squamous cell carcinoma of head and neck Osteosarcoma

Prostate tumor

Mammary carcinoma, Brain tumor

N /A

Hepatomas

Tumor model

[68]

[68]

[66] [67]

[141]

[65]

[140]

[64]

Reference

EVAc: ethylene–vinyl acetate; HPMC: hydroxypropylmethyl cellulose; PHBA: poly(hydroxy-n-butyric acid); PHIVA: poly(hydroxyisovaleric acid); PHIVA: poly(hydroxyisocaproic acid).

Histology, tumor growth

Histology, pharmacokinetics

5-Fluorouracil

PLA

Study

Chemotherapeutic agent

Polymer (formulation)

Table 7 Animal studies of the use of interstitial polymeric chemotherapy for tumors outside the brain

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221

Fig. 6. Mechanisms of drug transport and elimination in the tissue following administration. The rectangle on the left represents a drug-loaded polymeric pellet; the black circles represent drug molecules; the arrows denote modes of transport and reaction of drug molecules. Drug molecules are released from the polymer pellet to the extracellular space (ECS) (a), where they can diffuse down the concentration gradient in the ECS (b), or move with the convecting interstitial fluid (c). Also, the drug molecules can be internalized (d) and metabolized in the cells (e). Furthermore, drug molecules can permeate through the capillary wall (f), for subsequent systemic biotransformation or elimination (g).

constants describing drug elimination from the ECS, ICS and CM, respectively. The total concentration of bound drug, B, is defined by analogy to Eq. (1): 0 0 B 5 a ? B 0ECS 1 b ? B ICS 1 (1 2 a 2 b ) ? B CM

(3)

Eq. (2) can be combined with Eqs. (1) and (3) to yield:

the binding constant between bound and free drug in ICS (KICS 5B 0ICS /C 0ICS ), Pi:e is the partition coeffi0 0 cient between ICS and ECS (Pi:e 5C ICS /C ECS ), Pm:e is the partition coefficient between phase CM and ECS (Pm:e 5C 0cm /C 0ECS ). Using the definitions of total concentration (C) in Eq. (1) and partition coefficients (Pi:e and Pm:e ), Eq. (4) can be expressed as: ≠C ] 1 v ?=C 5 D= 2 C 2 k ? C ≠t

(4) with

a * 5 a ? (1 1 KECS ) 1 b ? Pi:e ? (1 1 KICS ) 1 (1 2 a 2 b ) ? Pm:e

(5)

where KECS is the binding constant between bound and free drug in ECS (KECS 5B 0ECS /C 0ECS ), KICS is

(6)

where v is the apparent velocity in the ECS (v5(a / a * )?vr ), D is the apparent diffusion coefficient of the drug in the brain (D5(a /a * )?DECS ) and k is the apparent first-order elimination constant (k5(a ? k ECS 1 b ?k ICS ?Pi:e ) /a * ). As we have described, reasonable approaches for estimating the parameters in Eq. (6) exist [77–79]; these approaches require some knowledge of the physicochemical and biological characteristics of the drug.

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Fig. 7. Concentration profiles in the vicinity of a polymer implant. Positions of the symbols were determined by scanning individual coronal sections and determining the concentration as a function of distance from the edge of the polymer at (a) 1 day, (b) 3 days, (c) 7 days and (d) 14 days. The solid lines show the steady-state diffusion / elimination or transient diffusion / elimination / convection models. (Reproduced from [53], permission granted by Plenum Publishing Corporation).

Solutions for Eq. (6) can be obtained, with appropriate boundary conditions, for a variety of delivery scenarios [79]; a few representative solutions are shown in Table 8. Typical concentration profiles predicted by these equations are useful for

examining the local transport of large and small molecules. Experimental concentration profiles, obtained from rats with intracranial implants containing tritiated carmustine, compare favorably with profiles calculated using these mathematical models (Fig. 7).

Table 8 Analytical solutions for drug transport equation Initial and boundary conditions

Analytical solutions in rectangular coordinates

Steady-state solution (convection not included)

C5Ci for x50 C50 for x→`

Transient solution (convection not included)

C50 for t50; x.0 C5Ci for t.0; x50 C50 for t.0; x→`

C 5 Ci

Transient solution (convection included)

C50 for t50; x.0 C5C0 for t.0; x50 C50 for t.0; x→`

C 5 C0

Ci 5concentration at the polymer / tissue interface. L5half-thickness of implant. ] f 5L Œk /D5diffusion / elimination modulus.

C 5 Ci exp

S 2 ]Lx fD

F H œJ H exp

] k 2x ] D

x ] ? erfc ]] ] 2Œk ? t 2 ?ŒD ? t

Hœ J H JG H S D S D S DJ

] k 1 exp x ] D

x ] ? erfc ]] ] 1Œk ? t Œ 2? D?t x2v?t x?v erfc ]] ] 1 exp ] D 2ŒD ? t

x1v?t erfc ]] ] 2ŒD ? t

? exp(2k ? t)

J

L.K. Fung, W. .M. Saltzman / Advanced Drug Delivery Reviews 26 (1997) 209 – 230

Fig. 8. Effectiveness of drug delivery (h ) versus diffusion / elimination modulus (f ). The f s for carmustine and taxol were estimated from experimental measurements.

Simple solutions to these equations provide insight into the factors influencing the effectiveness of local chemotherapy. We define the effectiveness of drug delivery to a local region, h, as the ratio of average drug concentration within a given tissue volume to drug concentration at the polymer / tissue interface. Using the simplest expression for concentration as a function of position (Table 8; steady-state with no convection), a relationship between effectiveness of delivery and properties of the drug can be calculated: 1 h 5 ] [1 2 exp(2f )] f

(7)

where the diffusion / elimination modulus, f, is the ratio between the rate of drug elimination and drug diffusion: ] k f 5L ] (8) D

œ

where L is the characteristic linear dimension of the tissue volume that needs treatment. For h values near unity, drug concentrations are nearly uniform throughout the treatment volume; therefore, drug delivery to the tissue is effective. Effective delivery occurs for drugs with a modulus that is less than 1 (Fig. 8). Larger values of f yield smaller h values, indicating less effective delivery. We used experimental data (Fig. 7) and the physical properties of compounds reported in the literature (see [78–80] for more complete description) to estimate f values

223

for chemotherapy compounds, including carmustine and taxol (Fig. 8). This model provides a framework for considering the consequences of local polymer chemotherapy. The effectiveness of delivery depends on the physical characteristics of the agent (which determine k and D in Eq. (8)), as well as the size of the region that must be treated (which determines L). For example, carmustine can penetrate farther from the polymer implant in the brain tissue than taxol [80] and, hence, has a higher effectiveness for a treatment volume with a characteristic dimension 0.1 or 0.5 cm. The effectiveness of delivery and, hence, the anticipated efficacy of the treatment, decreases dramatically as the size of the treatment region increases (Fig. 8). Only a few compounds can treat regions that are greater than 1 cm in diameter (see also [11,78]), so these models are particularly important in identifying agents that have the optimal characteristics for direct delivery to the brain. We have also used this model to guide the design of drugs that are better suited for localized delivery to the brain [81].

3.3. Polymeric microparticles for chemoembolization Liver cancer is not common in the US, but it is highly lethal [69]. In general, surgical resection is of limited value [82] and the response rate of liver cancer to systemic chemotherapy is low [3,83–85]. The blood supply of the liver can be isolated, however, providing different opportunities to deliver chemotherapy agents. In chemoembolization, for example, intra-arterial infusion of a chemotherapeutic agent and arterial embolization are used to focus chemotherapy within the liver (Fig. 9). Arterial embolization can be achieved by injecting agents that are retained preferentially in the vasculature, such as ethiodized oil with gelatin particles [86], starch microspheres [87] and albumin microspheres [88]. Certain drug suspensions, such as emulsions in oil, appear to move preferentially to the tumor vasculature in the liver, after injection into the hepatic artery (Fig. 9a). In these cases, more drug is delivered to the tumor than to the healthy liver tissue. Since the suspension moves slowly through the tumor capillaries, drug molecules have an extended residence time and can penetrate more completely into the

224

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Fig. 9. Microscopic representation of chemoembolization in tissue. (a) When a fluid is employed as the embolizing agent, drug particles are suspended in the agent. The agent is preferentially retained in the tumor vasculature for extended periods. (b) Microspheres can also be used as embolizing agents. A microsphere is shown, entrapped in a blood capillary; fluid flows in the annulus between the blood capillary and the microsphere. (c) When microspheres are loaded with anticancer agents, they can both embolize the blood capillaries and deliver drugs to the tumor.

tumor interstitium. For example, the half-life of adriamycin delivered by ethiodized oil is |25 days [89], much longer than the half-life of 0.5 to 3 days for adriamycin delivered in solution [90]. High drug concentrations are obtained in the tumor [89], with less drug circulating in the plasma [86]. This approach can be enhanced by using microparticles as embolizing agents. When particles of the correct size are injected into an artery, the particles are arrested in the microvasculature (Fig. 9b). As a result, the blood flow in tumor capillaries is reduced significantly. Depending on the degradation rate of the polymer, vascular blockade can be maintained for a period of minutes or weeks [16]. Since drug clearance from the tumor is reduced, tumor exposure to the injected drug is prolonged and drug concentrations in the plasma are reduced. This approach can have a significant impact on local drug concentrations in the tumor and tumor growth [86,87,91]. Biodegradable microspheres can potentially serve two roles, as embolizing agents and as drug delivery vehicles (Fig. 4c and 9c). In this situation, the anticancer drug is protected from metabolic and spontaneous degradation by encapsulation in a polymer. When appropriately sized, drug-loaded microspheres are delivered intrahepatically and entrapped in microvessels for local release (Fig. 9c). Due to the proximity of the entrapped microspheres to the tumor, the tumor cells are potentially exposed to

high levels of anticancer agents. Moreover, since only small amounts of drug are transported to the rest of the body, systemic toxicity is minimal [92]. In one study, using drug-loaded microspheres, the tumor-to-parenchyma ratio of drug concentrations was about 40, a ratio not achieved when free anticancer agents were administered with embolizing agents [93]. Chemoembolization is an attractive technique for delivery of chemotherapy, which attempts to take advantage of several aspects of polymer-based delivery systems. As such, it is being considered for treatment of pancreatic [94] and breast [95,96] cancer as well. Advanced materials, such as thermoresponsive polymers, may improve this technology even further [97].

4. Other emerging applications Rapid progress in the molecular biology of tumors has led to the development of new therapeutic agents to combat cancer. Many of these compounds are proteins that have short half-lives and cross biological barriers poorly. The advantages of polymer delivery systems for proteins have been discussed elsewhere [20,98]; protein delivery systems may become important in cancer therapy. For example, microspheres permitted localized granulocyte– macrophage colony-stimulating factor delivery, mak-

L.K. Fung, W. .M. Saltzman / Advanced Drug Delivery Reviews 26 (1997) 209 – 230

ing it an effective component of a tumor vaccine [99]. Similarly, polymer microspheres containing interferon enhanced the tumoricidal activity of macrophages, leading to the prevention of pulmonary metastasis of B16 melanoma in mice [100]. Similar approaches may be useful for other investigational drugs, such as immunotoxins [101], cytokines [99,102] and angiogenesis inhibitors [62], which are otherwise ineffective when delivered intravascularly.

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Acknowledgments Our original work on polymers for brain tumor treatment is supported by the National Institutes of Health (U01-CA52857).

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