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Augmenting Glioblastoma Chemotherapy with Polymers Matthew Skinner,† Sarah M. Ward,† Carol L. Nilsson,‡ and Todd Emrick*,† †
Polymer Science and Engineering Department, University of Massachusetts, 120 Governors Drive, Amherst, Massachusetts 01003, United States ‡ Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden ABSTRACT: Chemotherapeutics are vital for treating brain tumors such as glioblastoma, an aggressive and prolific cancer predominantly treated with DNA alkylating agents. The efficacy of antiglioblastoma drugs, such as temozolomide, is limited by their rapid clearance and instability under normal physiological conditions. Both local and systemic polymer-based therapeutics have shown promise for treating many cancers, and as such there is a growing interest in applying polymer techniques to augment the efficacy and stability of glioblastoma chemotherapeutics. Notably, brain tumor chemotherapy presents unique challenges and will require tailored delivery systems to develop markedly improved treatments. KEYWORDS: Glioblastoma, chemotherapy, brain tumor
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BACKGROUND Gliomas are primary neoplasms originating from non-neuronal central nervous system (CNS) cells. These represent the majority of diagnosed malignant CNS tumors and affect more than 100 000 patients annually.1 Because malignant gliomas primarily impact older patients, the number of diagnoses will increase with average life expectancy. Accounting for most gliomas,1 glioblastoma is an overwhelmingly lethal grade IV astrocytoma and is particularly challenging to treat due to its highly invasive and aggressive nature. The standard-of-care for glioblastoma involves surgical resection, radiation, and chemotherapy, a regimen which affords only a 12−15 month average survival time even with early detection.1 Due to the inherent complexities of surgical tumor removal, as well as the infiltrative nature of these tumors, chemotherapy is a fundamental component of treatment.1 Current glioblastoma drugs (Figure 1a), carmustine, lomustine, procarbazine, and Temozolomide (TMZ), are DNA alkylating agents administered orally or intravenously. Despite their potency, these drugs suffer from poor pharmacokinetics, off-target toxicity, and low aqueous solubility. While their lipophilicity allows for crossing of the blood-brain barrier (BBB), the semipermeable membrane that restricts entry of most molecules to the brain, this presents a catch-22 in that poor aqueous solubility necessitates complex drug formulation which limits dosing. Nanoscale (e.g., liposomal and nanoparticulate) and polymeric chemotherapeutic approaches thus provide new opportunities for overcoming the inherent challenges of treating glioblastoma.
treatment. However, side effects (e.g., seizures and cerebral edema) countering its benefits highlighted the complexities of local treatment.2 While tailoring the physical, mechanical, and chemical properties of implantable materials may offer improvement, a successful systemic delivery system would alleviate the need to address implant-related complications. Injectable polymeric chemotherapeutics offer advantages of prolonged drug circulation, increased drug accumulation in tumors via the enhanced permeability and retention (EPR) effect, and masked drug toxicity prior to its release from the polymer delivery vehicle. For lipophilic drugs, polymers improve aqueous solubility, either by physical encapsulation into nanostructures or covalent conjugation to biocompatible polymer scaffolds. While the fundamental benefits of polymer therapeutics have been demonstrated in breast, ovarian, and other cancers, such strategies for brain cancer are comparatively underexplored. Moreover, few strategies have been investigated for improving the efficacy of Temozolomide (TMZ), the firstline chemotherapeutic administered to newly diagnosed glioblastoma patients.2 Unlike conventional antineoplastic small molecules, TMZ is a prodrug which induces DNA alkylation following decomposition at physiological pH, as shown in Figure 1b. Despite the benefits of TMZ, including clinically proven antiglioblastoma activity, stability in aqueous acid which allows for oral administration, and relatively mild off-target toxicity, its efficacy is hindered by its own mechanism of action. Hydrolytic degradation and rapid in vivo clearance limit tumor uptake and necessitate frequent dosing to maintain antitumor activity. Discovering polymers which stabilize TMZ and prevent its rapid clearance thus offers potential improvements in vivo. Given the amenability of TMZ to synthetic modification at the carbamoyl position, recent efforts have focused on covalent
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POLYMER-BASED THERAPEUTIC STRATEGIES Polymer-based strategies for glioblastoma may involve either localized or systemic methods. For example, postsurgical implantation of delivery devices into the resection cavity bypasses the BBB and allows for sustained drug delivery into surrounding tissue to fully eradicate infiltrative tumor cells. For example, Gliadel was developed as a biodegradable wafer for carmustine delivery and is a United States Food and Drug Administration (FDA)-approved device for local glioblastoma © XXXX American Chemical Society
Special Issue: Precision Medicine in Brain Cancer Received: May 4, 2017 Accepted: May 23, 2017
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DOI: 10.1021/acschemneuro.7b00168 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 1. (a) Examples of chemotherapeutics used to treat glioblastoma. (b) Temozolomide (TMZ) decomposition at physiological pH affords 5(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and subsequent acid-catalyzed degradation yields 5-aminoimidazole-4-carboxamide (AIC) and the methyldiazonium cation which alkylates DNA (shown at the O6 position of guanine).
activity. While these examples demonstrate the feasibility of polymer-TMZ conjugates as viable systemic therapeutics, common to both is a reliance on postpolymerization drug conjugation that generally struggles to produce structures with consistent, well-defined drug loading. As such, simpler approaches for incorporating TMZ into polymers, such as from drug-containing monomers, may prove favorable. Drug incorporation using polymerizable chemotherapeutic derivatives has emerged as an alternative to postpolymerization drug attachment. For example, TMZ-methacrylate, shown in Figure 2b, is a novel and versatile TMZ derivative which allows its incorporation as pendent moieties into any of a variety of polymer materials by free radical polymerization methods which, importantly, also preserve the TMZ structure.5 TMZ can thus be inserted into polymers at very high drug loading (50 mol % or greater), such as into poly(2-methacryloyloxyethyl phosphorylcholine) (polyMPC), an FDA-approved biomimetic material of emerging interest for sustained chemotherapeutic delivery. PolyMPC-TMZ prodrugs exhibit excellent water solubility (>25 mg/mL) and significantly improve TMZ stability in aqueous environments. In general, this reactive TMZ derivative can be copolymerized with any of a range of biocompatible monomers, affording polymers with tunable and reproducible drug loading. Moreover, the TMZmethacrylate monomer opens easy access to many forms of therapeutic materials, including plastics (i.e., implantable materials), nanoparticles, soluble polymers, and hydrogels. This synthetic strategy further allows incorporation of biorecognition moieties suitable for promoting BBB crossing as well as tumor targeting and sensitization. To summarize, we view the role of polymers for chemotherapy as continually expanding and diversifying, highlighted specifically here for glioblastoma. For polymer-based cancer therapeutics to be considered feasible, they must be translatable from benchtop discoveries to clinical treatments. Beyond facile and reproducible therapeutic syntheses, understanding glioblastoma tumor biology is critical for translating promising in vitro results into viable medicines. For example, proteomic research gives comprehensive insight into protein expression associated with glioblastoma tumors, and thus opens opportunities to develop targeted and more efficacious chemotherapy. Polymer platforms which merge new biological
polymer-TMZ conjugation. For example, Ljubimova and coworkers conjugated TMZ-hydrazide to poly(β-L-malic acid) by postpolymerization amidation (Figure 2a).3 This strategy
Figure 2. (a) Poly(β-L-malic acid)-TMZ conjugates prepared by carbodiimide amidation (left) and PEG-chitosan-TMZ polymer prodrugs (right). (b) Chemical structure of a novel TMZ-methacrylate monomer and its use to prepare polyMPC-TMZ therapeutics by living free radical polymerization methods.
extended TMZ half-life in solution without impairing in vitro antitumor activity, while the incorporation of endosomolytic trileucine moieties to the backbone further improved prodrug efficacy in chemoresistant T98G cells. Zhang et al. reported the modification of poly(ethylene glycol) (PEG)-chitosan graft copolymers with a TMZ acid chloride.4 These macromolecular prodrugs, shown in Figure 2a, formed ∼50 nm diameter nanoparticles in water and extended TMZ lifetime more than 7fold at physiological pH. This enhanced TMZ stability was attributed to its encapsulation within the hydrophobic nanoparticle core, effectively shielding TMZ from rapid hydrolytic degradation. Additionally, this polymer scaffold allowed incorporation of tumor-targeting moieties to augment TMZ B
DOI: 10.1021/acschemneuro.7b00168 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience insights with therapeutic development stand to make the greatest clinical impact.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Todd Emrick: 0000-0003-0460-1797 Funding
The authors acknowledge the financial support provided by the National Institutes of Health under Award Number R21 CA167674 and the National Science Foundation Graduate Research Fellowship under Grant Number 1451512 (S.M.W.). Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Omuro, A., and DeAngelis, L. M. (2013) Glioblastoma and Other Malignant Gliomas. JAMA 310, 1842−1850. (2) De Bonis, P., Anile, C., Pompucci, A., Fiorentino, A., Balducci, M., Chiesa, S., Maira, G., and Mangiola, A. (2012) Safety and Efficacy of Gliadel Wafers for Newly Diagnosed and Recurrent Glioblastoma. Acta Neurochir. 154, 1371−1378. (3) Patil, R., Portilla-Arias, J., Ding, H., Inoue, S., Konda, B., Hu, J., Wawrowsky, K. A., Shin, P. K., Black, K. L., Holler, E., and Ljubimova, J. Y. (2010) Temozolomide Delivery to Tumor Cells by a Multifunctional Nano Vehicle Based on Poly(β-L-malic acid). Pharm. Res. 27, 2317−2329. (4) Fang, C., Wang, K., Stephen, Z. R., Mu, Q., Kievit, F. M., Chiu, D. T., Press, O. W., and Zhang, M. (2015) Temozolomide Nanoparticles for Targeted Glioblastoma Therapy. ACS Appl. Mater. Interfaces 7, 6674−6682. (5) Skinner, M., Ward, S. M., and Emrick, T. (2017) Versatile Synthesis of Polymer-Temozolomide Conjugates. ACS Macro Lett. 6, 215−218.
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DOI: 10.1021/acschemneuro.7b00168 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
