Injectable Poloxamer Hydrogels for Local Cancer Therapy: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Ana Camila Marques.

The widespread push to invest in local cancer therapies comes from the need to overcome the limitations of systemic treatment options. In contrast to intravenous administration, local treatments using intratumoral or peritumoral injections are independent of tumor vasculature and allow high concentrations of therapeutic agents to reach the tumor site with minimal systemic toxicity. Injectable biodegradable hydrogels offer a clear advantage over other delivery systems because the former requires no surgical procedures and promotes drug retention at the tumor site. More precisely, in situ gelling systems based on poloxamers have garnered considerable attention due to their thermoresponsive behavior, biocompatibility, ease of preparation, and possible incorporation of different anticancer agents.

  • cancer therapy
  • injectable hydrogels
  • poloxamer

1. Introduction

Local cancer therapy holds great potential to address the shortcomings of systemic treatment options, namely the lack of specificity for the target, low therapeutic efficiency, and drug resistance.
Different from intravenous (IV) administration, local treatments using intratumoral (IT) or peritumoral (PT) injections allow high concentrations of therapeutic agents to reach the tumor site, bypassing the bloodstream and non-specific interactions with healthy tissues.[1] Moreover, because local therapies are independent of tumor vasculature, delivery is not restricted to tumor regions with better perfusion. Besides increasing the stability of anticancer agents, local administration also allows for the use of novel combinations of co-solvents and polymers for solubilization, encapsulation, and incorporation of water-insoluble drugs.
In contrast to delivery systems based on implants (wafers, rods, and films) and particles, injectable biodegradable hydrogels require non-surgical procedures and promote retention of free or encapsulated drugs at the tumor site.[2] Indeed, treatment with injectable cisplatin (CDDP)/epinephrine gel has been proven practicable by direct injection into superficially accessible tumors or endoscopically for esophageal cancer.[3] Regarding the distribution dynamics, nanoparticles embedded in hydrogels were observed to cover larger areas of the tumor than free nanoparticles upon IT administration.[4]
Injectable gels include pre-formed gels with shear-thinning and self-healing properties and in situ-forming gels.[5][6] After injection as free-flowing polymer solutions, in situ gelling systems transform into gels at the injection site, acting as drug depots for sustained drug release. Generally, the mechanism of depot formation is an in situ phase transition triggered by external stimuli such as changes in temperature.

2. Local Tumor Administration of Poloxamer Hydrogels

The proof-of-concept of poloxamer hydrogels for local tumor administration has been demonstrated by the growth inhibition of several tumors in different mouse models. Nevertheless, it is noteworthy that most tumor models were established in mice through the subcutaneous inoculation of cancer cells. Subcutaneous (or ectopic) tumors might be advantageous to monitoring tumor growth and performing local injections, but fail to mimic the tumor microenvironment. Despite being more clinically relevant because tumor xenografts are placed in the tissue/organ of origin, orthotopic mouse models still do not reflect the size of tumors that develop naturally in patients. Moreover, potential adverse effects in cancer patients with intact immunity may go unnoticed if studies in immunodeficient animals are the case.[7]
The application of injectable poloxamer hydrogels in local cancer therapy is depicted in Figure 1 and discussed below, with several examples organized by therapeutic modality.
Figure 1. The in vivo administration of poloxamer hydrogels for local cancer therapies including chemotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), immunotherapy, and gene therapy.

2.1. Potential Applications in Cancer Chemotherapy

For local cancer chemotherapy, poloxamer 407 (P407) or Pluronic® F127 (PF127) solutions were mixed with free drugs, such as paclitaxel (PTX)[8], topotecan[9], doxorubicin (DOX)[10], and salinomycin[11]. Still, most PF127 hydrogels reported for IT or PT injection accommodate anticancer drugs encapsulated in nanoparticles[12][13], nanocrystals[14][15][16], cyclodextrin inclusion complexes[17][18], hyaluronic acid-based nanocomplexes[19][20], and mixed micelles[20][21]. The literature also contains several examples of in situ-forming gels using mixtures of PF127 and poloxamer 188 (Pluronic® F68, PF68) for the local delivery of free[22][23] and encapsulated[24][25][26][27] drugs.
The direct incorporation of free PTX into a P407 solution at the final concentration of 0.5 mg/mL, albeit simple, resulted in a very slow in vitro drug release from P407 hydrogel because of the poor water solubility of PTX. Moreover, although it was completely dissolved at lower concentrations, PTX formed a suspension when the final concentration was doubled (1.0 mg/mL).[8] This reflects the low solubilization of hydrophobic drugs in P407, which generally imparts limited drug loading and physical instability to poloxamer micelles. Therefore, hybrid systems integrating drug-loaded nanoparticles and thermoresponsive hydrogels have been intensively studied to improve drug release and increase drug loading capacity.[14][28]
The combination of liposomes and poloxamer hydrogels was proposed to stabilize the lactone form of 7-ethyl-10-hydroxycamptothecin[27] and prolong the release of PTX[12][26]. Whereas PF127/PF68 hydrogels enhanced the retention of drug-loaded liposomes at the tumor site[26][27], the use of liposomes made of 0.21–1.25% soybean phospholipids was suggested to allow a 3–9 wt% decrease in the poloxamer concentration required for an in situ-forming PF127 gel[12]. Notwithstanding the evidence from studies in MCF-7 breast cancer cells supporting the higher cytotoxic activity of tamoxifen citrate-loaded niosomes compared to the free drug, the low viscosity of niosomal suspensions prompted their dispersion into poloxamer hydrogels.[25] In a very interesting approach to the treatment of melanoma, Yu et al. prepared a PF127 hydrogel to intratumorally deliver CDDP-loaded poly(α-L-glutamate)-g-mPEG nanoparticles and microspheres entrapping losartan potassium that exerts antifibrotic effects, namely by inhibiting the production of collagen I in tumors. The incorporation of both microspheres and nanoparticles into the gel enabled most losartan to be released first and reduce the collagen content prior to the release of CDDP, which occurred in the following days after the nanoparticles have penetrated more deeply into the tumor.[13] Differently, Shen et al. combined nanotechnology and active targeting with thermoresponsive polymers for IT administration of PTX in pancreatic tumors. For that, they prepared a PF127/PF68/hydroxypropyl methylcellulose gel bearing PTX-loaded mPEG-poly(D,L-lactide-co-glycolide)-poly(L-lysine) nanoparticles functionalized with a cyclic peptide, which specifically binds to αvβ3 integrin overexpressed on the endothelial tumor cells.[29] Later, Xie et al. also developed a PF127/PF68/hydroxypropyl methylcellulose hydrogel to improve the efficacy and safety of norcantharidin (NCTD) for treating hepatic cancer.[30] In another work, Gao et al. took into consideration that NCTD has poor solubility in water, thereby preparing NCTD-loaded polymeric nanoparticles before incorporating them into a DOX-containing PF127 hydrogel to treat hepatocellular carcinoma via IT administration.[31]
The formulation and dispersion of drug nanocrystals into PF127 hydrogels deserved some attention, considering that nanocrystals provide higher drug loading than other nanocarriers.[14][15] Further, Gao et al. dissolved D-α-tocopherol PEG 1000 succinate in PF127 solutions to impair drug efflux and reverse drug resistance of P-glycoprotein-overexpressing liver cancer cells.[15] Together with lapatinib-loaded microparticles, PTX nanocrystals were incorporated into PF127 hydrogel for PT injection to imitate the slow and fast release of these two drugs in clinical use.[16]
Attempts to increase the water solubility of the anticancer agent β-lapachone involve the formation of inclusion complexes with cyclodextrins. Intending to design injectable thermoresponsive hydrogels containing β-lapachone, Landin’s group used Artificial Neural Network modeling to understand the interactions between the polymer (PF127) and the solubilizing agent (cyclodextrin) and obtain the optimal formulation.[17] A significant decrease in cell viability and tumor volume was observed following the treatment of MCF-7 cells and in the breast xenograft mouse model with this ternary system.[18] When studying the effect of methylated β-cyclodextrin and ethanol on the β-lapachone solubility and gel properties, these authors confirmed that both additives promote drug solubilization. However, the addition of ethanol as a co-solvent may render Pluronic® (F127 and P123) dispersions inappropriate for IT administration. Data from rheological characterization suggested that autoclaving may not affect the gelation temperature and gel strength of Pluronic® systems with β-lapachone.[32]
An injectable PF127 hydrogel containing DOX complexed with hyaluronic acid and MgCl2 was developed by Jhan et al. and was demonstrated to cause the growth inhibition of C26 colon cancer cells in a mouse model.[19] This drug delivery system was patented (US9364545B2)[33] and then ameliorated by adding a mixed micellar formulation composed of PF127 and Pluronic® L121 for carrying a second chemotherapeutic drug (docetaxel, DTX)[20]. Mixed micelles consisting of PF127 and another surfactant, such as Tween® 80[21], Solutol® HS15[24], or D-α-tocopherol PEG 1000 succinate[34], have been incorporated into PF127 hydrogels to deliver hydrophobic drugs, namely DTX[21][24] and PTX[34].
By synthesizing the dalteparin-P407 copolymer, Li et al. repositioned low-molecular-weight heparin as an anticancer agent and fabricated a novel thermosensitive and injectable hydrogel carrying DOX-loaded laponite nanoparticles.[35]
Only one of the articles reviewed reported the use of poloxamer hydrogels for local chemoradiotherapy. The concurrent IT administration of chemotherapeutics and radiation was achieved by using PF127 hydrogels co-loaded with DOX and gold nanoparticles.[36]

2.2. Potential Applications in Cancer Phototherapy

Considering the mechanisms of light conversion, phototherapy includes photothermal therapy (PTT) and photodynamic therapy (PDT). Phototherapy based on PTT or PDT can eliminate cancer cells by generating hyperthermia or reactive species of oxygen (ROS).[37][38]
PTT involves the laser activation of photothermal agents, followed by near-infrared (NIR) light conversion into heat. Despite great progress in cancer PTT, most photothermal agents are made of heavy metals and given intravenously, causing safety concerns to arise. To reduce putative systemic toxicity and enhance local retention, Fu and colleagues indicated PF127 hydrogels embedding copper sulfide nanodots[39] or Prussian blue nanospheres[40] for PT administration. Given that seaweed polysaccharides have good biocompatibility, biodegradability, and non-toxicity, Chen et al. prepared an injectable photothermal hydrogel using iota carrageenan-capped gold-silver nanoparticles and PF127. The in vivo results pointed to a multifunctional hydrogel that could prevent tumor growth and recurrence and promote post-surgical wound healing without chemotherapeutic drugs and antibiotics.[41] An alternative to metal nanoparticles as photothermal agents is organic agents (i.e., indocyanine green), but their intrinsic instability limits their therapeutic effects. As a result, organic–inorganic hybrid nanomaterials such as titanium carbide (Ti3C2) nanoparticles have received attention and have been combined with PF127 through a simple mixture to form an injectable hydrogel for local PTT.[42]
The combination of chemotherapy with other therapeutic modalities, namely phototherapy, has gained momentum in recent years. One such example is the work by Zhang et al., which was aimed at achieving complete tumor ablation via IT injection of hexamethylene diisocyanate-PF127 nanocomposite hydrogel incorporating PTX-loaded chitosan micelles and PEGylated gold nanorods.[43] Qin et al. chose PF127 as the hydrogel matrix and black phosphorus nanosheets as photothermal agents because of their broad absorption in the NIR region and extinction coefficient larger than other 2D materials. While investigating the in vitro release profile of gemcitabine, it was observed that black phosphorus nanosheets accelerated drug release from PF127 hydrogel under NIR irradiation (808 nm, 2.0 W/cm2, 10 min). Compared to chemotherapy alone, this hydrogel exhibited a superior antitumor effect and good photothermal effect in BALB/c mice bearing 4T1 xenograft tumors.[44]
Tumor destruction by conventional PDT relies on the photochemical reaction between a light-activated photosensitizer and molecular oxygen to produce ROS, resulting in cell death.[45] However, PDT often fails to completely eradicate tumors due to the limited penetration of currently available photosensitizers into the tissue. Building upon the use of two-photon excitation to improve light penetration, Luo et al. proposed the co-encapsulation of a two-photon absorption compound (T1) and a photosensitizer (pyropheophorbide a) into polymeric micelles combined with PF127. In 4T1 xenograft mice, the obtained hydrogel was shown to inhibit tumor growth in more than 50% (under 1 cm-thick muscle tissue) after IT administration and NIR irradiation.[46] By capitalizing on the synergistic effects of chemotherapy and PDT, Li et al. employed DTX-loaded micelles and black phosphorus nanosheets as a hydrophobic model drug and photosensitizer, respectively, incorporating them into a PF127/PF68 hydrogel.[47]

2.3. Potential Applications in Cancer Immunotherapy

The most recent revolutionary wave in cancer therapy came with immunotherapy and its improvements for patients in terms of survival and quality of life.[48] However, two of the most used classes of immunotherapeutics, cytokines and checkpoint inhibitors, face similar and appreciable delivery challenges. For example, the use of Toll-like receptor (TLR) 7/8 agonists is often limited to IT administration because IV administration can lead to systemic toxicity by stimulating the entire immune system.[49] Therefore, local delivery of TLR 7/8 agonists, such as MEDI9197[50] and imiquimod[51], is preferred, which can be attained by mixing them with P407 aqueous solutions. Fakhari et al. demonstrated significant antitumor activity of P407 thermogel with MEDI9197 after two IT injections in a B16-OVA melanoma tumor model.[50] In another work, imiquimod was first encapsulated in 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine liposomes before being incorporated into PF127 hydrogel, with the final delivery system producing promising results in a breast cancer model.[51]
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), belonging to the class of checkpoint inhibitors, can also be explored to generate antitumor immune responses. To control the release of anti-CTLA-4 antibodies, Chung et al. pioneered the optimization of CTLA-4 therapy using P407-based injectable hydrogels. The authors observed a significant reduction in serum anti-CTLA-4 levels and effective tumor growth inhibition in CT26 tumor-bearing mice receiving the hydrogel peritumorally.[52] A major feature of the tumor microenvironment is extracellular acidosis, which seems to antagonize the efficacy of immune checkpoint inhibitors. One prominent strategy to alleviate extracellular tumor acidity capitalizes on sodium bicarbonate therapy, but can cause metabolic alkalosis. As such, Jin et al. employed NaHCO3-loaded PF127 hydrogel for precise delivery into the tumor, rendering its microenvironment immunologically favorable. Indeed, tumor clearance was improved when treating MC-38-bearing mice with a low dose of immune checkpoint inhibitors after local tumor neutralization with the gel.[53] Very recently, the overall goal of maximizing the therapeutic index of vemurafenib and antagonistic programmed cell death protein 1 antibody used in combination to treat BRAF-mutated melanoma was achieved with PF127-g-gelatin hydrogel and IT administration.[54]
Although dendritic cells were initially recognized for their role in antiviral immunity, recent attention has been directed toward their potential to boost the patients’ immune system in the fight against cancer.[55] Still, considering their short viability and low in vivo migration capacity, treatment with adjuvants for the recruitment and maturation of dendritic cells is of great interest. To illustrate, Lemdani et al. designed a mucoadhesive hydrogel consisting of P407 and xanthan gum for IT co-delivery of granulocyte-macrophage colony-stimulating factor and heat-killed Mycobacterium tuberculosis to refine the local antitumor immune response. Though administering a solution of these immunomodulatory agents elicited minimal therapeutic effects, their IT injection in the gel led to the infiltration of T cells in the tumor, as well as growth inhibition.[56]

2.4. Potential Applications in Cancer Gene Therapy

To date, the utilization of poloxamer hydrogels in local cancer gene therapy is scarce, with only two works being reported.
After coupling conjugated linoleic acid (CLA) with P407, Guo et al. demonstrated that CLA-coupled poloxamer hydrogel could be a local delivery system for PTX with enhanced antitumor efficacy.[57] The evidence of apoptotic cell death inspired these authors to use the obtained hydrogel for combination therapy with PTX and Akt1 shRNA. Knowing that the phosphoinositide 3-kinase/Akt1 signaling pathway has emerged as a target for breast cancer therapy, it is no surprise that the inhibition of Akt1 warrants special attention. In addition to synergistic inhibitory effects in vitro (MDA-MB-231 and MCF-7 cells) and in vivo (MDA-MB-231 xenograft), local treatment with PTX and Akt1 via CLA-coupled PF127 hydrogel was confirmed to decrease Akt1 phosphorylation levels and inhibit angiogenesis.[58]
Another promising target for breast cancer is survivin, whose inhibition merits in situ injection to ensure tissue and cell specificity. Taking advantage of electrostatic interactions between a cationic polymer (poly[(R)-3-hydroxybutyrate]-b-poly(2-dimethylamino) ethyl methacrylate) and negatively charged survivin antisense oligonucleotide, Zhao et al. developed a gene delivery nanocomplex subsequently incorporated into injectable PF127 hydrogels for local retention. A single injection was enough to achieve a sustained gene release for up to 16 days and counteract PTX-induced multidrug resistance by silencing up-regulated survivin.[59]

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