Yuanzeng Min

Clinical Translation of Nanomedicine.

1. Introduction Nanomedicine, the application of nanotechnology to health and medicine, is a relatively new area of interdisciplinary science. The field involves a wide range of scientific disciplines, including physics, chemistry, engineering, biology, and medical science. The term nanomedicine can be traced back to the late 1990s and first appeared in research publications in the year 2000.1 Despite the wide adoption of the term nanomedicine, its definition varies among experts in this area.2 Some define nanomedicine broadly as any science that involves matters that are nanoscale. For example, the European Science Foundation in 2004 defined nanomedicine as “the science and technology of diagnosing, treating, and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and molecular knowledge of the human body”.2 While such a broad definition is all encompassing, it can be confusing. For example, such a definition would include traditional scientific fields such as molecular biology as part of nanomedicine, because molecules such as nucleic acids and proteins are also nanoscale materials. However, scientists have been studying these molecules decades before the term nanomedicine was even coined, and their research generally does not take advantage of unique properties that only exist for nanomaterials. A narrower definition of nanomedcine is the application of nanoscale material in medicine that takes advantage of the nanomaterials unique properties.1 This Review will adopt this narrower definition in our discussion of the clinical translation of nanomedicine. Nanomedicine has made a rapid and broad impact on healthcare. Despite being only several decades old, research in nanomedicine has already led to the development of a wide range of products including therapeutics, diagnostic imaging agents, in vitro diagnostics, and medical devices. There are more than 200 nanomedicine products that have been either approved or are under clinical investigation.3 On the other hand, successful clinical translation is a challenging process. It requires extensive preclinical research, carefully selected clinical indication, proper design of clinical trials, and the successful completion of these trials. Mistakes in clinical translation can be unforgiving. Unlike preclinical research where there are many if not unlimited chances of generating a successful study, a single failed clinical trial can doom a drugs translation. Hay et al. recently showed that the eventual success rate of approval for therapeutics entering phase I trial is only about 10%.4 Because of this sobering statistic, it is important for translational researchers to fully understand the clinical translation process and to develop a successful translation strategy in the early stages of research. As compared to diagnostics and devices, clinical translation of therapeutics is arguably the most challenging. The typical clinical translation path for a new drug starts with investigators generating robust preclinical data to demonstrate the safety and efficacy of the new drug to enable an investigational new drug (IND) application with the Food and Drug Administration (FDA).5 Once the FDA has approved the IND, the therapeutic will be evaluated in a first-in-human or a phase I clinical trial. The goal of such a study is to determine the safety profile and pharmacology of the drug. It will result in a dose and schedule for further clinical investigation, or the recommended phase 2 dose (RP2D). The typical phase I trial design used a “3 + 3” cohort expansion design.6 This design assumes toxicity increases with dose, and it aims to determine the dose level that has less than 1/3 chance of a dose-limiting toxicity (DLT).7 In general, such a trial starts with a low drug dose. If none of the three patients receiving this dose experiences a DLT, another three patients will be treated at the next higher dose level. If one of the three patients experiences a DLT, then three more patients will be treated at the same dose level. Dose escalation continues until two patients among a cohort of three to six patients experience DLT. The RP2D is the dose level just below this level. Dose escalation typically follows a modified Fibonacci sequence where dose increments decrease as the tested dose increases. Other types of phase I designs include the accelerated titration designs, Bayesian models-based designs, and many others.7 Each design has advantages and disadvantages, and investigators have to choose the design that best fits the therapeutic. The goal of a phase II clinical trial is to examine the effectiveness of a drug or treatment. Secondarily, it will acquire more data on the toxicity and tolerability of the therapeutic. Therapeutics will progress to phase III clinical investigation only if they can demonstrate efficacy in phase II. The designs of phase II trials are either single-arm trials or randomized trials.8 Single-arm trials are cheaper, require fewer patients, and are typically easier to accrue. However, the outcome is less reliable as there is no comparison/control arm, and data are more susceptible to bias. Data from randomized phase II trials are more predictive of phase III results. However, it requires more patients and can be more difficult to accrue. Randomized phase II trials do not replace phase III investigations. Although they are randomized, patients are generally stratified on the basis of very few variables, such as age, sex, and disease status in phase II trials to keep the accrual goal low. Randomized phase III trials stratify patients on the basis of a large number of variables, which leads to less bias and more robust data. Because of the stratifications, the sample size required for phase III investigation is much higher than that of randomized phase II trials. The goal of randomized phase III trials is to demonstrate that the investigational treatment is more effective than the “gold standard” treatment. In general, phase III data are required for FDA approval. However, in select cases where there are robust data and unmet clinical needs, conditional approval can be granted on the basis of phase II data or interim phase III data. The FDA has a range of programs to speed up the approval process, including accelerated approvals and the recent “break through therapy” designation.9 There is a “short-cut” to FDA approval for agents that are based on already approved drugs. This pathway is called the 505(b)(2) pathway. The process of timeline for 505(b)(2) is much more abbreviated when compared to a typical approval process. For nanomedicine, this pathway will typically require that the exact nanoparticle platform is already approved with another agent and the drug being delivered by the nanoparticle is also approved. Past examples of this include the approval of liposomal bupivacaine with the DepoFoam liposome platform. The FDA was granted the authority to regulate medical devices in 1976.10 The approval process for medical devices is very different from that of drugs. First, for devices that predate May 28, 1976, these devices can remain on the market without needing approval. For the devices entering the market after that date, they are classified into different classes (I, II, and III) on the basis of their risks (Table 1).10 Class I devices are of low risk and are generally exempt from premarket notification (referred to as 510(k)) and may even be exempt from compliance with the good manufacturing practice requirement. Class II devices typically will require 510(k) submission before marketing. Class III devices are subject to the most stringent regulatory controls. Their approval will require a premarket approval (PMA) application. The 510(k) pathway is for devices that can be compared to existing, legally marketed “predicate” devices. The new device needs to be shown to be at least as safe and as effective as the “predicate” device. For devices that do not have a “predicate” device with which to compare, they are classified as class III and will need PMA. PMA needs to include scientific evidence that the device is safe and effective for its intended use. Unlike therapeutics where approvals generally require large randomized studies, scientific evidence for devices can include randomized controlled trials, single-arm studies, well-documented case series, and reports of significant human experience. For new devices that pose significant potential risks, an investigational device exemption (IDE) application is required prior to clinical investigation. Overall, the approval process is much simpler for devices than for therapeutics. Table 1 Summary of the FDA Device Regulation Processa In this Review, we will examine preclinical evidence, chosen clinical path to translation, and clinical data of clinically approved nanomedicine products. We will also discuss the clinical data on nanomedicines that are under clinical investigation or failed clinical translation. Each of these clinical nanomedicine products has a unique clinical translation story. By examining this body of evidence, we aim to formulate important concepts that are keys to nanomedicines clinical translation and to identify challenges. Such concepts will facilitate the translation of future nanomedicine products.

Combating the Drug Resistance of Cisplatin Using a Platinum Prodrug Based Delivery System

Platinum-based anticancer drugs are widely used in the clinic for the treatment of a broad spectrum of human malignancies. These drugs are administered to 40–80% of all patients undergoing cancer chemotherapy, either as single agents or in combination with other agents. However, their application is limited by the presence of side effects and drug resistance. Although some tumors are intrinsically resistant to platinumbased drugs, other tumors acquire resistance only after initial treatment. The sensitivity of cells toward platinum-based drugs, such as cisplatin, is dependent on DNA platination because DNA is the ultimate drug target of cisplatin. Tumor cells can acquire cisplatin resistance, that is, can achieve a reduction in the level of DNA platination, through several mechanisms, for example, through reduced drug uptake, through drug deactivation in cells, through DNA repair, and through increased drug efflux. Several cellular processes can be associated with sensitivity of cells toward cisplatin. The uptake of cisplatin into cells is facilitated by the copper transport protein (Ctr1), which is expressed in low levels in some cisplatin-resistant cells. Metallothionein (MT) is a thiol-rich protein that binds strongly to many heavy-metal ions, including platinum(II). MT plays a role in cellular detoxification by sequestering these heavy-metal compounds, and an increased concentration of this protein in cells is associated with low efficacy of cisplatin. The small peptide glutathione (GSH), which also has high affinity toward cisplatin and is found in increased concentrations in some cisplatin-resistant cells, can play a similar role. Additionally, DNA repair proteins (such as NER) and efflux proteins (such as P-type ATPases) can also reduce the efficacy of cisplatin and contribute to cisplatin resistance. To avoid the problems of resistance associated with the use of cisplatin, several types of nonclassical platinum complexes have been developed, including trans-coordinated complexes, polynuclear platinum complexes, and platinum(IV) complexes. These platinum complexes differ from cisplatin in their uptake pathway, their reactivity toward cellular proteins, and their DNA binding modes. Because of these differences, some of these nonclassical platinum complexes, such as trans-EE, BBR3464, and satraplatin, have shown promising activity in cisplatin-resistant cells. These findings suggest that the design of platinum-based drugs that have different responses to cellular processes is a feasible approach toward circumventing the problems of resistance that affect the use of cisplatin. Drug delivery systems have drawn particular attention in recent years because they can facilitate the delivery of platinum-based drugs, thus enhancing drug efficacy. A number of drug delivery systems have been developed for the delivery of platinum-based drugs. These systems have been based on polymers, solid lipids, and inorganic nanoparticles; the latter can be further subdivided into magnetic iron oxide, single-walled carbon nanotubes, metallofullerene nanoparticles, gold nanoparticles, nanoscale metal-organic frameworks, and mesoporous silica microparticles. [17] Some of these systems have entered clinical trials. With the conjugation of biologically active molecules, some delivery systems have shown high selectivity in targeting tumor cells. Although the use of drug-delivery systems has been successful in improving the efficacy of platinum-based drugs, it remains a challenge to develop drug conjugates that combat drug resistances. We have previously reported that PEGylated gold nanorods (PEG-GNRs) can facilitate the delivery of platinum(IV) prodrugs and significantly enhance the cytotoxicity of these prodrugs in tumor cells. Herein, we report that the use of this drug-delivery system avoids the drug resistance that affects the use of cisplatin. We show that impaired drug uptake that results from the low expression of Ctr1 in the cisplatin-resistant cells A549R can be overcome by using a conjugate of a cisplatin prodrug and PEGylated gold nanorods (Pt-PEG-GNRs conjugate); this conjugate facilitates the delivery of the platinum-based drug into cells through endocytosis. Additionally, the platinum(IV) prodrug is less susceptible to deactivation by the detoxification protein MT and the peptide GSH, which were found in high concentrations in A549R cells. Consequently, the Pt-PEGGNRs conjugate was highly cytotoxic to tumor cells, especially cisplatin-resistant cells. [*] Y. Min, S. Chen, G. Ma, Prof. Y. Liu CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry University of Science and Technology of China Hefei, Anhui, 230026 (China) E-mail: liuyz@ustc.edu.cn

The ligation of aspirin to cisplatin demonstrates significant synergistic effects on tumor cells

Asplatin, a fusion of aspirin and cisplatin, exhibits significant cytotoxicity in tumor cells and almost fully overcomes the drug resistance of cisplatin resistant cells. Asplatin is highly accumulated in cancer cells and is activated upon the reduction by ascorbic acid.

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Immunotherapy holds tremendous promise for improving cancer treatment1. Administering radiotherapy with immunotherapy has been shown to improve immune responses and can elicit an “abscopal effect”2. Unfortunately, response rates for this strategy remain low3. Herein, we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NPs formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent upon NP surface properties. We showed that AC-NPs deliver tumor specific proteins to antigen-presenting cells and significantly improve the efficacy of αPD-1 treatment using the B16F10 melanoma model, generating up to 20% cure rate as compared to 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+/Treg and CD8+/Treg ratios. Our work presents a novel strategy for improving cancer immunotherapy with nanotechnology.

Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles

Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter diblock copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to maximize therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn-coencapsulated NPs are more efficient than each single-drug-loaded NPs or a combination of both single-drug-loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus improve the therapeutic efficiency.

Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

Histone deacetylase inhibitors (HDACIs) represent a class of promising agents that can improve radiotherapy in cancer treatment. However, the full therapeutic potential of HDACIs as radiosensitizers has been restricted by limited efficacy in solid malignancies. In this study, we report the development of nanoparticle (NP) formulations of HDACIs that overcome these limitations, illustrating their utility to improve the therapeutic ratio of the clinically established first generation HDACI vorinostat and a novel second generation HDACI quisinostat. We demonstrate that NP HDACIs are potent radiosensitizers in vitro and are more effective as radiosensitizers than small molecule HDACIs in vivo using mouse xenograft models of colorectal and prostate carcinomas. We found that NP HDACIs enhance the response of tumor cells to radiation through the prolongation of γ-H2AX foci. Our work illustrates an effective method for improving cancer radiotherapy treatment.

Unexpected helicity control and helix inversion: homochiral helical nanotubes consisting of an achiral ligand

The ligand tppda has been designed and synthesized as molecular leverage for helicity control when reacted with Cd(2+) ions. The guests MeOH or DMF preferentially stabilize the P-helical isomer, while the guest H2O causes a helix inversion to give the M-helical isomer as the major isomer without any chiral auxiliary.

Chemical and cellular investigations of trans-ammine-pyridine-dichlorido-platinum(II), the likely metabolite of the antitumor active cis-diammine-pyridine-chorido-platinum(II)

It has been proposed that the well-studied monofunctional platinum complex cis-[PtCl(NH3)2(py)](+) (cDPCP) forms DNA adducts similar to those of the trans platinum complex trans-[PtCl2(NH3)(py)] (ampyplatin, py=pyridine). Thus this latter could be the active form of cDPCP. Detailed studies on the mechanism of ampyplatin action were performed in this work. Results indicate that ampyplatin has significantly higher antiproliferative activity than cDPCP and is comparable to cisplatin. Cellular uptake experiments indicate that ampyplatin can be efficiently accumulated in A549 cancer cells. Binding of ampyplatin to DNA mainly produces monofunctional adducts; remarkably, these adducts can be recognized by the HMGB1 protein. Kinetic studies on the reaction with GMP indicate that the reactivity of ampyplatin is much lower than that of transplatin and is more similar to that of trans-[PtCl2{E-HN=C(Me)OMe}2] (trans-EE), a widely investigated antitumor active trans-oriented platinum complex. In addition, the hydrolysis of ampyplatin is significantly suppressed, whereas the hydrolysis of the mono-GMP adduct is highly enhanced. These results indicate that the mechanism of ampyplatin differs not only from that of antitumor inactive transplatin but also from that of antitumor active trans-EE and this could account for the remarkable activity of parent cDPCP.

Nanomedicine approaches to improve cancer immunotherapy

Significant advances have been made in the field of cancer immunotherapy by orchestrating the bodys immune system to eradicate cancer cells. However, safety and efficacy concerns stemming from the systemic delivery of immunomodulatory compounds limits cancer immunotherapies expansion and application. In this context, nanotechnology presents a number of advantages, such as targeted delivery to immune cells, enhanced clinical outcomes, and reduced adverse events, which may aid in the delivery of cancer vaccines and immunomodulatory agents. With this in mind, a diverse range of nanomaterials with different physicochemical characteristics have been developed to stimulate the immune system and battle cancer. In this review, we will focus on some recent developments and the potential advantages of utilizing nanotechnology within the field of cancer immunotherapy. WIREs Nanomed Nanobiotechnol 2017, 9:e1456. doi: 10.1002/wnan.1456 For further resources related to this article, please visit the WIREs website.

Co-delivery of all-trans-retinoic acid enhances the anti-metastasis effect of albumin-bound paclitaxel nanoparticles

Co-delivery of all-trans-retinoic acid and paclitaxel using albumin-bound nanoparticles demonstrated a significantly improved anti-metastatic effect to breast cancer both in vitro and in vivo. Notably, the co-delivery nanoparticles exhibited more pronounced therapeutic effects than the combination of two free drugs or two HSA loaded single drugs.