Review pubs.acs.org/molecularpharmaceutics
Overcoming the Road Blocks: Advancement of Block Copolymer Micelles for Cancer Therapy in the Clinic Loujin Houdaihed, James C. Evans, and Christine Allen*
Downloaded via UNIV OF TOLEDO on June 15, 2018 at 16:42:00 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 3M2 ABSTRACT: With countless preclinical studies on block copolymer micelles (BCMs) successfully demonstrating the superiority of these advanced drug delivery formulations over conventional formulations, it remains somehow discouraging that only a few have reached clinical evaluation and practice. With a critical eye, this review aims to compare and summarize the preclinical and clinical data available on several BCM formulations and to identify their primary role in drug delivery as “carrier” or “solubilizer”. This review focuses on polymeric micelles that have reached clinical evaluation and/or are being pursued commercially. Where available, we aim to compare the pharmacokinetics, toxicity, and efficacy data obtained in preclinical studies to identify the factors that likely played a key role in a decision to move these formulations forward from the bench to a first-in-human trial. Finally, we summarize clinical data obtained to date, where available, and conclude with the impact that each formulation has had on patients in terms of safety and efficacy. KEYWORDS: block copolymer micelles, targered delivery, EPR, nanoformulation, nano drug delivery systems, clinical translation
1. INTRODUCTION Block copolymer micelles (BCMs) encapsulating anticancer agents were first developed in the late 1980s and since then have gained widespread interest as a viable drug delivery platform. During the past three decades, intense preclinical research on this nanoplatform has enabled a number of promising BCM formulations to enter clinical development, with two receiving regulatory approval (Cynviloq and Nanoxel).1−3 Polymeric micelles were initially developed to improve the aqueous solubility of hydrophobic drugs. They were considered to be alternatives to the commonly used conventional excipients (e.g., Cremophor EL), which have been associated with significant toxicity. BCMs are advantageous as drug delivery systems in cancer therapy, with optimized formulations having high drug to material ratios and enabling solubilization of drugs up to 10 000-fold beyond their aqueous solubility.4−6 BCMs are best described as core−shell structures with hydrodynamic diameters ranging between 10 and 200 nm. They are composed of a hydrophobic core that encapsulates lipophilic drugs and a hydrophilic shell that is most commonly composed of poly(ethylene glycol) (PEG) and provides a protective barrier between the core and the external medium.7,8 The self-assembly of block copolymers to form BCMs in aqueous solution is usually driven by hydrophobic interactions to minimize the interfacial free energy of the copolymer−water system. Self-assembly is a thermodynamic process that depends on many factors, including the composition and the concentration of the copolymer.9 The critical physicochemical characteristics of drug-loaded BCMs that influence their performance in vivo include size, size © 2017 American Chemical Society
distribution, morphology, and stability. The stability of drug-free BCMs is considered to include two components, namely, thermodynamic and kinetic stability. The thermodynamic component is primarily governed by the copolymer concentration, such that when the total copolymer concentration in an aqueous solution is above the critical micelle concentration (CMC), the micelle is said to be thermodynamically stable. The kinetic component is largely determined by the nature and state of the hydrophobic core. For example, a solution of BCMs may be diluted to copolymer concentrations well below the CMC, yet the micelles may remain intact because of kinetic stability (e.g., a semicrystalline core).10 The performance-dependent parameters of BCMs can largely be tailored by optimizing the properties of the copolymer (i.e., nature, molecular weight, polydispersity, ratio of hydrophobic to hydrophilic block lengths) and method of preparation. Importantly, the properties of the drug and the ratio of drug to copolymer also play a significant role in determining the performance. For example, incorporation of drug into BCMs can alter their size, size distribution, and morphology.10 A major challenge with BCM-based drug formulations is the design of micelles that act as true drug carriers and not only as solubilizers. In most cases, it is preferable that BCM-based drug Special Issue: Polymers in Drug Delivery: Chemistry and Applications Received: Revised: Accepted: Published: 2503
March 8, 2017 May 2, 2017 May 8, 2017 May 8, 2017 DOI: 10.1021/acs.molpharmaceut.7b00188 Mol. Pharmaceutics 2017, 14, 2503−2517
Review
Molecular Pharmaceutics
Figure 1. Block copolymer micelles that have been advanced to clinical evaluation and/or approved and act as drug solubilizers (only those encapsulating platinum derivatives, taxanes, and doxorubicin have been included).
formulations are highly stable in vivo in order to prolong their blood circulation lifetime.11 The compatibility between the drug and the core-forming block of the copolymer is an important parameter that has been shown to influence drug loading and retention as well as formulation stability.1,9 As each drug has unique physicochemical characteristics, it is unlikely that a BCM system formed from a single copolymer can serve as the ideal platform for the delivery of all drugs. As a result, a number of distinct polymer materials have been considered for use as the hydrophobic blocks of the copolymer.12 To date, the most commonly used hydrophobic blocks have been polyesters, poly(amino acid)s (PAAs), and polyether derivatives. Polyesters, such as poly(lactic acid) (PLA) and poly(ε-caprolactone) (PCL), are biocompatible and biodegradable and have been approved by the U.S. Food and Drug Administration (FDA) for biomedical applications in humans. PAAs, such as poly(aspartic acid) (P(Asp)) and poly(glutamic acid) (P(Glu)), are biodegradable, and their multiple carboxy/ amine functional groups enable conjugation of drugs and formation of complexes with various metals or can be modified to optimize the core−drug compatibility, thus increasing drug loading and formulation stability.12 Polyethers of pharmaceutical interest are copolymers of poly(ethylene glycol)-block-poly(propylene oxide)-block-poly(ethylene glycol) (PEG-b-PPO-bPEG), known as poloxamers (Pluronic). They are nonbiodegradable, but the individual polymer chains with a size of 80% of the injected dose at 9 h and >16% at 27 h after administration of NC-4016, which are higher than those seen with NC-6004.43 In another study, NC-4016 resulted in 20-, 4-, and 25-fold greater accumulation of Pt in the liver, spleen, and tumor, respectively, than oxaliplatin at 48 h after administration.44 Correspondingly, when tested in rats, NC-4016 did not cause any signs of acute neuropathy, unlike oxaliplatin, which caused cold-induced allodynia (i.e., elevated sensitivity to pain).36 Importantly, while free oxaliplatin failed to suppress tumor growth, much greater antitumor efficacy was observed with NC-4016 in mice bearing colon carcinoma (C-26), even at lower doses of Pt.44 NC-4016 also induced significant tumor growth inhibition in oral carcinoma (KB)-bearing mice compared with oxaliplatin administered at equivalent doses of Pt.36 This superior antitumor activity of NC-4016 in comparison with oxaliplatin was made possible by the preferential accumulation of the micelles in the tumor tissue.36,44 Likely Drivers for Clinical Translation. In conclusion, the preclinical data demonstrated that NC-4016 shows considerably high stability and has a significantly improved PK profile compared with free oxaliplatin, resulting in superior antitumor effects and reduced peripheral neuropathya major toxicity associated with oxaliplatin. The significant tumor growth inhibition afforded by NC-4016 relative to the free drug was attributed to the elevated and extended accumulation of Pt in tumors. In contrast, the reduced peripheral neuropathy seen with NC4016 is a result of the high stability of the micelles and reduced exposure of normal tissue to Pt. Overall, the combination of the enhanced safety profile and antitumor efficacy likely served as the basis for pursuing clinical development of this formulation. A Phase I clinical trial (NCT01999491) in the U.S. evaluating NC4016 in patients with advanced solid tumors or lymphoma is now recruiting. 2509
DOI: 10.1021/acs.molpharmaceut.7b00188 Mol. Pharmaceutics 2017, 14, 2503−2517
Review
Molecular Pharmaceutics
Taxol.52 The increase in MTD allowed for the treatment of mice bearing MX-1 (breast) and SKOV-3 (ovarian) tumor xenografts with a higher drug dose, leading to superior tumor growth inhibition relative to Taxol.52 Likely Drivers for Clinical Translation. The PK profile of Cynviloq indicates that the BCMs in this formulation are rapidly cleared from blood circulation upon i.v. administration. Therefore, this formulation serves more as a solubilizer for PTX than as a true drug carrier. However, despite the lack of stability of Cynviloq (which prevents its full exploitation of the EPR effect), this formulation induced significantly greater antitumor effects in animal tumor models relative to Taxol. The biocompatibility of the copolymer used and the absence of allergenic excipients (Cremophor EL and ethanol) improved the MTD of Cynviloq compared with that of Taxol (3-fold increase) and allowed for higher doses of PTX to be administered, resulting in superior antitumor activity.52,53 Indeed, Cynviloq showed promising preclinical data, affording significantly improved toxicity and efficacy for PTX in breast and ovarian tumor models that warranted pursuing clinical trials. Clinical Studies. Consistent with observations from the preclinical studies, the first Phase I trial showed the unique PK profile of Cynviloqlower plasma AUC and a shorter plasma half-life in comparison with Taxol, suggesting rapid dissociation of the micelles after i.v. administration and enhanced partitioning of Cynviloq into tissues and tumors. Importantly, the MTD of Cynviloq was determined to be 390 mg/m2, which was significantly higher than that for Taxol and the nab-paclitaxel formulation (Abraxane) (200 and 300 mg/m2, respectively). In regard to toxicities, despite the absence of premedication, Cynviloq showed a favorable toxicity profile with no hypersensitivity reactions as observed with Taxol.6 Several Phase II clinical trials evaluated Cynviloq for different indications, including advanced breast cancer and NSCLC (Table 2).15,54,55 It is noteworthy that the administered dose of Cynviloq in these trials ranged from 230 to 435 mg/m2, which is higher than the dose commonly employed for Taxol (∼170 mg/ m2). In agreement with the results obtained in preclinical studies, a single-arm trial in 41 patients with MBC confirmed antitumor ̈ patients and patients activity for Cynviloq in chemonaive pretreated with anthracyclines. The overall response rate for patients in this trial was 58.5%, which is higher than those for Abraxane (47.6% at the same dose) and Taxol (21−54%) as a first-line therapy for patients with MBC.15 In another single-arm Phase II trial, 71 patients with advanced NSCLC received a combination of Cynviloq and CDDP as a first-line therapy. Data from this study were more favorable in terms of response rate and survival duration than most Phase II or Phase III clinical trials using Taxol in combination with CDDP.55 However, another Phase IIb trial that evaluated this combination in 276 patients with advanced NSCLC showed noninferiority in terms of PFS and OS in comparison to Taxol in combination with CDDP.56 The clinical data led to the approval of Cynviloq, originally developed by Samyang Biopharmaceuticals, in Korea. Approval was granted in the Philippines, India, and Vietnam for the treatment of a range of cancers (MBC, NSCLC, and ovarian). The exclusive distribution rights to Cynviloq were acquired by Sorrento Therapeutics (merged with IgDraSol) in the 27 countries of the European Union (EU), North America, and Australia in 2013.57−59 Cynviloq is currently in clinical development for multiple indications and is often combined with other chemotherapeutic agents such as doxorubicin, carboplatin, and gemcitabine (Table 2). Bioequivalence studies
which in turn results in significantly higher plasma and tumor AUCs for the drug and leads to greater antitumor effects. Clinical Studies. In a Phase I clinical trial, consistent with the preclinical findings, administration of NK105 resulted in significantly increased plasma and tumor concentrations of drug relative to administration of PTX as Taxol (the plasma AUC of NK105 at 150 mg/m2 was 15-fold higher than that previously reported for Taxol at 210 mg/m2).50 Hematologic toxicities associated with NK105 were comparable to those of Taxol, yet the hypersensitivity reactions were significantly reduced even when prophylactic premedication was not used. On the basis of this study, the MTD was determined to be 180 mg/m2. The recommended dose for Phase II was defined as 150 mg/m2 and the dose-limiting toxicity (DLT) as neutropenia.50 This trial demonstrated the advantages of NK105 over Taxol, namely, the reduction in hypersensitivity reactions and the triweekly short infusion time (1 h instead of 3 h), thus providing a better quality of life for patients.50 A Phase II clinical trial was conducted in 57 patients with previously treated advanced stomach cancer. Despite the markedly improved PK profile of PTX following administration in NK105 in comparison with administration of the free drug, the clinical efficacy was modest (the observed overall response rate (ORR) was 25%, the median progression-free survival (PFS) was 3.0 months, and the median overall survival (OS) was 14.4 months).51 Further interpretation of the results from this trial is difficult because there was no comparison with the free drug. In a Phase III clinical trial, NK105 was compared with PTX in patients with metastatic or recurrent breast cancer. Results from this trial were released in July 2016 and showed that the primary end point of the study (statistical noninferiority of PFS) could not be achieved.48 Taken together, the results indicate that in spite of the significantly improved PK profile of PTX following administration in NK105, this formulation seems to surpass conventional PTX formulations only in terms of safety in the clinical setting. Therefore, NK105 represents another example in which a seemingly promising BCM formulation failed to provide greater efficacy in clinical trials. 3.2.2. Cynviloq. Cynviloq (Genexol-PM, IG001, Paclitaxel PM), a BCM formulation of PTX, was the first BCM-based drug formulation to be approved for human use. It was approved exclusively in South Korea for patients with MBC, NSCLC, and ovarian cancer. Cynviloq is now on the market in India, the Philippines, and Vietnam for treatment of patients with MBC and metastatic NSCLC and is currently making its way through clinical trials in many countries, including a Phase IV trial in South Korea for MBC.3 The BCMs in Cynviloq are formed from the copolymer methoxy-PEG-b-poly(D,L-lactide) (mPEG-bPDLLA) (2000:1750 g/mol) using the solid dispersion method.52 The micelles are 20−50 nm in diameter and have 16.7% drug loading. In vitro stability studies of Cynviloq were not published, but further preclinical and clinical evaluation indicated that the formulation has relatively low stability.6,52 Preclinical Studies. In a preclinical study in healthy mice, Cynviloq was found to have unique PK and BD profiles: the plasma AUC for PTX following administration as Cynviloq was 30% lower than that obtained for the drug administered as Taxol. The rapid clearance of the drug from the bloodstream was attributed to the kinetic instability of the formulation, which leads to rapid release of PTX upon administration.52 When tested in mice bearing B16 melanoma xenografts, Cynviloq was found to have a 3-fold greater MTD. Cynviloq was also welltolerated in rats, with a significantly lower LD50 value relative to 2510
DOI: 10.1021/acs.molpharmaceut.7b00188 Mol. Pharmaceutics 2017, 14, 2503−2517
Review
Molecular Pharmaceutics
(5.5-fold lower plasma AUC) when the drugs were administered at the same dose.67 This was explained by the rapid (within minutes) dissociation of PTX from micelles following its i.v. administration in rats.53 Consequently, Paxceed has a safety profile similar to that of Taxol following i.v. administration on the basis of their similar MTD values and body weight losses. Interestingly, upon i.p. administration, Paxceed was found to have up to a 5-fold higher MTD relative to Taxol, which could be due to slower PTX transfer to the circulation.67 Accordingly, when administered i.v. at its MTD, Paxceed failed to result in an improvement in tumor growth inhibition in comparison to Taxol, yet it resulted in significantly greater tumor growth inhibition in comparison with Taxol following i.p. administration.67 Likely Drivers for Clinical Translation. Paxceed and Cynviloq are similar in terms of copolymer composition (i.e., mPEG-bPDLLA), differing only slightly in the molecular weight of the polymer blocks (2000:1333 g/mol in Paxceed vs 2000:1750 g/ mol in Cynviloq) and method of preparation employed for drugloaded micelle preparation.52,68 Therefore, it was unsurprising that Paxceed showed a lack of stability and low residence time in the blood circulation in animal models. Unlike Cynviloq, however, i.v. administration of Paxceed resulted in antitumor efficacy and toxicity profiles similar to those of Taxol (similar MTD). Therefore, there was no evident advantage to the use of Paxceed over conventional PTX via i.v. administration in animal tumor models. As a result, this formulation has not been advanced to clinical evaluation for oncology indications.67 However, Paxceed entered clinical trials for a number of nononcology indications, including psoriasis (NCT00006276), rheumatoid arthritis (NCT00055133), and multiple sclerosis. However, since 2004, no updates have been provided on clinical evaluation of Paxceed.3 3.2.4. Nanoxel. Nanoxel was developed by Dabur Pharma (India) and was later acquired by the Fresenius Kabi (Germany). Nanoxel is a Cremophor EL-free BCM formulation of PTX that was first approved in India in 2006 as an alternative to Taxol for use in MBC, NSCLC, ovarian cancer, and AIDS-related Kaposi’s sarcoma.2,69 The micelles are composed of the pH-sensitive block copolymer of polyvinylpyrrolidone (PVP) and poly(Nisopropylacrylamide) (NIPAM) (PVP-b-PNIPAM). The spherical micelles have a diameter of 80−100 nm and are said to release the drug by erosion of the copolymer, which occurs more rapidly at low pH.70 It was hypothesized that after cellular internalization of Nanoxel by endocytosis, the pH-sensitive polymer is degraded in lysosomes and the drug then released inside the cell. In vitro cellular uptake studies in three different human cancer cell lines, A549, HBL-100, and PA-1, representing NSCLC, breast cancer, and ovarian cancer, respectively, revealed that Nanoxel had significantly higher cellular uptake compared with Cremophor EL-based PTX formulations and similar uptake to that of Abraxane.71 It should be noted that in vitro stability studies of Nanoxel have not been published. Preclinical Studies. Published in vivo preclinical evaluation of Nanoxel is limited to one study that compared the efficacy and toxicity of Nanoxel to that of Abraxane.72 Following i.v. administration in healthy mice, no mortality was seen in Abraxane-treated animals, while 100% mortality occurred in animals treated with Nanoxel at the same doses. Abraxane induced significantly greater tumor growth inhibition compared with Nanoxel in mice bearing HT29 colorectal carcinoma tumors when the drugs were administered at equitoxic doses.72 The
were carried out to compare Cynviloq and Abraxane in patients with metastatic or locally recurrent breast cancer (NCT02064829) as well as NSCLC. Positive preliminary data from a total of eight patients that supported potential bioequivalence were reported in 2014.60 These studies concluded in July 2015, with no updates provided to date. Bioequivalence between Cynviloq and Abraxane could potentially allow for the approval of Cynviloq by the FDA through the 505(b)(2) pathway, which would eliminate the need for independent trials evaluating efficacy versus the standard of care.61,62 Several roadblocks might inhibit this, however, most notably the fact that Celgene (the supplier of Abraxane) has filed a citizen petition with the FDA highlighting the unique and complex characteristics of nanotechnology and reiterating the FDA’s own stance that the “technical assessments of such products should be product-specific”.63 Abraxane (currently on the market in the EU, North America, and India for the treatment of breast cancer) is Cremophor EL-free and composed of albumin-bound PTX nanoparticles.64 It should be noted that Cynviloq was acquired by the NantWorks company for up to $1.3 billion in May 2016; this company was founded by Dr. Patrick Soon-Shiong, who is the inventor and developer of Abraxane.64 A recently published Phase III trial (NCT00876486) evaluated the efficacy and safety of Cynviloq in comparison with conventional PTX in 212 patients with metastatic HER2negative breast cancer. Cynviloq was administered i.v. over 3 h once every 3 weeks without premedication. The administered dose of Cynviloq started at 260 mg/m2 and was increased to 300 mg/m2, while conventional PTX was administered at 175 mg/ m2. Compared with conventional PTX, Cynviloq demonstrated improved ORR (39.1% for Cynviloq vs 24.3% for conventional PTX).65 However, Cynviloq did not result in significant increases in PFS and OS relative to Cremophor EL-based PTX. Interestingly, the two groups had similar toxicity profiles, with higher neutropenia rates observed with Cynviloq. Hypersensitivity reactions were seen in both groups, and premedication was used as required.65 In conclusion, Cynviloq is superior to Taxol in terms of enabling administration of higher doses of drug in the absence of additional toxicities. Doses of 300−435 mg/m2 can be administered safely in patients,6 in comparison with Abraxane, which has an MTD of 300 mg/m2.66 In terms of clinical efficacy, Cynviloq has shown improved ORR compared with Cremophor EL-based PTX; however, the promising efficacy results seen in preclinical studies have not translated into significant clinical benefit (i.e., PFS and OS). 3.2.3. Paxceed. Paxceed, developed by Burt’s lab at the University of British Columbia and licensed by Angiotech Pharmaceuticals (Canada), is another BCM formulation that physically encapsulates PTX. Paxceed consists of mPEG-bPDLLA (2000:1333 g/mol) and is prepared by the film hydration method.67 The micelles are less than 50 nm in size and have a PTX loading level of 10% (w/w). In vitro biocompatibility studies showed the micelles to be biocompatible. The micelles were found to have good physical stability at room temperature with no drug precipitation for over 24 h; however, physiologically relevant stability studies and drug release studies were not available.67,68 Preclinical Studies. Preclinical studies in nude mouse models of lung carcinoma (MV-522) compared the PK and BD profiles for Paxceed with those of Taxol. A key difference was that the blood levels of micellar PTX were lower in Paxceed-treated mice 2511
DOI: 10.1021/acs.molpharmaceut.7b00188 Mol. Pharmaceutics 2017, 14, 2503−2517
Review
Molecular Pharmaceutics
profiles.74 Additionally, the amount of unmetabolized DTX excreted in feces and urine following i.v. administration of Nanoxel-M was comparable to that of Taxotere in rats. The MTD of Nanoxel-M was found to be similar to that of Taxotere, and the two formulations had comparable toxicities in terms of hematology and body weight loss. However, micellar DTX did not cause the severe hypersensitivity reactions and fluid retention that are seen with conventional DTX. In regard to antitumor efficacy, tumor growth reduction induced by Nanoxel-M was equivalent to that obtained with Taxotere in xenograft mouse models of human lung cancer (i.e., H-460 tumors).74 Likely Drivers for Clinical Translation. Nanoxel-M exhibited a PK profile equivalent to that of Taxotere, indicating that the micelles acted as solubilizers with most of the drug released immediately upon i.v. administration. There was no significant difference in antitumor efficacy between Nanoxel-M and Taxotere in animal tumor models. In terms of toxicity, however, Nanoxel-M showed a superior toxicity profile over Taxotere: the hypersensitivity reactions and fluid retention usually associated with Taxotere were not seen with Nanoxel-M. On the basis of these results, it was expected that Nanoxel-M could provide a safer treatment than Taxotere while retaining antitumor efficacy in cancer patients. Indeed, the significant improvement in the safety profile of Nanoxel-M was the main advantage of this formulation and supported proceeding to clinical trials. Clinical Studies. In 2012, Nanoxel-M completed a Phase I trial for advanced solid tumors (NCT01336582), but no results have yet been published. Nanoxel-M is now recruiting for a Phase II trial in patients with recurrent or metastatic head and neck squamous cell carcinoma (NCT02639858) and for a Phase III trial to evaluate Nanoxel-M in non-muscle-invasive bladder cancer patients (NCT02982395). Both trials are being conducted in South Korea (Table 2). 3.2.6. CriPec Docetaxel. CriPec Docetaxel, developed by Crystal Therapeutics, is a proprietary polymeric technology encapsulating DTX. Crystal Therapeutics indicates that this formulation was developed to overcome the side effects associated with the conventional formulation of DTX (Taxotere) and to result in better antitumor efficacy, which other DTXloaded nanomedicines have failed to show.75 In this formulation, DTX is covalently conjugated to core-cross-linked polymeric micelles (DTX-CCL-PMs) composed of methoxy-poly(ethylene glycol)-block-poly[N-(2-hydroxypropyl)methacrylamide lactate] (mPEG-b-p(HPMAm-Lacn)) copolymers by a hydrolyzable ester bond. The micelles are 66 nm in diameter and have a 12% (w/w) DTX loading level. In vitro drug release studies revealed that the covalent conjugation of DTX to the CCL-PMs allows for sustained release of the drug following first-order kinetics when tested in PBS (pH 7.4), rat blood, and human blood at 37 °C.75 Preclinical Studies. PK studies evaluating the DTX-loaded CriPec formulation carried out in healthy rats showed elevated and extended levels of DTX in the bloodstream (t1/2 = 16.2 h). Additionally, DTX could still be detected in blood up to 7 days after i.v. administration, successfully demonstrating that as a result of covalent conjugation of drug to the copolymer, DTX was retained within the micelles for several days. In terms of toxicity, the DTX-CCL-PM formulation was tested in healthy rats and compared with conventional DTX (Taxotere). DTXrelated toxicities (such as diarrhea and panleukopenia) were seen in both groups, but these toxicities were significantly reduced in the DTX-CCL-PM group despite administration of a 45% higher dose of drug.75
antitumor activity of Abraxane was still significantly higher even when half of the equitoxic dose of Abraxane was used.72 Likely Drivers for Clinical Translation. While in vitro studies revealed a significant increase in cellular uptake of PTX upon incubation of cells with the Nanoxel formulation in comparison with incubation with the Taxol formulation as well as uptake similar to that obtained with Abraxane, Nanoxel showed significantly reduced safety and antitumor activity in comparison with Abraxane in vivo. This could be attributed to a lack of Nanoxel stability that prevented full exploitation of the EPR effect and reduced accumulation of the micelles at the tumor site. Further interpretation of in vivo data is difficult, as there is no published comparison with the clinically used formulation of PTX (Taxol). Thus, overall there is no clear advantage associated with use of Nanoxel in terms of safety or efficacy, at least in published preclinical studies, to support forward movement into clinical evaluation. Clinical Studies. Nanoxel has been evaluated clinically, but at this time limited clinical data on the formulation have been published.73 In the clinical trial that led to the approval of Nanoxel in India, higher response rates were seen in patients treated with Nanoxel in comparison with those treated with Taxol. However, the study design, in particular the small number of patients accrued, restricted statistical analysis of the differences observed.2 This study also revealed high tolerability for Nanoxel, as no premedication of patients was required to prevent hypersensitivity reactions.70 A retrospective study published in 2013 assessed the incidence of hypersensitivity reactions and other adverse effects induced by administration of Nanoxel compared with Taxol in common practice (i.e., not in a clinical trial setting). This study found that Nanoxel results in the same adverse reactions as Taxol but with a lower incidence and less severity. This study confirmed what was found earlier, that Nanoxel administration is not associated with hypersensitivity reactions even in the absence of prophylactic premedication.2 Taken together, the accessible data show that Nanoxel is better tolerated and less expensive than Taxola reported $400 less per cyclebecause of its lower direct acquisition cost and the fact that it does not require premedication for hypersensitivity reactions.2,73 Nanoxel was later approved in several countries in Asia and Latin America. However, the lack of well-designed and adequately sized clinical trials comparing Nanoxel with Taxol and Abraxane have delayed its approval in other countries. It was previously argued that regulatory rules controlling new medications in low- and middle-income countries (LMICs) are less strict than those in the USA and Europe, which raises safety and efficacy concerns.73 3.2.5. Nanoxel-M. Nanoxel-M, also known as Nanoxel-PM, Doxetaxel-PM, and SYP-0704A, was developed in an effort to find an alternative for the conventional DTX formulation Taxotere. In this formulation, Samyang Biopharmaceuticals applied its proprietary “PM technology” used to produce Cynviloq for solubilization of DTX. As a result, this formulation eliminates the excipient Tween 80 that is included in Taxotere and associated with hypersensitivity reactions and fluid retention.74 Similar to Cynviloq, Nanoxel-M is composed of methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEGb-PDLLA) (2000:1765 g/mol) block copolymers and prepared using the solid dispersion method. The micelles have a diameter of 25 nm with a narrow size distribution. The micelles were found to be stable after reconstitution in saline for 6 h.74 Preclinical Studies. Preclinical studies in mice, rats, and beagles revealed that Nanoxel-M and Taxotere had similar PK 2512
DOI: 10.1021/acs.molpharmaceut.7b00188 Mol. Pharmaceutics 2017, 14, 2503−2517
Review
Molecular Pharmaceutics
the P(Asp) core-forming block (45% of P(Asp) repeat units are conjugated with DOX). The conjugation of DOX in the core serves to increase the affinity of the core for the physically incorporated drug, resulting in a high drug loading level and a stable formulation. NK911 has a small particle size, with a diameter of 40 nm. The micelles were found to gradually release the physically entrapped drug from the inner core within 8−24 h; however, the conditions of the release studies were not reported, and stability studies under physiological conditions have not been published.4 Preclinical Studies. Preclinical evaluation of NK911 in mice bearing subcutaneous murine C26 colon carcinoma xenografts revealed a significant increase in plasma AUC(0−24 h) and Cmax for DOX (28.9- and 36.4-fold higher than those of free DOX, respectively) and a 3.4-fold increase in tumor accumulation relative to administration of the free drug. Accordingly, NK911 resulted in superior efficacy in comparison with free DOX in C26, M5076, and P388 tumor-bearing mice when administered at the same dose. However, in Lu-24 and MX-1 tumor-bearing mice, the antitumor activity was not superior to that of the free drug.4 In terms of toxicity, NK911 had a toxicity profile superior to that of free DOX. When both were administered at the highest equivalent dose, free DOX induced a significantly higher number of deaths due to toxicity compared with NK911-encapsulated DOX. Notably, in preliminary experiments leading to the development of NK911, the antitumor activity of BCMs containing both chemically and physically encapsulated DOX resulted in significantly higher efficacy in mice bearing C26 tumor compared with the free drug and BCMs containing only chemically encapsulated drug. On this basis, the authors of the study suggested that the chemically conjugated DOX does not play a significant role in the observed pharmacological activity of the formulation. However, further studies are needed to confirm this hypothesis.81 The stability and biological behavior of NK911 were compared with that of Doxil in tumor spheroids. The study suggested that Doxil resulted in preferential distribution of DOX to the surface of the spheroids, while NK911 demonstrated greater release of DOX that was distributed more uniformly throughout the spheroids.82 Accordingly, NK911 exhibited significantly higher cytotoxic effects when evaluated in spheroids of a human colon cancer cell line (HT-29) compared with Doxil (at the same dose and after 24 h exposure).82 Likely Drivers for Clinical Translation. Preclinical data revealed that NK911 has a significantly different PK profile than free DOX and acts more as a carrier of the drug. As a result, the blood circulation lifetime of DOX is extended, leading to a significant increase in drug accumulation at the tumor site. Consequently, NK911 showed promising results with superior antitumor efficacy in colon, sarcoma, and leukemia tumor models and a significantly improved toxicity profile compared with free DOX. Interestingly, cytotoxicity studies conducted in tumor spheroids revealed that NK911 surpassed Doxil in inducing a greater cytotoxic effect. This was attributed to the fact that NK911 can release DOX uniformly within the tumor spheroidsa major advantage over Doxil, which has been associated with limited drug release at the tumor site.79 Taken together, encapsulation of DOX in NK911 has improved DOX safety and antitumor effects in animal models and shown promise in overcoming the limited antitumor efficacy associated with Doxil. Clinical Studies. NK119 was the first polymeric micelle formulation to be advanced to clinical trials. In a Phase I clinical trial of NK911 in 23 patients, a 2.5-fold increase in the plasma
Importantly, DTX-CCL-PMs were found to achieve superior antitumor efficacy in mice bearing MDA-MB-231 tumor xenografts in comparison with Taxotere. Surprisingly, a single i.v. injection of DTX-CCL-PMs resulted in complete regression of tumors for over 56 days. The superior efficacy observed with DTX-CCL-PMs was attributed to their significantly increased tumor accumulation compared with Taxotere20-fold higher when administered at chemically equivalent doses of drug and 40-fold higher at equitoxic doses. Interestingly, DTX-CCL-PMs were also found to reduce tumor stromal components such as pericytes and fibroblasts after single-dose administration, suggesting that the superior efficacy of DTX-CCL-PMs could be partially attributed to the depletion of tumor stroma. Likely Drivers for Clinical Translation. Preclinical studies of the CriPec Docetaxel formulation revealed that the covalent conjugation of the drug to the cross-linked micelles allowed this formulation to act more as a carrier for DTX, as reflected by the high in vitro stability and extended circulation lifetime of the drug in the bloodstream following i.v. administration.75 In regard to tolerability, DTX-CCL-PMs were much better tolerated compared with conventional DTX (Taxotere). The doselimiting toxicities of DTX that are typically encountered in the clinic, such as diarrhea and hematological changes, occurred with less severity and/or incidence in DTX-CCL-PM-treated rats in comparison with Taxotere-treated rats. The volume of distribution of drug was significantly reduced (0.06 L/kg) in comparison with that obtained with Taxotere (4 L/kg).75 Importantly, DTX-CCL-PMs have significantly improved the antitumor efficacy of DTX compared with Taxotere. This was mainly attributed to the enhanced tumor accumulation as well as the antistromal activity of the formulation. Taken together, the CriPec Docetaxel formulation was successful in improving the efficacy as well as the tolerability of DTX in tumor-bearing mice. These data strongly supported further clinical investigation of the CriPec Docetaxel formulation, and indeed, this formulation was advanced to a Phase I clinical trial (NCT02442531) in Belgium (currently recruiting) to be evaluated in patients with solid tumors.76,77 3.3. Doxorubicin. Doxorubicin (DOX) is an anthracycline drug that acts primarily by stabilizing topoisomerase II, leading to inhibition of DNA replication. Since its approval, DOX has been used in the treatment of several cancers, including breast, lung, gastric, ovarian, thyroid, and pediatric cancers. However, DOX is associated with DLTs, with the most severe being cardiotoxicity.78 Doxil, a liposomal formulation of DOX, and the first FDA-approved nanomedicine (in 1995), results in a prolonged circulation lifetime for the drug in vivo and a significantly improved toxicity profile in comparison with the free drug. Doxil has also been shown to result in an increase in tumor accumulation of the drug, yet its efficacy is in part limited by poor drug release once at the tumor site.79 In addition, the clinical use of Doxil has been associated with palmar plantar erythrodysthesia as a DLT. 80 Block copolymer micelle formulations of DOX were developed as a means to address these challenges, with the goal of attaining good formulation stability in the bloodstream and complete release of the drug at the tumor site. To date, only two of the BCM formulations that have been developed for delivery of DOX have reached clinical evaluation (NK911 and SP1049C). 3.3.1. NK911. NK911, developed by Nippon Kayaku and Prof. Kazunori Kataoka of the University of Tokyo, is a DOX-loaded polymeric micelle formulation composed of PEG-b-P(Asp) (5000:4000 g/mol) block copolymers with DOX conjugated to 2513
DOI: 10.1021/acs.molpharmaceut.7b00188 Mol. Pharmaceutics 2017, 14, 2503−2517
Review
Molecular Pharmaceutics
cancers, and this distinguished SP1049C from other DOX-based formulations. Indeed, the potential to overcome drug resistance and to exhibit not only a significantly higher but also a broader spectrum of antitumor activities compared with nonmicellar DOX served as the basis for proceeding to a clinical trial.86,88 Clinical Studies. Preclinical findings enabled a Phase I clinical trial for SP1049C in Canada in 1999. Patients with metastatic or recurrent solid tumors refractory to conventional chemotherapy or for which no suitable conventional therapy existed were eligible for this study. SP1049C was found to have a similar PK profile and toxicities as DOX, with neutropenia as the principal DLT. The MTD was defined as 70 mg/m2, which is similar to that for free DOX. Importantly, hand−foot syndrome, an adverse effect commonly encountered with Doxil, was not observed.87 Because of the small number of patients enrolled in the trial and the diversity of previous treatments, the cardiac safety of SP1049C could not be accurately evaluated in this study. In terms of antitumor efficacy, partial responses were seen with SP1049C in several patients with advanced Ewing’s sarcoma, carcinosarcoma, and esophageal adenocarcinoma.87 In a subsequent Phase II clinical trial, SP1049C was evaluated in 21 patients with advanced carcinoma of the esophagus and gastroesophageal junction. This trial concluded that SP1049C has high activity as a single agent in this patient population with a response rate of 47% and clinical benefit (response rate plus stable disease) of 89%.89 The median OS was 10 months and the PFS was 6.6 months, which were generally comparable to values seen with standard combination regimens of DOX.89 SP1049C was granted an orphan drug designation by FDA in 2008 and was planned to move into a Phase III clinical trial. However, since 2008, no updates regarding SP1049C are available.90
half-life of DOX with a 2-fold increase in plasma AUC in comparison with the free drug was reported. The steady-state volume of distribution (Vd,ss) and total clearance (Cltot) of NK911 were lower than those of free DOX. However, the plasma AUC and t1/2 of DOX in NK911 were significantly lower than those previously reported for Doxil. Importantly, the toxicity spectrum of NK911 resembled that of free DOX, with neutropenia as the DLT.83 As a consequence, the MTD for NK911 (67 mg/m2) was comparable to that of free DOX. However, infusion-related reactions common with Doxil84,85 were not seen with NK911. In terms of antitumor efficacy, a partial response was seen in only one patient.83 On the basis of the lack of infusion-related reactions and initial signs of efficacy, NK911 moved into a Phase II clinical trial. The results of this study have yet to be reported, and the latest publicly available updates are several years old.3,83 3.3.2. SP1049C. SP1049C, developed by Kabanov’s group and Supratek Pharma, was the first Pluronic-based polymeric micelle formulation of DOX to enter clinical trials. The formulation consists of a mixture of two Pluronic block copolymers, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-b-PPO-b-PEO), L61 and F127 (1:8 w/w). Pluronic L61 was primarily chosen to sensitize resistant cancer cells to DOX, while Pluronic F127 was used to stabilize the formulation by preventing aggregation of Pluronic L61. Formation of the Pluronic micelles is driven spontaneously after reconstitution of DOX in a 0.9% NaCl carrier solution containing 0.25% (w/v) Pluronic L61 and 2% (w/v) Pluronic F127.86,87 The micelles have a final drug loading level of 8.2% (w/w) and a size of
