Drug Delivery Depot Research Articles

Acoustically responsive scaffolds: Unraveling release kinetics and mechanisms for sustained, steady drug delivery

Hydrogels can serve as local drug delivery depots that protect the biological activity of labile therapeutics. However, drug release from conventional hydrogels is typically rapid, which is not ideal for many therapeutic agents. We developed a composite hydrogel that enables sustained drug release in response to ultrasound. The composite, termed an acoustically responsive scaffold (ARS), consists of a fibrin hydrogel and a phase-shift emulsion. Upon exposure to ultrasound, the emulsion is vaporized into bubbles, which leads to release of drugs contained within the emulsion. Previously, ARSs have been used in regenerative applications to stimulate blood vessel growth. Here, we characterize the release kinetics and mechanisms of ARSs. Release exhibits a triphasic pattern compromising a slow phase prior to ultrasound exposure; a transient, fast phase immediately after ultrasound exposure that follows a sigmoidal profile; and a sustained, steady phase. In each phase, we demonstrate how derived kinetics parameters are impacted by the ARS composition (e.g., fibrin and emulsion concentrations) and ultrasound properties (e.g., acoustic pressure, pulse duration). Using confocal microscopy, protein assays, and B-mode ultrasound imaging, we demonstrate that drug release from an ARS is independent of fibrin degradation and dependent on bubble growth. These results are critical in optimizing ARSs for delivery of therapeutic agents.

Hybrid Nanoparticle-Hydrogel Systems for Drug Delivery Depots and Other Biomedical Applications.

Hydrogel-based depots typically tend to remain where injected and have excellent biocompatibility but are relatively poor at controlling drug release. Nanoparticles (NPs) typically have the opposite properties. The smaller the NPs are, the more likely they are to leave the site of injection. Their biocompatibility is variable depending on the material but can be poor. However, NPs can be good at controlling drug release. In these and other properties, combining NPs and hydrogels can leverage their advantages and negate their disadvantages. This review highlights the rationale for hybrid NP-hydrogel systems in drug delivery, the basic methods of producing them, and examples where combining the two systems addressed specific problems.

Mixed Micellar Gel of Poloxamer Mixture for Improved Solubilization of Poorly Water-Soluble Ibuprofen and Use as Thermosensitive In Situ Gel.

The aqueous solution of binary mixtures of amphiphilic copolymers is a potential platform for fabricating mixed polymeric micelles for pharmaceutical applications, particularly in developing drug delivery depots for a poorly water-soluble compound. This study fabricated and investigated binary mixtures of poloxamer 403 (P403) and poloxamer 407 (P407) at varying P403:P407 molar ratios to develop a vehicle for the poorly water-soluble compound, using ibuprofen as a model drug. The cooperative formation of mixed micelles was obtained, and the solubility of ibuprofen in the binary mixtures was enhanced compared to the solubility in pure water and an aqueous single P407 solution. The binary mixture with the P403:P407 molar ratio of 0.75:0.25 at a total polymer concentration of 19% w/v exhibited the temperature dependence of micellization and sol-to-gel characteristics of the thermosensitive mixed micellar gels. It possessed suitable micellization and gelation characteristics for in situ gelling systems. The release of ibuprofen from the thermosensitive mixed micellar depots was sustained through a diffusion-controlled mechanism. The findings can aid in formulating binary mixtures of P403 and P407 to achieve the desired properties of mixed micelles and micellar gels.

Injectable, Adhesive Albumin Nanoparticle-Incorporated Hydrogel for Sustained Localized Drug Delivery and Efficient Tumor Treatment.

Injectable hydrogels are receiving increasing attention as local depots for sustained anticancer drug delivery. However, most current hydrogel-based carriers lack tissue-adhesive ability, a property that is important for the immobilization of drug-loaded systems at tumor sites to increase local drug concentration. In this study, we developed a paclitaxel (PTX)-loaded injectable hydrogel with firm tissue adhesion for localized tumor therapy. PTX-loaded bovine serum albumin (BSA) nanoparticles (PTX@BN) were prepared, and the drug-loaded hydrogel was then fabricated by cross-linking PTX@BN with o-phthalaldehyde (OPA)-terminated 4-armed poly(ethylene glycol) (4aPEG-OPA) via a condensation reaction between OPA and the amines in BSA. The hydrogel showed firm adhesion to various organs and tumor tissues ex vivo due to the condensation reaction of unreacted OPA groups and amines in the tissues. The PTX-loaded nanocomposite hydrogels sustained PTX release over 30 days following the Korsmeyer-Peppas model and exhibited notable inhibition activities against mouse C26 colon and 4T1 breast cancer cells in vitro. Following peritumoral injection into mice with C26 or 4T1 tumors, the PTX@BN-loaded hydrogel significantly enhanced the antitumor efficacy and prolonged animal survival time compared to free PTX solutions with low systemic toxicity. Therefore, the adhesive, PTX-loaded nanocomposite hydrogels have the potential for efficient localized tumor therapy.

Hydrogel‐Based Delivery of antimiR‐195 Improves Cardiac Efficacy after Ischemic Injury

AbstractMicroRNAs (miRs) are potent regulators of biology and disease. The miR‐15 family is shown to regulate cardiomyocyte proliferation and antimiR‐based inhibition induces a cardioprotective effect after myocardial infarction in mice. However, systemic delivery of antimiRs leads to accumulation in kidneys and liver, with relatively poor cardiac exposure. Injectable hydrogels are proposed to serve as sustained‐release drug delivery depots and can potentially be used to improve cardiac efficacy of antimiR therapeutics. Here, the effect of a hydrogel‐formulated antimiR‐195 after myocardial infarction in mice is studied. For this, an injectable, pH‐switchable supramolecular hydrogel based on poly(ethylene glycol) (PEG) functionalized with hydrogen bonding ureido‐pyrimidinone (UPy) units is used. Intracardiac injections under baseline conditions of this UPy–PEG hydrogelator induce a transient inflammatory response that is no longer present 7 days postinjection. In vitro experiments show that antimiR‐195 is released from the gel, and induces microRNA inhibition leading to downstream cardiomyocyte proliferation. In vivo, intramyocardial delivery of antimiR‐195 in UPy–PEG enhances cardiac target derepression compared to phosphate‐buffered‐saline‐dissolved antimiR‐195, despite a low cardiac retention. After ischemic injury, this translates into a greater therapeutic effect by increasing both target derepression and cardiomyocyte proliferation. Intramyocardial injection of UPy–PEG‐formulated antimiR‐195 is sufficient to improve cardiac efficacy of antimiR‐195.

A drug-delivery depot for epigenetic modulation and enhanced cancer immunotherapy

DNA methyltransferase inhibitors (DNMTis) have found widespread application in the management of cancer. Zebularine (Zeb), functioning as a demethylating agent, has exhibited notable advantages and enhanced therapeutic efficacy in the realm of tumour immunotherapy. Nevertheless, due to its lack of targeted functionality, standalone Zeb therapy necessitates the administration of a substantially higher dosage. In this investigation, we have devised an innovative nanodrug formulation, comprising the DNA methyltransferase inhibitor Zeb and pH-responsive chitosan (CS), hereinafter referred to as CS-Zeb nanoparticles (NPs). Our findings have unveiled that CS-Zeb NPs manifest heightened drug release within an acidic milieu (pH 5.5) in comparison to a neutral environment (pH 7.4). Furthermore, in vivo studies have conclusively affirmed that, in contrast to equivalent quantities of Zeb in isolation, the nanocomplex significantly curtailed tumour burden and protracted the survival duration of the B16F10 tumour-bearing murine model. Additionally, CS-Zeb NPs elicited an augmentation of CD8+ T cells within the peripheral circulation of mice and tumour-infiltrating lymphocytes (TILs). Notably, the dosage of CS-Zeb NPs was reduced by a remarkable 70-fold when juxtaposed with Zeb administered in isolation. To summarise, our study underscores the potential of CS-Zeb NPs as an alternative chemotherapeutic agent for cancer treatment.

Thermo-induced physically crosslinked polypeptide-based block copolymer hydrogels for biomedical applications.

Stimuli-responsive synthetic polypeptide-containing block copolymers have received considerable attention in recent years. Especially, unique thermo-induced sol-gel phase transitions were observed for elaborately-designed amphiphilic diblock copolypeptides and a range of poly(ethylene glycol) (PEG)-polypeptide block copolymers. The thermo-induced gelation mechanisms involve the evolution of secondary conformation, enhanced intramolecular interactions, as well as reduced hydration and increased chain entanglement of PEG blocks. The physical parameters, including polymer concentrations, sol-gel transition temperatures and storage moduli, were investigated. The polypeptide hydrogels exhibited good biocompatibility in vitro and in vivo, and displayed biodegradation periods ranging from 1 to 5 weeks. The unique thermo-induced sol-gel phase transitions offer the feasibility of minimal-invasive injection of the precursor aqueous solutions into body, followed by in situ hydrogel formation driven by physiological temperature. These advantages make polypeptide hydrogels interesting candidates for diverse biomedical applications, especially as injectable scaffolds for 3D cell culture and tissue regeneration as well as depots for local drug delivery. This review focuses on recent advances in the design and preparation of injectable, thermo-induced physically crosslinked polypeptide hydrogels. The influence of composition, secondary structure and chirality of polypeptide segments on the physical properties and biodegradation of the hydrogels are emphasized. Moreover, the studies on biomedical applications of the hydrogels are intensively discussed. Finally, the major challenges in the further development of polypeptide hydrogels for practical applications are proposed.

Adhesive ginsenoside compound K patches for cartilage tissue regeneration.

Biomaterial-based drug delivery systems have been developed to expedite cartilage regeneration; however, challenges related to drug recovery, validation, and efficient drug delivery remain. For instance, compound K (CK) is a major metabolite of ginsenosides that is known to protect against joint degeneration by inhibiting the production of inflammatory cytokines and the activation of immune cells. However, its effects on cartilage degradation and tissue regeneration remain unclear. Additionally, tissue-adhesive drug delivery depots that stably adhere to cartilage defects are required for CK delivery. In this study, CK-loaded adhesive patches were reported to seal cartilage defects and deliver CK to defect sites, preventing cartilage degradation and accelerating cartilage tissue regeneration. Adhesive patches are stable and suitable for application in surgical procedures under physiological conditions and show excellent adhesiveness to cartilage surfaces. In addition, there were no significant differences in the adhesive polymeric networks before and after CK loading. CK-loaded hydrocaffeic acid-conjugated chitosan patches significantly inhibited the stimulation of cartilage-degrading enzymes and apoptosis in osteoarthritic cartilage by releasing CK in cartilage defects. Additionally, the NFkB signaling pathway of released CK from the adhesive patches in the treatment of osteoarthritis is revealed. Thus, the CK-loaded adhesive patches are expected to significantly contribute to cartilage regeneration.

Injectable hydrogel imbibed with camptothecin-loaded mesoporous silica nanoparticles as an implantable sustained delivery depot for cancer therapy

In recent years, injectable stimuli-sensitive hydrogels are employed as suitable drug delivery carriers for the release of various anti-cancer drugs. However, large pore size of the microporous hydrogel trigger release of small molecular anticancer drug that limits hydrogel application in cancer therapy. Therefore, introducing reinforcing fillers such as mesoporous silica nanoparticles (MSNs) can not only load different type of anticancer drugs but also prevent the premature release of drugs due to the strengthening of the networks. Furthermore, high specific surface area, suitable size, large pore volume, and stable physicochemical properties of MSNs can improve the therapeutic efficacy. In this study, to sustain the release of hydrophobic anticancer drug, camptothecin (CPT) was loaded into MSNs, and then imbibed into the physiological stimuli-sensitive poly(ethylene glycol)-poly(β-aminoester urethane) (PAEU) hydrogels. MSN-imbibed PAEU hydrogels exhibited prolonged release of CPT than MSNs and PAEU hydrogel alone. Furthermore, MSN-imbibed PAEU copolymers form stable viscoelastic gel depot into the subcutaneous layers of Sprague-Dawley rats and found to be safe and not induced toxicity to healthy organs, implying biodegradability and safety of the hydrogels. Interestingly, CPT-loaded hydrogels shown dose-dependent toxicity to A549 and B16F10 cells. These results demonstrated that MSN-imbibed PAEU hydrogel with biocompatible, biodegradable, and in situ gel forming property could be a useful drug delivery depot for sustained release of anticancer drugs.

An Injectable Nanocomposite Hydrogel Improves Tumor Penetration and Cancer Treatment Efficacy

Hydrogel as a local drug depot can increase drug concentration at the tumor site. However, conventional drug-loaded hydrogel is typically formed by direct dissolution of drug molecules inside the hydrogel, which usually suffers from limited drug retention and poor tumor penetration. In this study, a nanocomposite hydrogel consisting of oxaliplatin (OXA)-conjugated G5 polyamidoamine (G5-OXA) and oxidized dextran (Dex-CHO) is constructed to improve local drug delivery. The OXA-containing nanocomposite hydrogel (denoted as PDO gel) is injectable and could maintain in vivo up to more than three weeks, which increases drug retention in tumor tissues. More interestingly, G5-OXA released from the PDO gel show potent tumor penetration mainly through an active transcytosis process. In vivo antitumor studies in an orthotopic 4T1 tumor model show that PDO gel significantly inhibits primary tumor growth as well as the metastasis. In addition, the PDO gel can also activate the immunosuppressive tumor microenvironment through immunogenic cell death effect, and further improves therapeutic efficacy with the combination of PD-1 antibody. These results demonstrate that the nanocomposite hydrogel can simultaneously enhance the retention and penetration of chemotherapeutic drugs via the combination of both advantages of hydrogel and nanoparticles, which provides new insights for the design of local drug delivery systems. Statement of significanceHydrogel represents an important class of local drug delivery depot. However, conventional drug-loaded hydrogel is usually achieved by direct dissolution of small drug molecules inside the hydrogel, which typically suffers from limited drug retention and poor tumor penetration. Herein, we developed a nanocomposite hydrogel, which could gradually degrade and release drug-conjugated small nanoparticles (∼ 6 nm) for improved tumor penetration through the combination of an active transcytosis process and a passive diffusion process. This nanocomposite hydrogel system improved tumor penetration and retention of drug in primary tumors as well as the drug deposition in lymph nodes, which significantly suppressed tumor growth and metastasis.

Bioorthogonal in situ assembly of nanomedicines as drug depots for extracellular drug delivery

Developing precise nanomedicines to improve the transport of anticancer drugs into tumor tissue and to the final action site remains a critical challenge. Here, we present a bioorthogonal in situ assembly strategy for prolonged retention of nanomedicines within tumor areas to act as drug depots. After extravasating into the tumor site, the slightly acidic microenvironment induces the exposure of cysteine on the nanoparticle surface, which subsequently undergoes a bioorthogonal reaction with the 2-cyanobenzothiazole group of another neighboring nanoparticle, enabling the formation of micro-sized drug depots to enhance drug retention and enrichment. This in situ nanoparticle assembly strategy remarkably improves the antimetastatic efficacy of extracellular-targeted drug batimastat, and also leads to the simultaneous enhanced retention and sustained release of multiple agents for combined cocktail chemoimmunotherapy to finally elicit a potent antitumor immune response. Such in situ assembly of nanomedicines represents a generalizable strategy towards extracellular drug delivery and cocktail chemoimmunotherapy.

Injectable Hydrogels of Stimuli-Responsive Elastin and Calmodulin-Based Triblock Copolypeptides for Controlled Drug Release.

A variety of block copolypeptides with stimuli responsiveness have been of growing interest for dynamic self-assembly. Here, multistimuli-responsive triblock copolypeptides composed of thermosensitive elastin-based polypeptides (EBP) and ligand-responsive calmodulin (CalM) were genetically engineered, over-expressed, and nonchromatographically purified by inverse transition cycling. Diluted EBP-CalM-EBP (ECE) triblock copolypeptides under physiological conditions self-assembled into vesicles at the nanoscale by temperature-triggered aggregation of the EBP block with lower critical solution temperature behaviors. Furthermore, concentrated ECE triblock copolypeptides under identical conditions exhibited thermally induced gelation, resulting in physically crosslinked hydrogels. They showed controlled rheological and mechanical properties depending on the conformational change of the CalM middle block induced by binding either Ca2+ or Ca2+ and trifluoperazines (TFPs) as ligands. In addition, both Ca2+-free and Ca2+-bound ECE triblock copolypeptide hydrogels exhibited biocompatibility, while those bound to both Ca2+ and TFPs showed severe cytotoxicity because of controlled TFP release of the CalM blocks. The ECE triblock hydrogels with stimuli responsiveness would be useful as injectable drug delivery depots for biomedical applications.

Branched PCL-Based Thermogelling Copolymers: Controlling Polymer Architecture to Tune Drug Release Profiles

Temperature-responsive hydrogels, or thermogels, are a unique class of biomaterials that show facile and spontaneous transition from solution to gel when warmed. Their high biocompatibility, and ease of formulation with both small molecule drugs and biologics have made these materials prime candidates as injectable gel depots for sustained local drug delivery. At present, controlling the kinetics and profile of drug release from thermogels is achieved mainly by varying the ratio of hydrophobic: hydrophilic composition and the polymer molecular weight. Herein, we introduce polymer branching as a hitherto-overlooked polymer design parameter that exhibits profound influences on the rate and profile of drug release. Through a family of amphiphilic thermogelling polymers with systematic variations in degree of branching, we demonstrate that more highly-branched polymers are able to pack less efficiently with each other during thermogel formation, with implications on their physical properties and stability towards gel erosion. This in turn resulted in faster rates of release for both encapsulated small molecule hydrophobic drug and protein. Our results demonstrate the possibility of exploiting polymer branching as a hitherto-overlooked design parameter for tailoring the kinetics and profile of drug release in injectable thermogel depots.

Development of functional hybrid scaffolds for wound healing applications

SummaryHybrid hydrogels composed of chitosan (CS) and hyaluronic acid (HA) and collagen (Coll) were prepared by polyelectrolyte complex self-assembly. These scaffolds displayed a good intermingling of the polymeric chains, with porosities above 80% and good interconnected structures with pore sizes lying between 30–115 μm. The ionic interactions between CS and HA make the scaffolds have larger storage modulus and longer LVR regions than their pure counterparts. Both quantities progressively decrease as the HA and Coll concentrations in the formulation rise. These hybrid hydrogels showed good swelling extents from ca. 420 to ca. 690% and suitable resistance to enzymatic degradation, which was slightly lower for scaffolds containing CS to larger extents or Coll in the formulation. All scaffolds were largely cytocompatible and allowed the proliferation of both mouse fibroblast and human keratinocytes with their infiltration inside, thus becoming optimal matrices for intended tissue engineering applications as well as transdermal drug delivery depots.

Tissue-reactive drugs enable materials-free local depots

Local, sustained drug delivery of potent therapeutics holds promise for the treatment of a myriad of localized diseases while eliminating systemic side effects. However, introduction of drug delivery depots such as viscous hydrogels or polymer-based implants is highly limited in stiff tissues such as desmoplastic tumors. Here, we present a method to create materials-free intratumoral drug depots through Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs diffuse into tissue and attach locally for sustained drug release. In TRAPs, potent drugs are modified with ECM-reactive groups and then locally injected to quickly react with accessible amines within the ECM, creating local drug depots. We demonstrate that locally injected TRAPs create dispersed, stable intratumoral depots deep within mouse and human pancreatic tumor tissues. TRAPs depots based on ECM-reactive paclitaxel (TRAP paclitaxel) had better solubility than free paclitaxel and enabled sustained in vitro and in vivo drug release. TRAP paclitaxel induced higher tumoral apoptosis and sustained better antitumor efficacy than the free drug. By providing continuous drug access to tumor cells, this material-free approach to sustained drug delivery of potent therapeutics has the potential in a wide variety of diseases where current injectable depots fall short.

Therapeutic supramolecular tubustecan hydrogel combined with checkpoint inhibitor elicits immunity to combat cancer

The clinical benefit of PD-1/PD-L1 blockade immunotherapy is substantially restricted by insufficient infiltration of T lymphocytes into tumors and compromised therapeutic effects due to immune-related adverse events following systemic administration. Some chemotherapeutic agents have been reported to trigger tumor-associated T cell responses, providing a promising strategy to achieve potent immune activation in a synergistic manner with PD-1 blockade immunotherapy. In light of this, a localized chemoimmunotherapy system was developed using an anti-cancer drug-based supramolecular polymer (SP) hydrogel to “re-edit” the host's immune system to combat cancer. This in situ forming injectable aPD1/TT6 SP hydrogel serves as a drug-delivery depot for sustained release of bioactive camptothecin (CPT) and aPD1 into the tumor microenvironment, priming the tumor for robust infiltration of tumor-associated T cells and subsequently prompting a response to the immune checkpoint blockade. Our in vivo results demonstrate that this chemoimmunotherapy hydrogel provokes a long-term and systemic anticancer T cell immune response, which elicits tumor regression while also inhibiting tumor recurrence and potential metastasis.

Genetically Encoded Elastin-Like Polypeptides for Drug Delivery.

Elastin-like polypeptides (ELPs) are thermally responsive biopolymers that consist of a repeated amino acid motif derived from human tropoelastin. These peptides exhibit temperature-dependent phase behavior that can be harnessed to produce stimuli-responsive biomaterials, such as nanoparticles or injectable drug delivery depots. As ELPs are genetically encoded, the properties of ELP-based biomaterials can be controlled with a precision that is unattainable with synthetic polymers. Unique ELP architectures, such as spherical or rod-like micelles or injectable coacervates, can be designed by manipulating the ELP amino acid sequence and length. ELPs can be loaded with drugs to create controlled, intelligent drug delivery systems. ELPs are biodegradable, nonimmunogenic, and tolerant of therapeutic additives. These qualities make ELPs exquisitely well-suited to address current challenges in drug delivery and have spurred the development of ELP-based therapeutics to treat diseases-such as cancer and diabetes-and to promote wound healing. This review focuses on the use of ELPs in drug delivery systems.

Defining Role of a High-Molecular-Weight Population in Block Copolymers Based on Poly(α-benzyl carboxylate-ε-caprolactone) and Poly(ethylene glycol) on the Formation of Thermoreversible Hydrogels

Biodegradable thermoreversible hydrogels with sol-to-gel transition temperatures a few degrees below the physiological temperature have great potential for application in depot drug delivery and ti...

Electrically Stimulated Tunable Drug Delivery From Polypyrrole-Coated Polyvinylidene Fluoride.

Electrical stimulus-responsive drug delivery from conducting polymers such as polypyrrole (PPy) has been limited by lack of versatile polymerization techniques and limitations in drug-loading strategies. In the present study, we report an in-situ chemical polymerization technique for incorporation of biotin, as the doping agent, to establish electrosensitive drug release from PPy-coated substrates. Aligned electrospun polyvinylidene fluoride (PVDF) fibers were used as a substrate for the PPy-coating and basic fibroblast growth factor and nerve growth factor were the model growth factors demonstrated for potential applications in musculoskeletal tissue regeneration. It was observed that 18-h of continuous polymerization produced an optimal coating of PPy on the surface of the PVDF electrospun fibers with significantly increased hydrophilicity and no substantial changes observed in fiber orientation or individual fiber thickness. This PPy-PVDF system was used as the platform for loading the aforementioned growth factors, using streptavidin as the drug-complex carrier. The release profile of incorporated biotinylated growth factors exhibited electrosensitive release behavior while the PPy-PVDF complex proved stable for a period of 14 days and suitable as a stimulus responsive drug delivery depot. Critically, the growth factors retained bioactivity after release. In conclusion, the present study established a systematic methodology to prepare PPy coated systems with electrosensitive drug release capabilities which can potentially be used to encourage targeted tissue regeneration and other biomedical applications.

Glabridin and Anti-Non-Muscle Myosin IIA Therapy Disrupts Non-Small Cell Lung Carcinoma Motility

Lung cancer is the leading cause of cancer related death in the United States killing over 130,000 people each year. While a combination of chemo and radiation therapy may be effective, surgery is still required for many patients. Without surgery, the disease may progress and lead to metastases. We sought to determine if treatment with anti-non-muscle myosin IIA antibody would inhibit movement of the cells in the presence and absence of glabridin (an isoflavonoid compound shown to inhibit cell migration by inhibiting myosin). We compared inhibition by glabridin to that of an anti-non-muscle myosin IIA antibody and a combination therapy of both at 12 and 24 hours post wound creation. Cells that took up the anti-non-muscle myosin IIA antibody were greatly inhibited in motility and exhibited no significant change in wound healing. Glabridin treatment resulted in a dramatic increase in wound size within 12 hours and regeneration within 24 hours. The greatest decrease in motility was observed in cells treated with the combination of both glabridin and anti-non-muscle myosin IIA antibody. By 24 hrs, cell migration had halted due to death of the cells resulting from this combination. Further testing needs to be done to determine a safe mode of delivery of the combination therapy to ensure only local distribution. Controlled release drug delivery depot systems have been used as a means to provide local release of drugs intra-tumorally or adjacent to the cancerous tissue after surgical resection and have great potential.