Engineered in-situ depot-forming hydrogels for intratumoral drug delivery

Journal of Controlled Release 220 (2015) 465–475

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Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel

Review article

Engineered in-situ depot-forming hydrogels for intratumoral drug delivery Amir Fakhari, J. Anand Subramony ⁎ Drug Delivery and Device Development, Medimmune LLC, United States

a r t i c l e

i n f o

Article history: Received 24 June 2015 Received in revised form 11 November 2015 Accepted 12 November 2015 Available online 14 November 2015 Keywords: In-situ gelling Engineered hydrogel Intratumoral drug delivery Anticancer drug Biologics sustained release

a b s t r a c t Chemotherapy is the traditional treatment for intermediate and late stage cancers. The search for treatment options with minimal side effects has been ongoing for several years. Drug delivery technologies that result in minimal or no side effects with improved ease of use for the patients are receiving increased attention. Polymer drug conjugates and nanoparticles can potentially offset the volume of drug distribution while enhancing the accumulation of the active drug in tumors thereby reducing side effects. Additionally, development of localized drug delivery platforms is being investigated as another key approach to target tumors with minimal or no toxicity. Development of in-situ depot-forming gel systems for intratumoral delivery of immuno-oncology actives can enhance drug bioavailability to the tumor site and reduce systemic toxicity. This field of drug delivery is critical to develop given the advent of immunotherapy and the availability of novel biological molecules for treating solid tumors. This article reviews the advances in the field of engineered in-situ gelling platforms as a practical tool for local delivery of active oncolytic agents to tumor sites. © 2015 Published by Elsevier B.V.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Advantages of intratumoral cancer therapy . . . . . . . . . . . . . . Engineering in-situ depot-forming systems for intratumoral drug delivery 3.1. Platforms based on in-situ cross-linking . . . . . . . . . . . . 3.1.1. Photo-polymerization . . . . . . . . . . . . . . . . 3.1.2. Chemical cross-linking . . . . . . . . . . . . . . . 3.1.3. Physical cross-linking . . . . . . . . . . . . . . . . 3.2. Platforms based on in-situ phase separation . . . . . . . . . . 3.2.1. pH sensitive platforms . . . . . . . . . . . . . . . . 3.2.2. Thermo-sensitive gels . . . . . . . . . . . . . . . . 3.2.3. Solvent based in-situ phase separation . . . . . . . . 4. Clinical studies using intratumoral route of administration . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: C/GP, chitosan/β-glycerophosphate; CMC, Carboxymethyl chitosan; DMSO, Dimethylsulfoxide; HA, hyaluronic acid; HEM, 2-hydroxyehthyl methacrylate; HPC, Hydroxypropylcellulose; HPMC, Hydroxypropylmethylcellulose; IL-2, interleukin-2; MA, maleic anhydride; MC, Methylcellulose; MM, methyl methacrylate; mPEG, Methoxy poly(ethyl glycol); mPEG-b-(PCL-ran-PLLA), Methoxypolyethylene glycol-b-polycaprolactone-ran-polylactide; NMP, N-Methyl-2-pyrrolidone; PAA, Poly(acrylic acid); PAH, α,βpolyaspartylhydrazide; PCL, Poly(ε-caprolactone); PDEAEM, Poly(N,N′-diethylaminoethyl methacrylate); PEEU, Poly(ether ester urethane); PEG, Poly(ethylene glycol); PEG–PAA, Poly(ethylene glycol)-b-poly(acrylic acid); PEG–PDLA, Poly(ethylene glycol)-poly(D-lactide) acid; PEG–PLA, Poly(ethylene glycol)-poly(lactic) acid; PEO, Poly(ethylene oxide); PHA, Poly (α-hydroxy acids); PLA, Polylactic acid; PLGA, Poly (lactic-co-glycolic acid); PMA, Poly(methacrylic acid); PNIPAAM, Poly(N-isopropyl acrylamide); Poly(HPMAL), Poly(N-(2hydroxypropyl) methacrylamine lactate); POPS, Poly(organophosphazene). ⁎ Corresponding author at: 1 Medimmune Way, Gaithersburg, MD 20878, United States. E-mail address: [email protected] (J. Anand Subramony).

http://dx.doi.org/10.1016/j.jconrel.2015.11.014 0168-3659/© 2015 Published by Elsevier B.V.

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A. Fakhari, J. Anand Subramony / Journal of Controlled Release 220 (2015) 465–475

1. Introduction The most effective treatment for cancers for localized solid tumor is to remove the tumor by surgery followed by post-operative chemotherapy or radiation treatment. However, this approach is not suitable for many cancers since many patients are not candidates for surgical procedure due to tumor size, location of tumor, and stage of cancer. In some cases, even after the surgery, the overall survival rates for some patients are not promising [1]. While an anticancer drug is administrated intravenously (IV), high plasma concentrations in the systemic circulation can result in undesirable side effects with just a portion of the entire administrated dose reaching the tumor [1–3]. Additionally, several anticancer drugs have rapid plasma clearance resulting in minimal tumor exposure that is not sufficient to build an effective treatment. To enhance efficacy of chemotherapy and reduce systemic side effects, new drug delivery approaches are being developed and have received significant attention in recent years [1,4]. One such approach is the advancement of drug delivery depot technologies for localized intratumoral delivery of anticancer drugs to achieve greater efficacy and minimize systemic side effects. Several configurations, such as gels, wafers, particles, rods, and films, have been evaluated for direct distribution of anticancer drugs to the tumor site [5–7]. In most cases, these platforms are made from biodegradable polymeric materials such as natural polymers including polysaccharides and polypeptides, and synthetic polymers such as PLA and PLGA [1,5,8]. These biopolymers are shown to be biocompatible in-vivo and applicable as in-situ depot-forming systems for localized intratumoral drug delivery [5,9–23]. Hydrogel depot systems are three-dimensional networks of polymers with high capacity to hold water and biological fluids [24]. Hydrogels are classified into two categories with regard to the cross-linking type used for the three dimensional depot formation: 1) depot-gelling systems in which the network is formed by covalent bond formation (chemical cross-linking); and 2) depot-gelling systems in which the network is formed by physical association between the components (physical cross-linking) [24,25]. Both categories have been investigated as injectable sustained release drug delivery systems that form a depot gel in-situ [24,26–28]. A key requirement of in-situ depot-forming systems for local delivery and more specifically intratumoral delivery is the injectability using standard gauge needles in either a vial/syringe or a pre-filled syringe configuration. The injection should be easy to administer and also provide minimal discomfort to the patient. Intratumoral injections based on in-situ gelling polymers are solutions that have low viscosity and can easily flow during administration but rapidly form gel networks once injected. This article focuses on the approaches for in-situ gelation for local intratumoral drug delivery, and the application of in-situ gelling formulation as a practical tool for improved local biodistribution and potential uptake of anticancer drugs to the tumor via intratumoral injection. 2. Advantages of intratumoral cancer therapy Several anticancer drugs have low aqueous solubility that limits IV administration; chemical modifications have been introduced to convert these drugs to produce water soluble prodrugs for administration [5]. However, some of these systems are prone to poor bioavailability, cause sensitization and other adverse reactions [5,29,30]. Additionally, IV administration of anticancer drugs does not specifically target the tumor site, resulting in less than optimum drug concentration in the tumor. Moreover, large quantities of anticancer drugs are distributed to healthy tissues resulting in acute adverse effects and toxicity. For example, during the first 24 h after IV administration of free paclitaxel, almost 50% of the administrated dose is eliminated and only less than 0.5% of the administrated dose is bioavailable locally at the tumor site within the lung [5,31].

The high prevalence of systemic side effects for current treatment in the early and intermediate cancer stages indicates that improvements are required on treatment approaches [5]. Intratumoral drug delivery can be a tool to enhance the current cancer treatment approaches via local delivery. At each stage of cancer, there are potential intervention points in which intratumoral cancer therapy could be implemented or completely replace existing treatments. There are numerous potential advantages of intratumoral drug delivery, and it is applicable to both improving effective treatment and lowering patient morbidity. When compared to traditional IV administration of anticancer drugs (Fig. 1), intratumoral drug delivery systems have the potential to (a) provide controlled and sustained drug distribution ensuring sufficient drug transport and diffusion into cells, (b) enable the loading and release of insoluble anticancer drugs through novel solvent/polymer combinations, (c) deliver anticancer drugs locally to the tumor site leading to low dose requirements, (d) reduce multiple drug administration cycles, and (e) reduce or eliminate adverse effects of the drug due to local delivery, and prevention of systemic drug uptake [5,32,33]. 3. Engineering in-situ depot-forming systems for intratumoral drug delivery Injectable gelling depots and pre-shaped implant systems are two types of intratumoral delivery systems for anticancer drugs [5]. Injectable biodegradable in-situ forming depots are shown to be less invasive and have less pain upon injection as compared to pre-formed implants, making them desirable systems for local administration of anticancer drugs [8]. Injectable biomaterials are suitable for development as delivery systems to localize the drug molecules at the tumor site [8]. According to the mechanism of depot formation, engineered in-situ gelling depots can be classified into two categories: (1) platforms based on in-situ cross-linking, and (2) platforms based on in-situ phase separation (Table 1) [8,34–37]. 3.1. Platforms based on in-situ cross-linking In this platform, in-situ gels form by either photo-polymerization, chemical cross-linking, or physical cross-linking (Fig. 2) [8,38–41]. 3.1.1. Photo-polymerization In the photo-polymerization approach, the starting materials are liquid solutions that can be injected into the tumor site. Upon exposure to light, the injected materials polymerize to form the depot matrix in-situ. Monomers with a minimum of two free radicals (or cross-linkable polymer), a photo-initiator, and visible or ultraviolet (UV) light are required for in-situ depot formation (Fig. 2) [8,42–47]. Examples of polymers used for in-situ photo-polymerization are triblock copolymerized materials of poly(HPMAL) and PEG, di-block copolymerized materials of PEG and PHA containing acrylated terminal groups, and modified chitosan [8,45,48]. Obara and his colleagues showed slow paclitaxel release from photocrosslinked chitosan based hydrogels [49]. The in-vivo results indicated that the paclitaxel incorporated gel prevented the expansion of subcutaneously induced tumors more effectively compared to free paclitaxel group. In another attempt, Sharifi et al. employed modified PCL to develop in-situ depot forming system based on photocrosslinking for sustained release of tamoxifen citrate as a potential treatment for breast cancer [50]. Results showed a slow release of drug in-vitro resulting in death of cancer cells. The main concern for applying this approach is the presence of reactive species generated by photo-polymerization. The reactive species can expose free radicals to the surrounding tissues and affect incorporated anticancer drugs. Moreover, performance of depot formation based on photo-polymerization is limited by the penetration depth of visible

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Fig. 1. Schematic showing systemic vs. intratumoral delivery of an anticancer drug. By delivery of drugs intratumorally, drug biodistribution is localized to tumor site resulting in lower systemic side effect and higher treatment efficacy as compared to systemic delivery.

and UV light within the tissues and can result in non-homogenous polymerization. To decrease the possible undesirable effects and increase the performance of this approach, optimization of photo-

initiator concentration and UV light intensity are considered. This approach may be applicable for peritumoral injection after removing the tumor by surgery (Tables 1 and 2) [8,35,51].

Table 1 Advantages and challenges of engineered in-situ depot-forming systems [8,26]. In-situ depot-forming platforms Platforms based on in-situ cross-linking

Platforms based on in-situ phase separation

Advantages

Challenges

Photo-polymerization

• Superior mechanical properties • Formation of stable depots

Chemical cross-linking

• Formation of stable depots • Elastic materials can be generated

Physical cross-linking

• No chemical reaction is required • Suitable for biologics and sensitive actives

pH sensitive platforms Thermo-sensitive gels

• No chemical reaction is required • Suitable for biologics and sensitive actives

Solvent based in-situ phase separation

• Using organic solvent as a solubilize

• • • • • • • • • • • • • • •

Gelation is only triggered by external light Presence of reactive species post gelation Limited penetration of visible and UV light Toxicity of unreacted free species Use of toxic cross-linker Toxicity for active and surrounding tissues Slow rate of cross-linking Mechanical instability in-vivo Impact of drug properties on gel formation Viscoelastic materials formation Mechanical instability in-vivo Burst release for hydrophilic actives Slow rate of gel formation Stability of biodegradable polymer and active Toxicity of organic solvent in-vivo

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Fig. 2. Platforms based on in-situ cross-linking: (A) photo-polymerization is used for local delivery of anticancer drugs. Injectable materials including monomers and photoinitiator are administrated intratumorally. By applying visible or UV light to the injection site, in-situ depot formation incorporated with anticancer drug occurs. (B) In-situ based chemical cross-linking for intratumoral drug delivery. Upon injection of the polymer, cross-linker, and anticancer drug, gel network forms in-situ as a result of chemical reaction between the polymer and crosslinker. (C) Physical based cross-linking can be used for in-situ depot formation. Upon injection of the formulation into the tumor site, physically entangled gel formation happens with incorporated anticancer drug. Platforms based on in-situ phase separation: (D) application of pH sensitive polymer for intratumoral drug delivery. Upon injection, the pH of the gelling system is adjusted to physiological pH by exchanging the ions resulting in formation of depot in-situ. (E) Thermogels are flowable at room temperature for easy injection and form semi-solid or solid gels at physiological temperature. After injection of thermo-sensitive polymer with an anticancer drug into the tumor site, drug incorporated depot forms at the tumor site as a result of increasing thermogels temperature to physiological temperature. (F) Solvent exchange forms in-situ depot incorporated with anticancer drug at the site of injection. Upon injection, organic solvent leaches out from injected material to surrounding tissues resulting in polymer precipitation and gel formation at the tumor site.

3.1.2. Chemical cross-linking In the chemical crosslinking approach, covalent bonds result in the formation of gel matrix (Fig. 2). Changing the terminal functional groups or attaching cross-linkable functional groups to the starting polymer is required for this approach. Cross-linking agents such as benzyl peroxide, di-aldehydes, and oxalic acid have been used for in-situ chemical crosslinking [40,52–54]. For example, in-situ cross-linking of HA was performed by mixing HA derivatives with a cross-linker containing hydrazide or aldehyde moieties [24]. Thiol based cross-linking is another category for chemical cross-linking used for in-situ PEG-based depot formation for delivery of anticancer drugs such as topotecan [24,50]. Emoto and coworkers used a modified HA based material with in-situ cross-linking capability for sustained release of cisplatin via interaperitoneal administration for cancer treatment [55]. Modified HA forms (HA-aldehyde and HA-adipic dihydrazide) were used for in-situ gelation based on chemical cross-linking. The study showed a tunable cross-linking platform in which the time of gelation could be varied by changing the concentration of the two modified HA polymers. With the proposed platform, four days in-vitro release of cisplatin was achievable. An in-vivo study in mice indicated reduction in the weight of peritoneal nodules with cisplatin loaded gel, whereas no significant anti-tumoral effect was achieved in mice treated with free drug [55]. The HA-based system therefore demonstrated utility as a controlled release hydrogel matrix for local delivery of an anticancer drug. Even though chemical cross-linking can form a stable depot system for intratumoral delivery of anticancer drugs, chemical toxicity in-vivo is a predominant issue for this approach and restricts the reaction

condition to non-toxic crosslinking approaches [8]. Most of the proposed cross-linking agents are toxic and are associated with concerns of poor biocompatibility for in-situ depot formulations. Additionally, some crosslinking approaches require several hours for gelation (Table 2). Slow processes may impact the functionality of the biomaterial and result in unexpected drug release to surrounding tissues [8,56,57], which in turn may result in systemic uptake and adverse side effects.

3.1.3. Physical cross-linking In the physical cross-linking approach, a network structure based on secondary bond forces such as hydrogen bonding or electrostatic interaction are commonly employed (Fig. 2) [8,34,40]. For example, alginate (an anionic polysaccharide) is a biopolymer that has the capability of gel formation in the presence of calcium ions [23,35,46]. Chitosan (a polycationic polysaccharide) also undergoes gelation through ionic interaction with negatively charged compounds [35,53,58,59]. Based on this approach, Zhu et al. developed an injectable hydrogel incorporating cisplatin-loaded nanoparticles and α–cyclodextrins that undergoes gelation based on physical interactions [60]. Di-block copolymer of PEG–PAA was used to make cisplatin-loaded nanoparticles. Then, the hydrogel was developed by introducing α–cyclodextrins onto the PEG segments of the nanoparticles to form physical crosslinks. The gelling of the formed construct could be tuned by adjusting polymer and cisplatin concentrations and addition of PEG or poloxamer (Pluronic®). Drug-loaded gels showed similar tumor growth inhibition of human bladder carcinoma cells compared to the free drug during

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Table 2 Selected applications of in-situ depot-forming platforms for intratumoral drug delivery. In-situ depot-forming platforms

Main polymer

Anticancer drug

Study outcome

Ref.

Platforms based on in-situ cross-linking

Chitosan Poly(ε-caprolactone) (PCL) Hyaluronic acid (HA) PEG–PAA Dextran PEG–PLLA & PEG–PDLA Glycol chitosan & PEG-PPG-PEG Pluronic® F127

Paclitaxel Tamoxifen citrate Cisplatin Cisplatin rhIL-2 rhIL-2 Doxorubicin & paclitaxel Paclitaxel

More effective as compared to free active to inhibit tumor growth Slow drug release could cause cancer cells death.

[49] [50]

Tunable cross-linking platform Tunable properties based on polymer and drug concentrations Sustained release of active without losing biological and therapeutic activity Effective therapy to reduce the tumor size Co-delivery of both hydrophilic & hydrophobic drug simultaneously

[55] [60] [61] [62] [69] [84]

Pluronic® F127 Poloxamer Poloxamer

Paclitaxel R-837 Paclitaxel

PLGA–PEG–PLGA PLGA–PEG–PLGA

Paclitaxel IL-2

PLGA–PEG–PLGA Poly(ether ester urethane) mPEG–PCL mPEG–PCL mPEG–PCL

Topotecan Paclitaxel

Gel containing liposomes exhibited the longest drug release as compared to gel without liposomes and free drug High drug loading, acceptable efficacy and low toxicity Reduction of systemic absorption of R-837 Thermo-sensitive micelles-hydrogel hybrid with strong mechanical properties, longer term drug release, & higher loading efficiency Minimal drug distribution to the other organs and less drug side effects Release of IL-2 without loss of bioactivity, significant reduction in tumor growth and improve survival Five days sustained release with mild initial burst Sustained release of paclitaxel for more than two weeks

Photo-polymerization

Chemical cross-linking Physical cross-linking

Platforms based on in-situ phase separation

pH sensitive platforms Thermo-sensitive gels

Solvent based in-situ phase separation

mPEG-b-(PCL-ran-PLLA)

Paclitaxel Doxorubicin Paclitaxel & doxorubicin 5-fluorouracil

Poly(organophosphazene) Methylcellulose Chitosan Phospholipid

Doxorubicin Docetaxel Paclitaxel Doxorubicin

cytotoxicity studies in-vitro and provided sustained delivery of cisplatin [60]. In another study, Bos and coworkers developed an in-situ biodegradable gelling platform based on physically cross-linked dextran hydrogel for sustained release of rhIL-2 to SL2 lymphoma in mice [61]. Crosslinking was carried out via stereo-complexation of D-lactic acid oligomers and L-lactic acid oligomers separately conjugated to dextrans. In-vivo data indicated similar therapeutic effect of a single administration of loaded gels with rhIL-2 to administration of free rhIL-2. The study showed that physically cross-linked dextran hydrogel slowly released rhIL-2 without losing biological and therapeutic activity of rhIL-2 demonstrating its utility for intratumoral delivery of biological molecules such as rhIL-2 for cancer immunotherapy [61]. Hiemstra et al. used a PEG–PLA based hydrogel to make a biodegradable injectable system for local delivery of rhIL-2 [62]. They showed the formation of hydrogel with a high physical cross-linking density upon mixing eight-arms PEG–PLA and PEG–PDLA in aqueous solutions. Study results indicated 50% release of rhIL-2 from the gel in 16 days. In-vivo study showed that this system could be easily injected intratumorally in a mouse model. Moreover, the outcome indicated that release of rhIL-2 was effective in reducing the tumor size whereas no treatment effect was observed when rhIL-2 was not administrated. However, the rate of drug release from gel incorporated with drug was lower compared to single injection of the free drug (not statistically significant), but the treatment effect of rhIL-2 incorporated gel lasted for roughly 1–2 weeks due to constant release of rhIL-2 as compared to free rhIL-2 [62]. The impact of the drug and environment on in-situ gelling processes, the risk of dissolving the gel due to the presence of ions, and low mechanical strength are some parameters that need to be considered when designing in-situ depot forming systems based on physical crosslinking [8,23,59,63]. Nevertheless, these approaches may be suitable for intratumoral drug delivery (Tables 1 and 2).

More effective treatment as compared to free drug Few off-side target side effect Paclitaxel incorporated nanoparticles with doxorubicin loaded in PEG–PCL thermogel, burst release for doxorubicin & sustained release for paclitaxel Effective suppression of tumor resulted by single injection as compared to repeated injection Lower systemic drug biodistribution as compared to free drug administration Tunable system to reduce tumor size Controlled delivery of paclitaxel over one month High drug concentration in tumor site as compared to major organs

[85] [86] [87] [74] [94] [95] [99] [100] [101] [102] [103] [105] [110] [111] [67]

3.2. Platforms based on in-situ phase separation In-situ phase separation is another strategy to deliver anticancer drugs to the tumor site (Fig. 2). Phase separation can be induced by changing the solubility of the polymer with respect to changes in pH, temperature, or by elimination of solvent (Table 2) [8].

3.2.1. pH sensitive platforms Changing pH is one approach to gelate polymers containing ionized functional groups by undergoing sol-to-gel transition (Fig. 2). Several polymers undergo pH responsive phase transition from solution to the gel form. pH-sensitive polymers undergo phase transition due to the functional groups on the polymers that either accept or donate protons as a result of changes in the environmental pH. These functional groups can be acidic groups such as sulfonic acid and carboxylic acid or basic groups such as ammonium salts [64]. Polyelectrolytes which are polymers with several ionizable groups have also been used as pH-sensitive polymers for this approach. For instance, anionic and cationic polyelectrolytes including PAA, PDEAEM, chitosan, alginate, chondroitin sulfate, heparin, and hyaluronic acid have been utilized in this approach [8,23,40,65–68]. Increasing the pH ionizes anionic polyelectrolytes such as PAA and alginate while decreasing the pH ionizes cationic polymers such as PDEAEM and chitosan [64]. The swelling of hydrogels can be controlled by conditions that impacts electrostatic repulsion, such as ionic strength, pH, and the type of counterions. Natural co-monomers such as MM, MA, and HEM can be used to adjust the pH-responsiveness and the swelling of polyelectrolyte hydrogels [64]. In general, pH-sensitive hydrogels have been broadly utilized for development of formulations with controlled release behavior for oral delivery due to stomach pH (b3) which is lower than the neutral pH in the intestine [64]. In addition to oral delivery, pH-sensitive hydrogels

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can be engineered in such a way that the drugs can be released in a desired pH environment. Zhao and his colleagues showed the application of a pH triggered amphiphilic hydrogel for intratumoral co-delivery of both doxorubicin and paclitaxel [69]. It was shown that release of both drugs (doxorubicin and paclitaxel) can be obtained and the drug release rate can be managed by changing the pH. Intratumoral administration of an in-situ depot-forming system showed effective tumor growth inhibition in a mouse model [69]. In another study, Li and co-workers introduced an injectable and biodegradable pH-responsive hydrogel for intratumoral delivery of doxorubicin based on PEG derivative with PAH. The pH-sensitive hydrogel used for this study was a free-flowing fluid before injection but would rapidly transform to semisolid hydrogel upon injection under physiological conditions. It was observed that inhibition of tumor growth in an animal mouse model was more pronounced using doxorubicin-loaded hydrogel as compared to free doxorubicin [70]. 3.2.2. Thermo-sensitive gels Thermogel-based platforms undergo sol-to-gel transformation with changing temperature (Figs. 2 and 3). Since thermogels do not require the use of organic solvents, polymerization agents, or any exterior applied triggers for in-situ depot-formation, they are especially attractive for delivery of small molecules and biological molecules [8,64,71,72]. Temperature-dependent phase transitions are governed by interactions between molecules including hydrogen bonding or hydrophobic responses. Water-polymer hydrogen bonding tends to be undesirable as compared to polymer–polymer interactions at the lower critical solution temperature (LCST). In this state, the solvated macromolecules lose the water of hydration and polymer–polymer interaction increases resulting in formation of polymeric network structure with an increase in viscosity of the system. For intratumoral drug delivery, the ideal requirement would be an aqueous polymer solution that easily flows at room temperature followed by formation of gel at physiological temperature (37 °C) [8]. For this approach, both synthetic and natural polymeric materials are considered [8,35,73–75]. Copolymerized materials of PEO and PPO (PEO–PPO–PEO), recognized as Pluronic® (BASF) or Poloxamer (ICI), and copolymerized materials of PNIPAAM are well-known synthetic polymers with this approach [24,65,73,76–79]. Above the critical micelle concentration (CMC), these amphiphilic copolymers can self-assemble into micellar structures in water. Above the critical micelle concentration (CMC), these amphiphilic copolymerized materials can self-assemble into micellar structures in water. Above the critical gelation concentration (CGC), these tri-block copolymerized materials can form thermoreversible gels in aqueous solution [24,80,81].

Fig. 3. Sol-to-gel transition temperature in thermo-sensitive gels is dependent on the polymer concentration.

3.2.2.1. Poloxamer based thermo-sensitive gels. Poloxamer based hydrogels undergo sol-to-gel phase transition in a thermal reversible manner. Poloxamers (Pluronic®) are broadly employed as thickening and solubilizing agents. For biomedical applications, poloxamers with concentrations between 16% to 30% weight/weight have been used to form semisolid gels, however, the release profiles were limited to a few days and gels had low mechanical strength [8,73,82,83]. Nie et al. demonstrated the application of poloxamer 407 (Plorunic® F127)-based thermogel incorporated with liposomes for delivery of anticancer drug paclitaxel [84]. An in-vitro drug release study indicated that the liposome-incorporated gel had longer drug release profile compared to the gels without liposomes and Taxol® [84]. Lin et al. demonstrated thermo-sensitive gel based on Pluronic® F127 for intratumoral delivery of paclitaxel with high drug loading that had continuous drug release, better efficacy and, lower toxicity [85]. Intratumoral injection of thermogels showed more effective treatment with much lower toxicity compared to free drug (Taxol®). In another study, Hayashi et al. showed that a poloxamer-based system was used for local delivery of R-837, a toll-like receptor 7 agonist, for treatment of bladder cancer [86]. The outcome indicated that intravesical delivery of agonist in lactic acid alone promoted systemic and bladder tumor necrosis factor α (TNFα) and keratinocyte-derived chemokine (KC). Introduction of poloxamer to the drug formulation lowered systemic absorption of agonist and resulted in remarkable decrease of local and systemic production of KC [86]. The application of this poloxamer based platform for intratumoral delivery of anticancer drugs might reduce the chance of systemic absorption of the agonist and overall increase the efficacy of the anti-cancer drug. Ju et al. used Poloxamer 407 (Plorunic® F127) to develop thermosensitive micelles–hydrogel hybrid system for intratumoral delivery of paclitaxel [87]. Glutaraldehyde (GA) was introduced to enable crosslinked networks with CMCs interpenetrated in poloxamer gel materials to reduce degradation of gel and increase loading capability of hydrophobic drugs such as paclitaxel in poloxamer thermogels. The results showed greater mechanical properties, improved sustained drug release, and higher loading efficiency. Moreover, the thermogel formulation also showed better tumor size reduction with lower toxicity compared to control formulation with Taxol® [87]. 3.2.2.2. PLGA and PEG based thermo-sensitive gels. Tri-block copolymerized materials of PLGA and PEG has been studied as thermo-sensitive biodegradable materials. At temperatures less than 15 °C, both PLGA– PEG–PLGA and PEG–PLGA–PEG tri-block copolymerized materials form micellar structures in aqueous solution (PLGA forms the hydrophobic inner core of the micellar structure). At physiological temperature, entanglement of micellar structures results in gelation of the polymer. Thermogelation occurs at polymer concentration of 10% to 30% weight/weight [35,58,80,82,88]. The hydrophobicity of drugs strongly affects the gel forming properties and their release profile. ReGel® platform (BTG International Ltd.) consisted of low molecular weight tri-block copolymerized materials of PEG–PLGA–PEG and PLGA– PEG–PLGA and has been widely investigated for anticancer drug delivery (paclitaxel and cyclosporine A) and protein delivery (IL-2, zinc-insulin, porcine growth hormone) [50,89]. It was shown in one study that using PLGA–PEG–PLGA at 23% weight/weight increased the solubility of paclitaxel 400-fold and resulted in controlled release of paclitaxel over 50 days in-vitro [89]. After 4– 6 weeks post injection of ReGel® formulation, it was fully eliminated from the site of injection. The performance of ReGel® loaded with paclitaxel (OncoGel®) for treatment of human breast cancer was greater than the control formulation Taxol®. The intratumoral delivery of OncoGel® and sustained release of drug from the depot resulted in minor localization of paclitaxel to main organs and lower adverse effects compared to control formulation Taxol® [74,90]. A phase I human clinical trial was designed to assess the toxicity, antitumor activity, and pharmacokinetics of intratumorally delivered

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OncoGel® for local management of superficial solid tumors lesions. The outcome indicated that OncoGel® was tolerated properly [91]. A phase II human clinical trial was also carried out for the OncoGel® formulation in a dose-escalation study and as combination local therapy with radiation in patients with inoperable esophageal cancer. Dose-limiting toxicities were not observed and reduction of tumor was reported in almost all of the patents [5,92,93]. In another study for cancer immunotherapy, ReGel® was used to develop controlled delivery of IL-2 [94]. Samlowski et al. showed 72–96 h in-vitro IL-2 release from ReGel® without loss of bioactivity. The pharmacokinetic analysis indicated an initial burst with slow release over 96 h. A low percentage of the administered dose (b 1.5%) was detected in blood or kidney within the first 48 h after injection. Data based on peritumoral injection of ReGel® in an in-vivo mouse model showed a remarkable increase in tumor growth inhibition and survival. Their findings concluded that ReGel® is a promising delivery platform for IL-2 for cancer immunotherapy, while reducing IL-2 toxicity [50,94]. Chang et al. proposed the application of PLGA–PEG–PLGA tri-block copolymerized material to deliver topotecan, an anti-tumor drug, to the tumor site [95]. The release study showed five days of continuous release of drug with minimal initial burst. Additionally, it was showed that the active lactone form fraction of topotecan was higher in the hydrogel matrix as compared to phosphate saline buffer in physiological condition [95]. At 30 °C, di-block copolymerized materials of PLGA–PEG form micellar structures in aqueous solution that undergo sol-to-gel transition [88]. In-vivo studies have shown that the di-block copolymerized materials eventually dissolve. The composition of the di-block copolymerized material can then be modified to achieve longer residence time in-vivo with sustained release of the drug for up to 2 months [8,96,97]. Approaches involving PLGA are not optimal due to the generation of acidic environment as a result of PLGA degradation into its monomeric acids. To overcome this limitation, another di-block copolymerized material, mPEG–PCL was introduced, which undergo sol-to-gel transition within a few seconds [98]. It was shown that the degradation of this di-block copolymerized material does not lower pH resulting in acidic condition and the gel maintains its structural integrity in-vivo for longer than 30 days. In another study, Lon et al. introduced a thermo-sensitive gel system based on a multi-block PEEU consisting of PCL, PEG, and PPG segments for sustained delivery of paclitaxel [99]. A drug release study showed continuous release of paclitaxel for greater than couple of weeks. Acceptable in-vivo efficacy of doxorubicin- and paclitaxel-loaded mPEG–PCL gels was observed in other studies [100,101]. Lee et al. described the application of mPEG–PCL, a biodegradable di-block copolymerized material, as a depot-forming injectable system for paclitaxel [100]. In-vivo results indicated that paclitaxel was released from mPEG–PCL gel over a period of more than 14 days and was more effective compared to Taxol® in treating localized solid tumors. Kang and his colleagues suggested mPEG–PCL di-block copolymerized material for intratumoral delivery of doxorubicin. They developed a 20 day sustained release system in animal models for doxorubicin based on mPEG–PCL gel with a few side effects outside the tumor [101]. In another study, Xu et al. introduced the application of paclitaxelincorporated nanoparticles with doxorubicin loaded in PEG–PCL thermogel as a combination therapy to both modify the burst release of the drug and to improve anti-tumor efficacy [102]. The results indicated that both hydrophilic and hydrophobic drugs were able to be successfully incorporated in thermogel together with no influence on gelation properties. Drug release results showed initial burst of doxorubicin and continued release for paclitaxel. Anti-tumoral response was enhanced as a result of doxorubicin burst release followed by the continuous release of paclitaxel from nanoparticles [102]. Seo et al. studied a thermo-sensitive 5-fluorouracil (5-Fu) loaded gel based on mPEG-b-(PCL-ran-PLLA) di-block copolymerized material for intratumoral administration [103]. A single injection of the proposed

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sustained release system showed an effective suppression of tumor compared to the repeated injection of free 5-Fu.

3.2.2.3. Other polymer based thermo-sensitive gels. POPS, PSA-C-RA, modified cellulose, and chitosan are some of the polymers that have been well studied as thermosensitive gels. POPS is one of the thermosensitive hydrogel with sol-to-gel conversion at physiological temperature. Al-Abd and his group used POPS for intratumoral delivery of doxorubicin. They demonstrated controlled release of doxorubicin from thermo-sensitive POPS hydrogels over a period of 30 days [50, 104]. The in-vivo study in tumor-bearing mice showed that gel formulations have demonstrated lower systemic biodistribution compared to administration of free drug intratumorally [105]. Shikanov et al. also developed an in-situ gelation system based on PSA-c-RA for sustained delivery of paclitaxel [106,107]. The results indicated that treatment with intratumoral injection of gel inhibited tumor growth. Furthermore, an in-vivo animal study showed high and effective paclitaxel concentration at the tumor site [106,107]. Modified cellulose can be used as a thermo-sensitive gel for drug delivery. While cellulose is insoluble in aqueous solutions, modifying cellulose with hydrophilic groups make it water soluble. Modification of cellulose results in an ideal balance of hydrophilic and hydrophobic moieties and thus modified cellulose can gel in aqueous solutions at elevated temperatures. MC, HPC, and HPMC are typical examples (Fig. 4). Addition of salt can further modulate their phase transition temperatures [8,73,82,108]. As an example, introducing sodium chloride to MC reduced its LCST to 32–34 °C. The limitation of cellulose-based thermo-sensitive gels is their slow rate of gelling. To overcome this limitation, hyaluronic acid (HA) was mixed with MC to increase the gelling rate for local delivery to the spinal cord [109]. However, the biocompatibility in intrathecal space of a rat model for one month showed that cellulose by-products are not bioerodible and accordingly their application is restricted to cellulose molecules that have lower degree of polymerization and hence lower mass. Kim and his coworkers showed that the combination low molecular weight MC and Pluronic® can be used as a thermo-sensitive gel that possesses tunable system for intratumoral delivery of docetaxel [110]. Their results showed that this approach can be an encouraging approach for tumor size reduction and enhancing tumor growth inhibition [110]. In another study, a chitosan based hydrogel was introduced for intratumoral delivery of paclitaxel [111]. This system falls into the BST-Gel™ platform (developed by Biosyntech Inc.) and consists of chitosan solution with β-glycerophosphate. At room temperature, the system is liquid and suitable for injection while at physiological temperature it forms a gel. In-vitro release study showed sustained delivery of paclitaxel over a month. In-vivo results indicated that one intratumoral injection of this paclitaxel loaded gel was as effective as four intravenous injection of control formulation Taxol® for inhibition of tumor growth in a mouse model.

Fig. 4. Chemical structure of Methylcellulous (MC), Hydroxypropyl cellulose (HPC), and Hydroxypropyl methylcellulose (HPMC).

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Combinations of chitosan with polyol salts are used as thermosensitive neutral solutions. Chitosan is soluble in acidic solutions without mixing with additives, and phase separates at pH greater than 6. To increase the pH of acidic chitosan solutions to natural pH without phase separation, polyol salts are added. These chitosan based systems are thermo-sensitive and form gels at body temperature [112]. Chitosan-based thermogels are acceptable for local delivery of macromolecules and anticancer drugs, as it provides slow release from hours to days [111,113]. A proposal to achieve longer sustained release for a hydrophilic drug is to first incorporate the drug into liposomes and then mix the liposomes with chitosan/polyol solution. The release rate of the drug could be tuned by both the properties of liposomes (size and composition) and the properties of chitosan-based thermogel [8,112,114,115]. In another attempt, Pluronic® and acrylated chitosan conjugated with doxorubicin was introduced to develop injectable sustained delivery system [50]. The in-situ gel formed from both photo-crosslinking and thermogelling, exhibited robust mechanical properties as compared to gels obtained by mixing chitosan and Pluronic® loaded with free doxorubicin. Moreover, doxorubicin release was slower in this case with no burst release [50]. Li and his colleagues developed a C/GP based thermogel for intratumoral sustained delivery of docetaxel. Results showed that the antitumor efficacy of docetaxel-C/GP in animal mouse model was greater compared to the intratumoral injection of free drug. DTXloaded gel significantly showed prolonged drug retention and high concentration of drug in the tumor while minimizing toxicity in the normal tissues [116]. Even though thermogels have been well studied for intratumoral delivery, there are still limitations that need to be addressed. Burst release of the active may be an issue specifically for hydrophilic actives. Additionally, slow kinetics for gelling may occur post injection, resulting in the leaching of the drug from the site of the injection to the surrounding tissue before depot formation. Tuning the polymer to rapidly undergo gelation instantaneously at the site of injection could be potentially beneficial to limit drug leaching. 3.2.3. Solvent based in-situ phase separation In the solvent based approach, the anticancer drug is introduced to an organic solvent that has dissolved polymer to formulate an injectable solution or dispersion. Upon administration, the organic solvent diffuses into the adjacent tissue while body fluid penetrates into the depot. Thus, solvent exchange leads to precipitation of the polymer, resulting in a depot formation at the site of injection. The added therapeutic agent is entrapped within the depot matrix and gets released by diffusion or depot degradation (Fig. 2). In this approach, hydrophobic polymers such as polyorthoesters, polyhydroxylacids, polyanhydrides and other biopolymers can be used as a biodegradable material. Water miscible organic solvents such as DMSO, THF, acetone, NMP, propylene glycol, 2-pyrrolidone, glycofurol, ethyl acetate or low molecular weight PEG have been tested in this approach as well (Tables 1 and 2) [8,36,68, 117,118]. Eligard® is an example of subcutaneous drug delivery solution of leuprolide developed for prostate cancer treatment based on Atrigel® technology (Atrix Laboratories, now QTL Inc.) [50,72]. Atrigel® technology is a delivery system that can be employed for local and sustained delivery of drugs. Briefly, a biodegradable water insoluble polymer such as PLA and PLGA dissolves in a biocompatible organic solvent. The drug is then added to the polymer solution either to form a suspension or solution. This mixture can then be injected into the body to form an implant inside the tissue while diffusing the solvent out [50,72]. Wu and coworkers showed the application of a phospholipid in-situ gelling system with ethanol for intratumoral delivery of doxorubicin [67]. An in-vivo biodistribution study indicated high drug concentration at the tumor site compared to other main organs after intratumoral delivery.

Stability of the biodegradable polymer and drug is a main concern in these phase separating in-situ forming depots. Therefore, storing polymeric solution at 4 °C and adding the drug as a dry powder to the polymeric solution prior to injection was suggested. Organic solvents may also denature sensitive therapeutic agents such as proteins in solventbased systems [8].

4. Clinical studies using intratumoral route of administration Even though acceptable biodistribution was obtained for several anti-cancer drugs via intratumoral administration in animal models, the translational aspects of demonstrating the same in human studies was limited only to few studies [119]. Waiser and Saltzman reported that locally delivered drugs can escape from injection site in humans more significantly than animal models due to the relative tumor size, accessibility of depot to the capillaries, and increased chance of drug diffusion from depot to capillaries resulting to systemic toxicity [119]. The authors concurred that due to this reason, intratumoral administration of an anti-cancer drug in humans may not reduce systemic toxicity with increased efficacy as compared to systemic administration. Intratumoral administration of in-situ forming hydrogels has been tested in few human trials. OncoGel® study previously mentioned in Section 3.2.2.2 was one of the first studies to be conducted [5,92,93]. In another attempt, intratumoral administration of cisplatin/ epinephrine in a collagen based gel formulation was studied in a human clinical trial as a potential treatment for solid tumors [120–122]. Intratumoral injections have also been proposed for human use to deliver oncolytics such as engineered viruses, immune cells, and plasmid DNA based compounds to directly treat the cancer cells. There are several trials currently for immuno-oncology using intratumoral delivery [28,37,123]. Clinical studies have shown the application of engineered viruses via intratumoral administration for cancer treatments. Gendicine™ (Shenzen SiBiono GeneTech), a recombinant adenovirus, is the first gene therapy product marketed for head and neck cancer treatment administered via intratumoral injection [124,125]. Oncorine® is another marketed product (Shanghai Sunway Biotech Co.), a recombinant human adenovirus type 5 injection, a gene therapy based on intratumoral injection [126]. Currently in phase II clinical trials, Pexa-Vec (JX-594) is an oncolytic virus administered via intratumoral delivery [127–129]. Onco-Vex (Developed by BioVex Inc., acquired by Amgen), also called T-VEC, is another oncolytic virus that is intratumorally administrated and currently under human clinical evaluation for treatment of melanoma and advanced cancers [123,130]. Local delivery is also proposed for the delivery of plasmid DNA directly into the tumor. BC-819 is an example of plasmid DNA currently in human clinical trial. BC-819 targets the expression of the diphtheriatoxin gene under the control of H19 regulatory sequence [131]. CYL-02 is another example of a nonviral gene therapy in phase I clinical trial using intratumoral route of administration [132]. Intratumoral immunization using an immune-trigger molecule is also currently under clinical investigation. For example, VB4-845 is an anti-EpCAM recombinant fusion protein for treatment of the head and neck carcinoma cells [133–135]. Intratumoral administration of ipilimumab with radio therapy for treatment of recurrent melanoma, colon, rectal or non-Hodgkin lymphoma cancer is under phase I/II clinical trial [123]. In another ongoing human clinical trial, a toll like receptor (TLR) agonist is administrated intratumorally as an immuno-stimulant to generate anti-tumor CD8 T cell responses for treatment of low-grade lymphoma with low-dose radiotherapy [123]. Phase I clinical study, for intratumoral delivery of ipilimumab and interleukin-2 (IL-2) that treats patients with unresectable stages III-IV melanoma has also been reported. The goal of this work is to assess the safety of the drug combination and generate data on the clinical efficacy [123].

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In recent study, a novel protein kinase C (EBC-45) was demonstrated for refractory cutaneous and subcutaneous tumors. In this phase I firstin-human study, dose-escalation and selection criteria have been clearly outlined based on positive results in animal models. According to the authors, EBC based therapy led to rapid healing in animal models [136]. In summary, local delivery via intratumoral injection, of immunooncology actives can potentially minimize high systemic drug concentration and allow high concentration of immuno-stimulatory signals at the tumor site. Intratumoral delivery of actives could therefore lower systemic toxicity and increase efficacy. However the active has to be localized and the formulation should minimize the chance of escaping the active from injection site. In-situ depot-forming hydrogels can be used to secure the active locally at the site of injection and to obtain more localization of the immuno-stimulatory signals at the tumor site. Furthermore, engineered hydrogel platforms can also be employed to manage the release of oncolytic at injection site if such a target release profile is needed to have more effective treatment.

[11] [12]

[13]

[14]

[15]

[16]

[17]

5. Conclusion [18]

Several approaches have been demonstrated to deliver anticancer drugs locally into the tumor site. The primary objective is effective delivery of anti-tumor molecules to the tumor site with minimal or no systemic drug bioavailability and no toxicity to the healthy organs. Engineered in-situ gelling platforms provide suitable sustained release mechanism for delivery of anticancer actives, specifically immunooncology actives, not only because of their capability to deliver the drug effectively with minimal or no systemic side effects, but also their ability to be a suitable formulation for easy injection prior to in-situ gelation and show sustained release. With continued development in this area, engineered in-situ gelling platforms can be optimized further to enhance the performance of drug delivery to the tumor site and maintain the drug concentration locally. Controlling the kinetics of in-situ gelling and release of the drug more effectively to local tissues can lower systemic toxic side effects. In-situ gelling technologies provide an ideal platform for new anticancer drugs, specifically for biological molecules. Incorporation of biologics into the engineered in-situ gelling platforms to develop controlled delivery systems offers new possibilities for localized delivery. Combination therapy is another area in which in-situ gelling systems could add value for co-delivery of at least two or more actives for a variety of therapies. In addition to improved patient convenience and reduced systemic toxicity, programmable delivery and sustained release are two added advantages of novel engineered in-situ gelling systems.

[19]

[20] [21]

[22]

[23]

[24] [25] [26] [27] [28] [29]

[30]

[31]

References [1] B.D. Weinberg, E. Blanco, J. Gao, Polymer implants for intratumoral drug delivery and cancer therapy, J. Pharm. Sci. 97 (2008) 1681–1702. [2] J. Crawford, D.C. Dale, G.H. Lyman, Chemotherapy-induced neutropenia, Cancer 100 (2004) 228–237. [3] K.B. Wallace, Doxorubicin-induced cardiac mitochondrionopathy, Pharmacol. Toxicol. 93 (2003) 105–115. [4] Y. Brudno, D.J. Mooney, On-demand drug delivery from local depots, J. Control. Release (2015). [5] J.B. Wolinsky, Y.L. Colson, M.W. Grinstaff, Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers, J. Control. Release 159 (2012) 14–26. [6] B. Kwong, H. Liu, D.J. Irvine, Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy, Biomaterials 32 (2011) 5134–5147. [7] B. Kwong, S.A. Gai, J. Elkhader, K.D. Wittrup, D.J. Irvine, Localized immunotherapy via liposome-anchored anti-CD137+ IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity, Cancer Res. 73 (2013) 1547–1558. [8] S. Kempe, K. Mäder, In situ forming implants—an attractive formulation principle for parenteral depot formulations, J. Control. Release 161 (2012) 668–679. [9] X. Liu, W.S. Heng, Q. Li, L.W. Chan, Novel polymeric microspheres containing norcantharidin for chemoembolization, J. Control. Release 116 (2006) 35–41. [10] T. Abe, M. Sakane, T. Ikoma, M. Kobayashi, S. Nakamura, N. Ochiai, Intraosseous delivery of paclitaxel-loaded hydroxyapatitealginate composite beads delaying

[32]

[33] [34] [35] [36] [37] [38] [39]

[40]

[41]

473

paralysis caused by metastatic spine cancer in rats: laboratory investigation, J. Neurosurg. Spine 9 (2008) 502–510. K.H. Bouhadir, E. Alsberg, D.J. Mooney, Hydrogels for combination delivery of antineoplastic agents, Biomaterials 22 (2001) 2625–2633. A.M. Al-Ghananeem, A.H. Malkawi, Y.M. Muammer, J.M. Balko, E.P. Black, W. Mourad, E. Romond, Intratumoral delivery of paclitaxel in solid tumor from biodegradable hyaluronan nanoparticle formulations, AAPS PharmSciTech 10 (2009) 410–417. D.E. Gerber, G.L. Gallia, B.M. Tyler, C.G. Eberhart, G. Royer, S.A. Grossman, A novel polymer gel for the delivery of local therapies to intracranial tumors: in vivo safety evaluation, J. Biomed. Mater. Res. A 99 (2011) 479–484. X. Li, X. Kong, J. Zhang, Y. Wang, Y. Wang, S. Shi, G. Guo, F. Luo, X. Zhao, Y. Wei, A novel composite hydrogel based on chitosan and inorganic phosphate for local drug delivery of camptothecin nanocolloids, J. Pharm. Sci. 100 (2011) 232–241. L. Ampollini, F. Sonvico, E. Barocelli, A. Cavazzoni, R. Bilancia, C. Mucchino, A.M. Cantoni, P. Carbognani, Intrapleural polymeric films containing cisplatin for malignant pleural mesothelioma in a rat tumour model: a preliminary study, Eur. J. Cardiothorac. Surg. 37 (2010) 557–565. V. Vassileva, J. Grant, R. De Souza, C. Allen, M. Piquette-Miller, Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model, Cancer Chemother. Pharmacol. 60 (2007) 907–914. B.S. Davidson, F. Izzo, D.M. Cromeens, L.C. Stephens, Z.H. Siddik, S.A. Curley, Collagen matrix cisplatin prevents local tumor growth after margin-positive resection, J. Surg. Res. 58 (1995) 618–624. B.A. Almond, A.R. Hadba, S.T. Freeman, B.J. Cuevas, A.M. York, C.J. Detrisac, E.P. Goldberg, Efficacy of mitoxantrone-loaded albumin microspheres for intratumoral chemotherapy of breast cancer, J. Control. Release 91 (2003) 147–155. S. Kakinoki, T. Taguchi, Antitumor effect of an injectable in-situ forming drug delivery system composed of a novel tissue adhesive containing doxorubicin hydrochloride, Eur. J. Pharm. Biopharm. 67 (2007) 676–681. J.R. McDaniel, D.J. Callahan, A. Chilkoti, Drug delivery to solid tumors by elastin-like polypeptides, Adv. Drug Deliv. Rev. 62 (2010) 1456–1467. M. Konishi, Y. Tabata, M. Kariya, A. Suzuki, M. Mandai, K. Nanbu, K. Takakura, S. Fujii, In vivo anti-tumor effect through the controlled release of cisplatin from biodegradable gelatin hydrogel, J. Control. Release 92 (2003) 301–313. K. Stuart, K. Stokes, R. Jenkins, C. Trey, M. Clouse, Treatment of hepatocellular carcinoma using doxorubicin/ethiodized oil/gelatin powder chemoembolization, Cancer 72 (1993) 3202–3209. C. Alvarez-Lorenzo, B. Blanco-Fernandez, A.M. Puga, A. Concheiro, Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery, Adv. Drug Deliv. Rev. 65 (2013) 1148–1171. L. Yu, J. Ding, Injectable hydrogels as unique biomedical materials, Chem. Soc. Rev. 37 (2008) 1473–1481. A. Fakhari, Q. Phan, C. Berkland, Hyaluronic acid colloidal gels as self-assembling elastic biomaterials, J. Biomed. Mater. Res. B Appl. Biomater. 102 (2014) 612–618. D.J. Overstreet, D. Dutta, S.E. Stabenfeldt, B.L. Vernon, Injectable hydrogels, J. Polym. Sci. B Polym. Phys. 50 (2012) 881–903. M.K. Nguyen, D.S. Lee, Injectable biodegradable hydrogels, Macromol. Biosci. 10 (2010) 563–579. A.H. Van Hove, D.S. Benoit, Depot-based delivery systems for pro-angiogenic peptides: a review, Front. Bioeng. Biotechnol. 3 (2015). R.B. Weiss, R. Donehower, P. Wiernik, T. Ohnuma, R. Gralla, D. Trump, J. Baker, D. Van Echo, D. Von Hoff, B. Leyland-Jones, Hypersensitivity reactions from taxol, J. Clin. Oncol. 8 (1990) 1263–1268. H. Gelderblom, J. Verweij, K. Nooter, A. Sparreboom, Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation, Eur. J. Cancer 37 (2001) 1590–1598. A. Sparreboom, O. van Tellingen, W.J. Nooijen, J.H. Beijnen, Tissue distribution, metabolism and excretion of paclitaxel in mice, Anti-Cancer Drugs 7 (1996) 78–86. S.E. Shackney, G.W. McCORMACK, G.J. Cuchural, Growth rate patterns of solid tumors and their relation to responsiveness to therapy: an analytical review, Ann. Intern. Med. 89 (1978) 107–121. J.S. Meyer, Cell kinetic measurements of human tumors, Hum. Pathol. 13 (1982) 874–877. C. Packhaeuser, J. Schnieders, C. Oster, T. Kissel, In situ forming parenteral drug delivery systems: an overview, Eur. J. Pharm. Biopharm. 58 (2004) 445–455. D. Chitkara, A. Shikanov, N. Kumar, A.J. Domb, Biodegradable injectable in situ depot-forming drug delivery systems, Macromol. Biosci. 6 (2006) 977–990. M. Dittgen, S. Fricke, H. Gerecke, I. Möller, C. Völkel, Injection Implant, Germany Patent WO/1998/030245, (1998). R. Vaishya, V. Khurana, S. Patel, A.K. Mitra, Long-term delivery of protein therapeutics, Expert Opin. Drug Deliv. 12 (2015) 415–440. A.K. Burkoth, K.S. Anseth, A review of photocrosslinked polyanhydrides: in situ forming degradable networks, Biomaterials 21 (2000) 2395–2404. S.-Y. Lee, G. Tae, Formulation and in vitro characterization of an in situ gelable, photo-polymerizable Pluronic hydrogel suitable for injection, J. Control. Release 119 (2007) 313–319. J. Berger, M. Reist, J.M. Mayer, O. Felt, N. Peppas, R. Gurny, Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications, Eur. J. Pharm. Biopharm. 57 (2004) 19–34. F.L. Mi, S.S. Shyu, C.Y. Kuan, S.T. Lee, K.T. Lu, S.F. Jang, Chitosan—polyelectrolyte complexation for the preparation of gel beads and controlled release of anticancer drug. I. Effect of phosphorous polyelectrolyte complex and enzymatic hydrolysis of polymer, J. Appl. Polym. Sci. 74 (1999) 1868–1879.

474

A. Fakhari, J. Anand Subramony / Journal of Controlled Release 220 (2015) 465–475

[42] K. Anseth, S. Newman, C. Bowman, Polymeric dental composites: properties and reaction behavior of multimethacrylate dental restorations, Biopolymers Ii, Springer 1995, pp. 177–217. [43] J.A. Burdick, L.M. Philpott, K.S. Anseth, Synthesis and characterization of tetrafunctional lactic acid oligomers: a potential in situ forming degradable orthopaedic biomaterial, J. Polym. Sci. A Polym. Chem. 39 (2001) 683–692. [44] J.A. Burdick, R.F. Padera, J.V. Huang, K.S. Anseth, An investigation of the cytotoxicity and histocompatibility of in situ forming lactic acid based orthopedic biomaterials, J. Biomed. Mater. Res. 63 (2002) 484–491. [45] T. Vermonden, N.E. Fedorovich, D. van Geemen, J. Alblas, C.F. van Nostrum, W.J. Dhert, W.E. Hennink, Photopolymerized thermosensitive hydrogels: synthesis, degradation, and cytocompatibility, Biomacromolecules 9 (2008) 919–926. [46] B. Balakrishnan, A. Jayakrishnan, Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds, Biomaterials 26 (2005) 3941–3951. [47] J.B. Leach, C.E. Schmidt, Characterization of protein release from photocrosslinkable hyaluronic acid-polyethylene glycol hydrogel tissue engineering scaffolds, Biomaterials 26 (2005) 125–135. [48] A.S. Sawhney, C.P. Pathak, J.J. van Rensburg, R.C. Dunn, J.A. Hubbell, Optimization of photopolymerized bioerodible hydrogel properties for adhesion prevention, J. Biomed. Mater. Res. 28 (1994) 831–838. [49] K. Obara, M. Ishihara, Y. Ozeki, T. Ishizuka, T. Hayashi, S. Nakamura, Y. Saito, H. Yura, T. Matsui, H. Hattori, Controlled release of paclitaxel from photocrosslinked chitosan hydrogels and its subsequent effect on subcutaneous tumor growth in mice, J. Control. Release 110 (2005) 79–89. [50] A. Wadee, V. Pillay, Y.E. Choonara, L.C. du Toit, C. Penny, V.M. Ndesendo, P. Kumar, C.S. Murphy, Recent advances in the design of drug-loaded polymeric implants for the treatment of solid tumors, Expert Opin. Drug Deliv. 8 (2011) 1323–1340. [51] L. Pescosolido, Interpenetrating Polymer Network Hydrogels Based on Polysaccharides for Biomedical Applications, 2011. [52] A. Hatefi, B. Amsden, Biodegradable injectable in situ forming drug delivery systems, J. Control. Release 80 (2002) 9–28. [53] M. Hamdine, M.-C. Heuzey, A. Bégin, Viscoelastic properties of phosphoric and oxalic acid-based chitosan hydrogels, Rheol. Acta 45 (2006) 659–675. [54] M. Nickerson, J. Patel, D. Heyd, D. Rousseau, A. Paulson, Kinetic and mechanistic considerations in the gelation of genipin-crosslinked gelatin, Int. J. Biol. Macromol. 39 (2006) 298–302. [55] S. Emoto, H. Yamaguchi, T. Kamei, H. Ishigami, T. Suhara, Y. Suzuki, T. Ito, J. Kitayama, T. Watanabe, Intraperitoneal administration of cisplatin via an in situ cross-linkable hyaluronic acid-based hydrogel for peritoneal dissemination of gastric cancer, Surg. Today 44 (2014) 919–926. [56] A. Bernkop-Schnürch, A.H. Krauland, V.M. Leitner, T. Palmberger, Thiomers: potential excipients for non-invasive peptide delivery systems, Eur. J. Pharm. Biopharm. 58 (2004) 253–263. [57] A. Vashist, A. Vashist, Y. Gupta, S. Ahmad, Recent advances in hydrogel based drug delivery systems for the human body, J. Materi. Chem. B 2 (2014) 147–166. [58] P. Agarwal, I.D. Rupenthal, Injectable implants for the sustained release of protein and peptide drugs, Drug Discov. Today 18 (2013) 337–349. [59] A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. 81 (2012) 463–469. [60] W. Zhu, Y. Li, L. Liu, Y. Chen, C. Wang, F. Xi, Supramolecular hydrogels from cisplatin-loaded block copolymer nanoparticles and α-cyclodextrins with a stepwise delivery property, Biomacromolecules 11 (2010) 3086–3092. [61] G.W. Bos, J.J. Jacobs, J.W. Koten, S. Van Tomme, T. Veldhuis, C.F. van Nostrum, W. Den Otter, W.E. Hennink, In situ crosslinked biodegradable hydrogels loaded with IL-2 are effective tools for local IL-2 therapy, Eur. J. Pharm. Sci. 21 (2004) 561–567. [62] C. Hiemstra, Z. Zhong, S.R. Van Tomme, M.J. van Steenbergen, J.J. Jacobs, W. Den Otter, W.E. Hennink, J. Feijen, In vitro and in vivo protein delivery from in situ forming poly (ethylene glycol)–poly (lactide) hydrogels, J. Control. Release 119 (2007) 320–327. [63] N. Bhattarai, J. Gunn, M. Zhang, Chitosan-based hydrogels for controlled, localized drug delivery, Adv. Drug Deliv. Rev. 62 (2010) 83–99. [64] Y. Qiu, K. Park, Environment-sensitive hydrogels for drug delivery, Adv. Drug Deliv. Rev. 64 (2012) 49–60. [65] F. Tirnaksiz, J. Robinson, Rheological, mucoadhesive and release properties of pluronic F-127 gel and pluronic F-127/polycarbophil mixed gel systems, Die Pharmazie-An Int. J. Pharm. Sci. 60 (2005) 518–523. [66] J. Berger, M. Reist, J.M. Mayer, O. Felt, R. Gurny, Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications, Eur. J. Pharm. Biopharm. 57 (2004) 35–52. [67] W. Wu, H. Chen, F. Shan, J. Zhou, X. Sun, L. Zhang, T. Gong, A novel doxorubicinloaded in situ forming gel based high concentration of phospholipid for intratumoral drug delivery, Mol. Pharm. 11 (2014) 3378–3385. [68] R.E. Eliaz, J. Kost, Characterization of a polymeric PLGA-injectable implant delivery system for the controlled release of proteins, J. Biomed. Mater. Res. 50 (2000) 388–396. [69] L. Zhao, L. Zhu, F. Liu, C. Liu, Q. Wang, C. Zhang, J. Li, J. Liu, X. Qu, Z. Yang, pH triggered injectable amphiphilic hydrogel containing doxorubicin and paclitaxel, Int. J. Pharm. 410 (2011) 83–91. [70] L. Li, J. Gu, J. Zhang, Z. Xie, Y. Lu, L. Shen, Q. Dong, Y. Wang, Injectable and biodegradable pH-responsive hydrogels for localized and sustained treatment of human fibrosarcoma, ACS Appl. Mater. Interfaces 7 (2015) 8033–8040. [71] H.J. Moon, M.H. Park, M.K. Joo, B. Jeong, Temperature-responsive compounds as in situ gelling biomedical materials, Chem. Soc. Rev. 41 (2012) 4860–4883. [72] O. Sartor, M.K. Dineen, R. Perez-Marreno, F.M. Chu, G.J. Carron, R.C. Tyler, An eightmonth clinical study of LA-2575 30.0 mg: a new 4-month, subcutaneous delivery

[73] [74] [75] [76]

[77]

[78] [79]

[80]

[81] [82] [83]

[84]

[85]

[86]

[87]

[88]

[89]

[90] [91]

[92]

[93]

[94]

[95]

[96] [97]

[98]

[99]

[100]

system for leuprolide acetate in the treatment of prostate cancer, Urology 62 (2003) 319–323. E. Ruel-Gariépy, J.-C. Leroux, In situ-forming hydrogels—review of temperaturesensitive systems, Eur. J. Pharm. Biopharm. 58 (2004) 409–426. M.K. Joo, M.H. Park, B.G. Choi, B. Jeong, Reverse thermogelling biodegradable polymer aqueous solutions, J. Mater. Chem. 19 (2009) 5891–5905. C. He, S.W. Kim, D.S. Lee, In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery, J. Control. Release 127 (2008) 189–207. Y. Liu, W.-L. Lu, J.-C. Wang, X. Zhang, H. Zhang, X.-Q. Wang, T.-Y. Zhou, Q. Zhang, Controlled delivery of recombinant hirudin based on thermo-sensitive Pluronic® F127 hydrogel for subcutaneous administration: in vitro and in vivo characterization, J. Control. Release 117 (2007) 387–395. A. Sosnik, D. Cohn, J.S. Román, G.A. Abraham, Crosslinkable PEO–PPO–PEO–based reverse thermo-responsive gels as potentially injectable materials, J. Biomater. Sci. Polym. Ed. 14 (2003) 227–239. A. Sosnik, D. Cohn, Reverse thermo-responsive poly (ethylene oxide) and poly (propylene oxide) multiblock copolymers, Biomaterials 26 (2005) 349–357. D. Coughlan, O. Corrigan, Drug–polymer interactions and their effect on thermoresponsive poly (N-isopropylacrylamide) drug delivery systems, Int. J. Pharm. 313 (2006) 163–174. C.T. Huynh, M.K. Nguyen, D.S. Lee, Injectable block copolymer hydrogels: achievements and future challenges for biomedical applications, Macromolecules 44 (2011) 6629–6636. M.H. Park, M.K. Joo, B.G. Choi, B. Jeong, Biodegradable thermogels, Acc. Chem. Res. 45 (2011) 424–433. B. Jeong, S.W. Kim, Y.H. Bae, Thermosensitive sol–gel reversible hydrogels, Adv. Drug Deliv. Rev. 54 (2002) 37–51. G. Dumortier, J.L. Grossiord, F. Agnely, J.C. Chaumeil, A review of poloxamer 407 pharmaceutical and pharmacological characteristics, Pharm. Res. 23 (2006) 2709–2728. W. Pan, Z. Yang, Thermoreversible Pluronic® F127-based hydrogel containing liposomes for the controlled delivery of paclitaxel: in vitro drug release, cell cytotoxicity, and uptake studies, Int. J. Nanomedicine 6 (2011) 151–166. Z. Lin, W. Gao, H. Hu, K. Ma, B. He, W. Dai, X. Wang, J. Wang, X. Zhang, Q. Zhang, Novel thermo-sensitive hydrogel system with paclitaxel nanocrystals: high drugloading, sustained drug release and extended local retention guaranteeing better efficacy and lower toxicity, J. Control. Release 174 (2014) 161–170. T. Hayashi, B. Crain, M. Corr, M. Chan, H.B. Cottam, R. Maj, A. Barberis, L. Leoni, D.A. Carson, Intravesical toll-like receptor 7 agonist R-837: optimization of its formulation in an orthotopic mouse model of bladder cancer, Int. J. Urol. 17 (2010) 483–490. C. Ju, J. Sun, P. Zi, X. Jin, C. Zhang, Thermosensitive micelles–hydrogel hybrid system based on poloxamer 407 for localized delivery of paclitaxel, J. Pharm. Sci. 102 (2013) 2707–2717. A. Alexander, J. Khan, S. Saraf, S. Saraf, Poly (ethylene glycol)–poly (lactic-coglycolic acid) based thermosensitive injectable hydrogels for biomedical applications, J. Control. Release 172 (2013) 715–729. G.M. Zentner, R. Rathi, C. Shih, J.C. McRea, M.-H. Seo, H. Oh, B. Rhee, J. Mestecky, Z. Moldoveanu, M. Morgan, Biodegradable block copolymers for delivery of proteins and water-insoluble drugs, J. Control. Release 72 (2001) 203–215. N.L. Elstad, K.D. Fowers, OncoGel (ReGel/paclitaxel)—clinical applications for a novel paclitaxel delivery system, Adv. Drug Deliv. Rev. 61 (2009) 785–794. S.J. Vukelja, S.P. Anthony, J.C. Arseneau, B.S. Berman, C.C. Cunningham, J.J. Nemunaitis, W.E. Samlowski, K.D. Fowers, Phase 1 study of escalating-dose OncoGel®(ReGel®/paclitaxel) depot injection, a controlled-release formulation of paclitaxel, for local management of superficial solid tumor lesions, Anti-Cancer Drugs 18 (2007) 283–289. G.A. DuVall, D. Tarabar, R.H. Seidel, N.L. Elstad, K.D. Fowers, Phase 2: a doseescalation study of OncoGel (ReGel/paclitaxel), a controlled-release formulation of paclitaxel, as adjunctive local therapy to external-beam radiation in patients with inoperable esophageal cancer, Anti-Cancer Drugs 20 (2009) 89–95. B. Choi, X.J. Loh, A. Tan, C.K. Loh, E. Ye, M.K. Joo, B. Jeong, Introduction to in situ forming hydrogels for biomedical applications, In-Situ Gelling Polymers, Springer 2015, pp. 5–35. W.E. Samlowski, J.R. McGregor, M. Jurek, M. Baudys, G.M. Zentner, K.D. Fowers, ReGel® polymer-based delivery of interleukin-2 as a cancer treatment, J. Immunother. 29 (2006) 524–535. G. Chang, T. Ci, L. Yu, J. Ding, Enhancement of the fraction of the active form of an antitumor drug topotecan via an injectable hydrogel, J. Control. Release 156 (2011) 21–27. Y.-M. Chung, K.L. Simmons, A. Gutowska, B. Jeong, Sol–gel transition temperature of PLGA-g-PEG aqueous solutions, Biomacromolecules 3 (2002) 511–516. B. Jeong, L.-Q. Wang, A. Gutowska, Biodegradable thermoreversible gelling PLGA-gPEG copolymers Electronic supplementary information (ESI) available: 1 H NMR spectrum of PLGA-g-PEG in CDCl3. 13C NMR (75 MHz) spectra of 25 wt.% PLGAg-PEG copolymer in D2O as a function of T. See http://www. rsc. org/suppdata/ cc/b1/b102819g, Chem. Commun. (2001) 1516–1517. H. Hyun, Y.H. Kim, I.B. Song, J.W. Lee, M.S. Kim, G. Khang, K. Park, H.B. Lee, In vitro and in vivo release of albumin using a biodegradable MPEG–PCL diblock copolymer as an in situ gel-forming carrier, Biomacromolecules 8 (2007) 1093–1100. X.J. Loh, B.J.H. Yee, F.S. Chia, Sustained delivery of paclitaxel using thermogelling poly (PEG/PPG/PCL urethane) s for enhanced toxicity against cancer cells, J. Biomed. Mater. Res. A 100 (2012) 2686–2694. J.Y. Lee, K.S. Kim, Y.M. Kang, E.S. Kim, S.-J. Hwang, H.B. Lee, B.H. Min, J.H. Kim, M.S. Kim, In vivo efficacy of paclitaxel-loaded injectable in situ-forming gel against subcutaneous tumor growth, Int. J. Pharm. 392 (2010) 51–56.

A. Fakhari, J. Anand Subramony / Journal of Controlled Release 220 (2015) 465–475 [101] Y.M. Kang, G.H. Kim, J.I. Kim, B.N. Lee, S.M. Yoon, J.H. Kim, M.S. Kim, In vivo efficacy of an intratumorally injected in situ-forming doxorubicin/poly (ethylene glycol)-bpolycaprolactone diblock copolymer, Biomaterials 32 (2011) 4556–4564. [102] S. Xu, W. Wang, X. Li, J. Liu, A. Dong, L. Deng, Sustained release of PTX-incorporated nanoparticles synergized by burst release of DOX ⋅ HCl from thermosensitive modified PEG/PCL hydrogel to improve anti-tumor efficiency, Eur. J. Pharm. Sci. 62 (2014) 267–273. [103] H.W. Seo, D.Y. Kwon, J.S. Kwon, L.M. Jin, B. Lee, J.H. Kim, B.H. Min, M.S. Kim, Injectable intratumoral hydrogel as 5-fluorouracil drug depot, Biomaterials 34 (2013) 2748–2757. [104] G.D. Kang, S.H. Cheon, S.-C. Song, Controlled release of doxorubicin from thermosensitive poly (organophosphazene) hydrogels, Int. J. Pharm. 319 (2006) 29–36. [105] A.M. Al-Abd, K.-Y. Hong, S.-C. Song, H.-J. Kuh, Pharmacokinetics of doxorubicin after intratumoral injection using a thermosensitive hydrogel in tumor-bearing mice, J. Control. Release 142 (2010) 101–107. [106] A. Shikanov, S. Shikanov, B. Vaisman, J. Golenser, A.J. Domb, Paclitaxel tumor biodistribution and efficacy after intratumoral injection of a biodegradable extended release implant, Int. J. Pharm. 358 (2008) 114–120. [107] A. Shikanov, B. Vaisman, S. Shikanov, A.J. Domb, Efficacy of poly (sebacic acid-coricinoleic acid) biodegradable delivery system for intratumoral delivery of paclitaxel, J. Biomed. Mater. Res. A 92 (2010) 1283–1291. [108] K. Kobayashi, C.-i. Huang, T.P. Lodge, Thermoreversible gelation of aqueous methylcellulose solutions, Macromolecules 32 (1999) 7070–7077. [109] D. Gupta, C.H. Tator, M.S. Shoichet, Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord, Biomaterials 27 (2006) 2370–2379. [110] J.K. Kim, Y.-W. Won, K.S. Lim, Y.-H. Kim, Low-molecular-weight methylcellulosebased thermo-reversible gel/pluronic micelle combination system for local and sustained docetaxel delivery, Pharm. Res. 29 (2012) 525–534. [111] E. Ruel-Gariépy, M. Shive, A. Bichara, M. Berrada, D. Le Garrec, A. Chenite, J.-C. Leroux, A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel, Eur. J. Pharm. Biopharm. 57 (2004) 53–63. [112] A. Chenite, C. Chaput, D. Wang, C. Combes, M. Buschmann, C. Hoemann, J. Leroux, B. Atkinson, F. Binette, A. Selmani, Novel injectable neutral solutions of chitosan form biodegradable gels in situ, Biomaterials 21 (2000) 2155–2161. [113] E. Ruel-Gariepy, A. Chenite, C. Chaput, S. Guirguis, J.-C. Leroux, Characterization of thermosensitive chitosan gels for the sustained delivery of drugs, Int. J. Pharm. 203 (2000) 89–98. [114] E. Ruel-Gariepy, G. Leclair, P. Hildgen, A. Gupta, J.-C. Leroux, Thermosensitive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules, J. Control. Release 82 (2002) 373–383. [115] S. Supper, N. Anton, N. Seidel, M. Riemenschnitter, C. Schoch, T. Vandamme, Rheological study of chitosan/polyol-phosphate systems: influence of the polyol part on the thermo-induced gelation mechanism, Langmuir 29 (2013) 10229–10237. [116] C. Li, S. Ren, Y. Dai, F. Tian, X. Wang, S. Zhou, S. Deng, Q. Liu, J. Zhao, X. Chen, Efficacy, pharmacokinetics, and biodistribution of thermosensitive chitosan/ β-glycerophosphate hydrogel loaded with docetaxel, AAPS PharmSciTech 15 (2014) 417–424. [117] R.L. Dunn, A.J. Tipton, G.L. Southard, J.A. Rogers, Biodegradable Polymer Composition, in, Google Patents, 1994. [118] W.J. Lambert, K.D. Peck, Development of an in situ forming biodegradable polylactide-coglycolide system for the controlled release of proteins, J. Control. Release 33 (1995) 189–195. [119] J.R. Weiser, W.M. Saltzman, Controlled release for local delivery of drugs: barriers and models, J. Control. Release 190 (2014) 664–673. [120] T. Leung, S. Yu, P. Johnson, J. Geschwind, T. Vogl, K. Engelmann, G. Gores, M. Giovannini, J. O'Grady, M. Heneghan, Phase II study of the efficacy and safety of cisplatin-epinephrine injectable gel administered to patients with unresectable hepatocellular carcinoma, J. Clin. Oncol. 21 (2003) 652–658. [121] H.A. Burris, C.L. Vogel, D. Castro, L. Mishra, M. Schwarz, S. Spencer, D.D. Oakes, R. Korey, E.K. Orenberg, Intratumoral cisplatin/epinephrine-injectable gel as a

[122]

[123] [124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132]

[133]

[134]

[135]

[136]

475

palliative treatment for accessible solid tumors: a multicenter pilot study, Otolaryngol. Head Neck Surg. 118 (1998) 496–503. D.J. Castro, K.S. Sridhar, H.S. Garewal, G.M. Mills, B.L. Wenig, F.R. Dunphy, P.D. Costantino, R.D. Leavitt, M.E. Stewart, E.K. Orenberg, Intratumoral cisplatin/ epinephrine gel in advanced head and neck cancer: a multicenter, randomized, double-blind, phase III study in North America, Head Neck 25 (2003) 717–731. A. Marabelle, H. Kohrt, C. Caux, R. Levy, Intratumoral immunization: a new paradigm for cancer therapy, Clin. Cancer Res. 20 (2014) 1747–1756. Y. Li, B. Li, C.-J. Li, L.-J. Li, Key points of basic theories and clinical practice in rAd-p53 (Gendicine™) gene therapy for solid malignant tumors, Expert. Opin. Biol. Ther. 15 (2015) 437–454. X. Li, S. Xiao, Y. Li, S. Zhang, Clinical antiangiogenic effect of recombinant adenovirus-p53 combined with hyperthermia for advanced cancer, Chin. J. Cancer Res. 25 (2013) 749. W. Lu, S. Zheng, X.-F. Li, J.-J. Huang, X. Zheng, Z. Li, Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers: a pilot phase II clinical trial, World J. Gastroenterol. 10 (2004) 3634–3638. J. Heo, Y. Chao, D.J. Jonker, A.D. Baron, F. Habersetzer, J. Burke, C. Breitbach, R.H. Patt, R. Lencioni, M. Homerin, Phase IIb randomized trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), a targeted oncolytic vaccinia virus, plus best supportive care (BSC) versus BSC alone in patients with advanced hepatocellular carcinoma who have failed sorafenib treatment (TRAVERSE), ASCO Annual Meeting Proceedings 2013, p. TPS4161. T.P. Cripe, M.C. Ngo, J.I. Geller, C.U. Louis, M.A. Currier, J.M. Racadio, A.J. Towbin, C.M. Rooney, A. Pelusio, A. Moon, Phase 1 study of intratumoral Pexa-Vec (jx-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients, Mol. Ther. (2014). C.J. Breitbach, K. Parato, J. Burke, T.-H. Hwang, J.C. Bell, D.H. Kirn, Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic, Curr. Opin. Virol. 13 (2015) 49–54. J.C. Hu, R.S. Coffin, C.J. Davis, N.J. Graham, N. Groves, P.J. Guest, K.J. Harrington, N.D. James, C.A. Love, I. McNeish, A phase I study of OncoVEXGM-CSF, a secondgeneration oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor, Clin. Cancer Res. 12 (2006) 6737–6747. N. Hanna, P. Ohana, F. Konikoff, G. Leichtmann, A. Hubert, L. Appelbaum, Y. Kopelman, A. Czerniak, A. Hochberg, Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC819 in patients with unresectable pancreatic cancer, Cancer Gene Ther. 19 (2012) 374–381. L. Buscail, B. Bournet, F. Vernejoul, G. Cambois, H. Lulka, N. Hanoun, M. Dufresne, A. Meulle, A. Vignolle-Vidoni, L. Ligat, First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings, Mol. Ther. (2015). M. Kowalski, J. Entwistle, J. Cizeau, D. Niforos, S. Loewen, W. Chapman, G.C. MacDonald, A phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCGrefractory and BCG-intolerant patients, Drug Des. Devel. Ther. 4 (2010) 313. G.C. MacDonald, M. Rasamoelisolo, J. Entwistle, J. Cizeau, D. Bosc, W. Cuthbert, M. Kowalski, M. Spearman, N. Glover, A phase I clinical study of VB4-845: weekly intratumoral administration of an anti-EpCAM recombinant fusion protein in patients with squamous cell carcinoma of the head and neck, Drug Des. Devel. Ther. 2 (2008) 105. G. MacDonald, M. Rasamoelisolo, J. Entwistle, W. Cuthbert, M. Kowalski, M.A. Spearman, N. Glover, A phase I clinical study of intratumorally administered VB4-845, an anti-epithelial cell adhesion molecule recombinant fusion protein, in patients with squamous cell carcinoma of the head and neck, Med. Oncol. 26 (2009) 257–264. J.D. Lickliter, B. Panizza, C.S. Karapetis, V.A. Gordon, P.W. Reddell, K.T. Lingard, R.M. Cusack, P. De Souza, Phase 1 dose-escalation study of EBC-46 given by intratumoral injection to patients with refractory cutaneous and subcutaneous tumors, ASCO Annual Meeting Proceedings 2015, p. TPS2616.