Development of Intratumoral Drug Delivery Based Strategies for Antitumor Therapy.

Research for tumor treatment with significant therapy effects and minimal side-effects has been widely carried over the past few decades. Different drug forms have received a lot of attention. However, systemic biodistribution induces efficacy and safety issues. Intratumoral delivery of agents might overcome these problems because of its abundant tumor accumulation and retention, thereby reducing side effects. Delivering hydrogels, nanoparticles, microneedles, and microspheres drug carriers directly to tumors can realize not only targeted tumor therapy but also low side-effects. Furthermore, intratumoral administration has been integrated with treatment strategies such as chemotherapy, enhancing radiotherapy, immunotherapy, phototherapy, magnetic fluid hyperthermia, and multimodal therapy. Some of these strategies are ongoing clinical trials or applied clinically. However, many barriers hinder it from being an ideal and widely used option, such as decreased drug penetration impeded by collagen fibers of a tumor, drug squeezed out by high density and high pressure, mature intratumoral injection technique. In this review, we systematically discuss intratumoral delivery of different drug carriers and current development of intratumoral therapy strategies.

Endoscopic Ultrasound-Guided Local Ablative Therapies for the Treatment of Pancreatic Neuroendocrine Tumors and Cystic Lesions: A Review of the Current Literature.

Since its emergence as a diagnostic modality in the 1980s, endoscopic ultrasound (EUS) has provided the clinician profound access to gastrointestinal organs to aid in the direct visualization, sampling, and subsequent identification of pancreatic pathology. In recent years, advancements in EUS as an interventional technique have promoted the use of local ablative therapies as a minimally invasive alternative to the surgical management of pancreatic neuroendocrine tumors (pNETs) and pancreatic cystic neoplasms (PCNs), especially for those deemed to be poor operative candidates. EUS-guided local therapies have demonstrated promising efficacy in addressing a spectrum of pancreatic neoplasms, while also balancing local adverse effects on healthy parenchyma. This article serves as a review of the current literature detailing the mechanisms, outcomes, complications, and limitations of EUS-guided local ablative therapies such as chemical ablation and radiofrequency ablation (RFA) for the treatment of pNETs and PCNs, as well as a discussion of future applications of EUS-guided techniques to address a broader scope of pancreatic pathology.

An Injectable In Situ Depot-Forming Lipidic Lyotropic Liquid Crystal System for Localized Intratumoral Drug Delivery.

To address the need for localized chemotherapy against unresectable solid tumors, an injectable in situ depot-forming lipidic lyotropic liquid crystal system (L3CS) is explored that can provide spatiotemporal control over drug delivery. Although liquid crystals have been studied extensively before but their application as an injectable intratumoral depot system for locoregional chemotherapy has not been explored yet. The developed L3CS in the present study is a low-viscosity injectable fluid having a lamellar phase, which transforms into a hexagonal mesophase depot system on subcutaneous or intratumoral injection. The transformed depot system can be preprogrammed to provide tailored drug release intratumorally, over a period of one week to one month. To establish the efficacy of the developed L3CS, doxorubicin is used as a model drug. The drug release mechanism is studied in detail both in vitro and in vivo, and the efficacy of the developed system is investigated in the murine 4T1 tumor model. The direct intratumoral injection of the L3CS provided localized delivery of doxorubicin inside the tumor and restricted its access within the tumor only for a sustained period of time. This led to an over 10-fold reduction in tumor burden, reduced cardiotoxicity, and a significant increase in the median survival rate, compared to the control group. The developed L3CS thus provides an efficient strategy for localized chemotherapy against unresectable solid tumors with a great degree of spatial and temporal control over drug delivery.

Combined chemotherapy for triple negative breast cancer treatment by paclitaxel and niclosamide nanocrystals loaded thermosensitive hydrogel.

Triple negative breast cancer (TNBC) is the most dangerous subtype of breast cancer accompanying by unfavorable prognosis due to lack of specific therapeutic targets. Paclitaxel (PTX) is the first-line chemotherapeutic drug for TNBC and niclosamide (NLM) was identified as an inhibitor for TNBC and breast cancer stem cells (BCSCs). Intratumoral drug delivery system was a hopeful alternative for chemotherapeutic drug administration due to its targeting efficiency with lower systemic toxicity. Herein, an injectable PTX nanocrystals (PTX-NCs) and NLM nanocrystals (NLM-NCs) co-loaded PLGA-PEG-PLGA thermosensitive hydrogel (PNNCs-Ts Gel) was designed for TNBC intratumoral treatment. The final formulation realized high drug loading and appropriate particle size. PNNCs-Ts Gel displayed sustained drug release for up to 8 days in vitro. In vitro antitumor tests observed synergetic effects of combined therapy in terms of inhibiting cell proliferation and migration, inducing apoptosis. In vivo combined therapy presented a tumor growth inhibition rate about 68.8% and desired safety. Moreover, tumors after PNNCs-Ts Gel intratumoral injection possessed the lowest ratio of BCSCs, exhibiting this formulation had good ability in suppressing BCSCs and therefore could possibly prevent TNBC recurrence and metastasis. These results suggested that PNNCs-Ts Gel could be a promising strategy for TNBC treatment.

Electromagnetic Field-Programmed Magnetic Vortex Nanodelivery System for Efficacious Cancer Therapy.

Effective delivery of anticancer drugs into the nucleus for pharmacological action is impeded by a series of intratumoral transport barriers. Despite the significant potential of magnetic nanovehicles in electromagnetic field (EF)-activated drug delivery, modularizing a tandem magnetoresponsive activity in a one-nanoparticle system to meet different requirements at both tissue and cellular levels remain highly challenging. Herein, a strategy is described by employing sequential EF frequencies in inducing a succession of magnetoresponses in the magnetic nanovehicles that aims to realize cascaded tissue penetration and nuclear accumulation. This nanovehicle features ferrimagnetic vortex-domain iron oxide nanorings coated with a thermo-responsive polyethylenimine copolymer (PI/FVIOs). It is shown that the programmed cascading of low frequency (Lf)-EF-induced magnetophoresis and medium frequency (Mf)-EF-stimulated magneto-thermia can steer the Doxorubicin (DOX)-PI/FVIOs to the deep tissue and subsequently trigger intracellular burst release of DOX for successful nuclear entry. By programming the order of different EF frequencies, it is demonstrated that first-stage Lf-EF and subsequent Mf-EF operation enables DOX-PI/FVIOs to effectively deliver 86.2% drug into the nucleus in vivo. This nanodelivery system empowers potent antitumoral activity in various models of intractable tumors, including DOX-resistant MCF-7 breast cancer cells, triple-negative MDA-MB-231 breast cancer cells, and BxPC-3 pancreatic cancer cells with poor permeability.

Emerging technologies for local cancer treatment.

The fundamental limitations of systemic therapeutic administration have prompted the development of local drug delivery platforms as a solution to increase effectiveness and reduce side effects. By confining therapeutics to the site of disease, local delivery technologies can enhance therapeutic index. This review highlights recent advances and opportunities in local drug delivery strategies for cancer treatment in addition to challenges that need to be addressed to facilitate clinical translation. The benefits of local cancer treatment combined with technological advancements and increased understanding of the tumor microenvironment, present a prime breakthrough opportunity for safer and more effective therapies.

Injectable SN-38-embedded Polymeric Microparticles Promote Antitumor Efficacy against Malignant Glioma in an Animal Model.

Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of healthy rats and intratumorally injected into F98 glioma-bearing rats for estimating the pharmacodynamics and therapeutic efficacy. SN-38 was rapidly released after injection and its local (brain tissue) concentration remained much higher than that in the blood for more than 8 weeks. Glioma-bearing rats were divided into three groups-group A (n = 13; stereotactically injected pure PLGA microparticles), group B (n = 12; stereotactically injected Gliadel wafer and oral temozolomide), and group C (n = 13; stereotactic and intratumoral introduction of SMPs). The SMPs exhibited significant therapeutic efficacy, with prolonged survival, retarded tumor growth, and attenuated malignancy. The experimental results demonstrated that SMPs provide an effective and potential strategy for the treatment of MG.

Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer.

Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit efficient anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for injections or clinician intervention. In this study, the NDES was used to deliver immunotherapeutics intratumorally in the 4 T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti-tumor immune response and inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors.

Preparation of a paclitaxel-loaded cationic nanoemulsome and its biodistribution via direct intratumoral injection.

In this study, a nano-preparation based on nanoemulsome (NES) modified with cetyltrimethylammonium bromide (CTAB) loading paclitaxel (PTX) was designed, and its biodistribution were explored after intratumoral (i.t.) administration on Heps tumor-bearing mice. The PTX-loaded nanoemulsome (PTX-NES) was prepared by using a solvent evaporation method and CTAB, chosen as a cationic material, was absorbed onto the surface of the NES via electrostatic interaction to yield paclitaxel-loaded cationic nanoemulsome (PTX-CTAB-NES). The MTT results exhibited that PTX-CTAB-NES (IC50: 0.50±0.035µg/mL in MCF-7 cells and 0.13±0.048µg/mL in SMMC-7721 cells) had the strongest cytotoxicity compared to Taxol (IC50: 0.88±0.054µg/mL in MCF-7 and 0.15±0.011µg/mL in SMMC-7721) and PTX-NES (IC50: 1.93±0.062µg/mL in MCF-7 and 0.32±0.027µg/mL in SMMC-7721). Body distribution of PTX revealed that the percent of PTX retained in the tumor after i.t. administration of PTX-CTAB-NES (approximately 92.99% at 0.167h and 15.35% at 48h) was higher when compared to that after i.t. injection of Taxol (approximately 58.94% at 0.167h and 0.83% at 48h) or PTX-NES (approximately 83.63% at 0.167h and 6.52% at 48h). Moreover, less PTX accumulated in liver, spleen, kidney, lung and heart after i.t. administration of PTX-CTAB-NES when compared with that after i.v. administration of PTX-CTAB-NES. In conclusion, PTX-CTAB-NES was a prospective in-situ delivery system for the therapy of tumor.

Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor.

In an attempt to spatiotemporally control both tumor retention and the coverage of anticancer agents, we developed a photoradiation-controlled intratumoral depot (PRCITD) driven by convection enhanced delivery (CED). This intratumoral depot consists of recombinant elastin-like polypeptide (ELP) containing periodic cysteine residues and is conjugated with a photosensitizer, chlorin-e6 (Ce6) at the N-terminus of the ELP. We hypothesized that this cysteine-containing ELP (cELP) can be readily crosslinked through disulfide bonds upon exposure to oxidative agents, specifically the singlet oxygen produced during photodynamic stimulation. Upon intratumoral injection, CED drives the distribution of the soluble polypeptide freely throughout the tumor interstitium. Formation and retention of the depot was monitored using fluorescence molecular tomography imaging. When imaging shows that the polypeptide has distributed throughout the entire tumor, 660-nm light is applied externally at the tumor site. This photo-radiation wavelength excites Ce6 and generates reactive oxygen species (ROS) in the presence of oxygen. The ROS induce in situ disulfide crosslinking of the cysteine thiols, stabilizing the ELP biopolymer into a stable therapeutic depot. Our results demonstrate that this ELP design effectively forms a hydrogel both in vitro and in vivo. These depots exhibit high stability in subcutaneous tumor xenografts in nude mice and significantly improved intratumoral retention compared to controls without crosslinking, as seen by fluorescent imaging and iodine-125 radiotracer studies. The photodynamic therapy provided by the PRCITD was found to cause significant tumor inhibition in a Ce6 dose dependent manner. Additionally, the combination of PDT and intratumoral radionuclide therapy co-delivered by PRCITD provided a greater antitumor effect than either monotherapy alone. These results suggest that the PRCITD could provide a stable platform for delivering synergistic, anti-cancer drug depots.

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

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.