Small Molecular Weight Drugs Research Articles

Abstract PL04-02: Ras and Raf signaling: From biology to therapeutics

Abstract The protein kinase BRAF is mutated in about 50% of human melanomas and the small G-protein NRAS is mutated in another 20% of cases. We have developed mouse models of melanoma driven by oncogenic BRAF, NRAS and KRAS. These studies have established that acquisition of BRAF, NRAS or KRAS mutations can be founder events in melanomagenesis and we are currently using these models to investigate gene-gene and gene-environment interactions in cutaneous melanoma. We are also investigating other targets of BRAF in melanoma cells and have shown that BRAF drives melanoma cell migration and invasion by down-regulating expression of the cyclic GMP phosphodiesterase PDE5A. 2011 was a landmark year in melanoma research with the registration of vemurafenib and ipilimumab, drugs that show clinical benefit in patients with advanced disease. Critically, BRAF inhibitory drugs achieve objective clinical responses in about 80% of melanomas that harbour mutations in BRAF. Surprisingly however, these drugs also drive paradoxical activation of CRAF in melanoma cells that harbour mutations in NRAS, or in cells in which RAS is activated due to increased upstream signalling. This is due to the induction of BRAF/CRAF heterodimers and CRAF homodimers and importantly, activation of the pathway by this paradox can drive tumourigenesis in some circumstances. We have used a two-stage skin carcinogenesis model to show that BRAF inhibitors are not tumour promoters pre se, but rather that they work by accelerating the growth of tumours carrying pre-existing mutations in HRAS. Thus, we conclude that BRAF inhibitors appear to accelerate the inevitable in susceptible patients, but do not induce these lesions de novo. Notably, concurrent administration of a MEK inhibitor with a BRAF drug blocks the development of these skin lesions, providing a rationale for combining BRAF and MEK inhibitors in melanoma patients. Unexpectedly, we have also found that the ABL/CKIT inhibitor nilotinib also drives paradoxical activation of the RAF pathway because it possesses weak off-target activity against BRAF and CRAF. The consequence of this paradoxical activation is that nilotinib provides a survival advantage to chronic myeloid leukaemia (CML) cells that are resistant to nilotinib, but also provides an Achilles heel to these cells because they become dependent on MEK signalling in the presence of nilotinib. Thus, MEK inhibitors cooperate with nilotinib to drive synthetic lethality in nilotinib-resistant CML cells. Thus, paradoxical activation of the RAF proteins by small molecular weight drugs can have important consequences to patient responses, creating specific clinical problems in some circumstances, but therapeutic opportunities in others. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr PL04-02. doi:1538-7445.AM2012-PL04-02

Hollow Gold Nanoshells for Near Infra Red Cell by Cell Treatment

The temporal and spatial control over the delivery of materials such as siRNA or small molecular weight drugs into specific cells remains a significant technical challenge. We demonstrate the pulsed near-infrared (NIR) laser dependent release of siRNA or the chemotherapy drugs cisplatin and doxorubicin via the thermo-mechanical influence of 40 nm hollow gold nanoshells (HGN). Ligand-receptor interactions promote the cellular uptake of HGNs in targeted cells, resulting in HGN clusters within endosomes in the targeted cells. Non-targeted cells take up individual HGNs or no HGNs. The spatiotemporal silencing of a reporter gene (green fluorescence protein) was studied using photomasking to selectively irradiate targeted cells with NIR light to release chemically bound siRNA and rupture endosomes. GFP silencing followed siRNA release to the cytoplasm in NIR irradiated cells. The NIR laser induced release of siRNA from the nanoshells is found to be power and time dependent, through surface-linker bond cleavage, while the escape of the siRNA from endosomes occurs above a critical pulse energy attributed to local heating and nanobubble formation and collapse (cavitation). The same HGN could be used to selectively increase the permeability of multi-drug resistant cancer cells to doxorubicin or cisplatin to enhance the efficacy and selectivity of conventional chemotherapy. NIR induced nanobubbles enhanced the chemotherapeutic efficacy of liposome encapsulated doxorubicin (Doxil™) 33 times, allowing a reduction in drug dose by an order of magnitude while reducing non-specific toxicity to 15% (from 100%) among normal cells in a model of drug resistant oral cavity squamous cell carcinoma.

Bioethical issues in the development of biopharmaceuticals

Development of biopharmaceuticals is a challenging issue in bioethics. Unlike conventional, small molecular weight drugs, biopharmaceuticals are proteins derived from DNA technology and hybrid techniques with complex three dimensional structures. Immunogenicity of biopharmaceuticals should always be tested in clinical settings due to low predictive value of preclinical animal models. However, non-human primates (NHP) and transgenic mice could be used to address certain aspects of immunogenicity. Substantial efforts have been made to reduce NHP use in biopharmaceutical drug development, e.g. study design improvements and changes in regulatory policy. In addition, several expert groups are active in this field (e.g. NC3Rs, BioSafe, and Biopharmaceutical Technical Group). Despite that, there is an increasing trend of use of NHP in preclinical safety testing of biopharmaceuticals, especially regarding monoclonal antibodies. Other potential bioethical issues related biopharmaceutical drug development are their cost/effectiveness ratio, clinical safety assessment, production of biosimilars, and comparison of their efficacy with placebo in countries without intention to market. Identification of the human genome has opened many new bioethical issues. Development of biopharmaceuticals is an important bioethical issue for several reasons. It connects all aspects of contemporary bioethics: bio?medicine (e.g. clinical trials in vulnerable subjects), animal welfare and the most recent ad?vances in biotechnology. In particular, biopharmaceutical drug development is a challenging issue regarding treatment of rare diseases.

Supercritical fluid-mediated Methods to Encapsulate Drugs: Recent Advances and New Opportunities

With the advent of the development of novel pharmaceutical products and therapies, there is a need for effective delivery of these products to patients. Dependent on whether they are small-molecular weight drugs or biologics, many new compounds may suffer from poor solubility, poor stability or require frequent administration and therefore require optimized delivery. For example, the utilization of polymorphism and the enhanced solubility in the amorphous state is being exploited to improve the dissolution of small-molecular weight poorly soluble drugs. This can be achieved by the formation of solid dispersions in water-soluble matrices. In addition, encapsulation in biodegradable polymeric materials is one potential route to reduce the frequency of administration through the formation of sustained-release formulations. This is desirable for biologics, for example, which generally require administration once or twice daily. Supercritical fluid processing can achieve both of these outcomes, and this review focuses on the use of supercritical CO2 to encapsulate active pharmaceutical ingredients to enhance solubility or achieve sustained release. Using supercritical CO2-mediated processes provides a clean and potentially solvent-free route to prepare novel drug products and is therefore an attractive alternative to conventional manufacturing technologies.

Experimental characterization of dye-loaded echogenic liposomes

Liposomes are submicron sized vesicles with a lipid bilayer encapsulating an aqueous phase inside. Due to their favorable properties like longer circulation time, lesser toxicity, and greater uptake, they are a prime candidate for drug delivery. Recently, they are being specially prepared so as to encapsulate air, making them good scatterers of ultrasound wave. These echogenic liposomes, therefore, can be used both for ultrasound contrast imaging and drug delivery. We will report in vitro attenuation and scattering measurement from echogenic liposomes loaded with carboxyfluorescein (used as a surrogate for small molecular weight drugs). The results will be compared with non-dye-loaded ones. Effects of dye loading and presence of bovine serum albumin (BSA) on size distribution, echogenicity, and release characteristics will also be discussed.

Inducible and reversible breaching of the blood brain barrier by RNAi

Sequence-specific knockdown of gene expression is a goal that has been long sought by both basic and clinical investigators. In this regard, the discovery of RNA interference (RNAi) in Caenorhabditis elegans was immediately recognized as a potential breakthrough for studying gene function (Fire et al, 1998). These findings demonstrated that double-stranded (ds)RNAs are triggers for sequence-specific, post-transcriptional gene silencing via targeted degradation of messenger RNAs harbouring a complementary sequence to one of the two strands. Initially, it was thought that such post-transcriptional regulation of gene expression could not be achieved in mammalian systems due to the strong induction of interferon by dsRNAs. This potential restriction was short lived with the demonstration that endonuclease processed dsRNAs of 21–25 nucleotides in length, designated small interfering RNAs (siRNAs), were able to elicit sequence-specific degradation of mRNAs in mammalian cells without triggering interferon responses (Elbashir et al, 2001). These findings provided a huge impetus to develop RNAi as a therapeutic modality. The dream to selectively block the expression of deleterious proteins and treat formerly non-drugable diseases led to the rapid establishment of new biotech companies and branches of major pharmaceutical companies devoted to RNAi therapeutics.

Formulation Strategies for Sustained Release of Proteins

Proteins constitute an increasing proportion of the drugs in development. The barriers to their entry into the blood stream and rapid clearance means that they often have to be injected several times a day, affecting patient compliance. This paper reviews the major technologies enabling the development of injectable sustained-release products and formulation strategies to maintain protein integrity and modify release rates. Whilst many injectable sustained-release products are on the market, these are all delivering small molecular weight drugs and peptides. This is due to the manufacturing processes that denature and degrade the proteins upon encapsulation and release into the body. Formulation strategies are discussed and a number of new technologies reviewed that are able to overcome the issues with conventional manufacturing processes. The reliance of many processes on organic solvents has prevented their application to the development of injectable sustained release protein products. The development of entirely solvent free and aqueous methods of manufacture of these products has meant that numerous sustained-release protein products are close to reaching the market.

PAMAM-camptothecin conjugate inhibits proliferation and induces nuclear fragmentation in colorectal carcinoma cells.

To synthesize and characterize a poly (amido amine) dendrimer-camptothecin (PAMAM-CPT) conjugate and evaluate its activity on human colorectal carcinoma cells (HCT-116). The attachment of CPT to amine-terminated PAMAM was facilitated through a succinic acid-glycine linker. The conjugate was characterized for absence of small molecular weight impurities, size and drug content. Stability of the conjugate in PBS and growth media and its in vitro activity on HCT-116 were studied. Cell cycle arrest and nuclear fragmentation upon PAMAM-CPT treatment were investigated. The conjugate was stable under physiological pH (7.4) in PBS and in growth media (with 10% FBS) with minimal release of 4% and 6% drug, respectively, at 48 h. PAMAM-CPT inhibited proliferation of HCT-116 cells with an IC50 value of 1.6 ± 0.3 µM. The conjugate induced signs of cell cycle arrest with up to 68% of cells blocked in the G(2) phase. Confocal images of cells treated with PAMAM-CPT suggest nuclear fragmentation and formation of apoptotic bodies. Results show that the PAMAM-CPT conjugate was active against colorectal cancer cells in vitro, inhibiting their growth and inducing nuclear fragmentation. Coupled with the ability to target macromolecular therapeutics to tumors, this conjugate shows promise for cancer chemotherapy.

Abstract 5219: Relationship between intratumoral drug distribution and tumor microenvironment

Abstract Purpose: Anticancer agents released from nanocarriers have to reach cancer cells in order to demonstrate their cytotoxic activity. The distribution pattern of anticancer agents can be affected by the tumor microenvironment which varies among different types of tumors. The purpose of this study is to delineate the relationship between drug transport and tumor microenvironmental factors, such as extracellular matrix (ECM) integrity. Such studies provide insight into the factors that hinder the accessibility of cargo molecules to cancer cells. Hypothesis: In tumors with a “permissive” ECM, small molecules are likely to diffuse farther after release from nanocarriers, while they are likely to be hindered in the tumors with denser ECM. Non-invasive monitoring of drug release and subsequent intratumoral distribution of the released drug can be visualized using a dual MR contrast technique capable of distinguishing between released and intact molecules in vivo. Methods: GdDTPA was used as a surrogate tracer for a water-soluble, small molecular-weight drug. Liposomes were used as the model nanocarrier in this study. Xenografts derived from the highly-invasive and metastatic MDA-MB-231 human breast carcinoma cell line, and weakly-metastatic MCF-7 human breast carcinoma cells were used. Liposomes encapsulating GdDTPA, iron particles, and rhodamine (Lip-Gd/Fe/Rho) were prepared using a sonication method, followed by extrusion. Orthotopic xenografts were grown in female SCID mice by injecting 3×106 of cancer cells into the mammary fat pad of the animal. All MR studies were carried out on a horizontal bore Bruker Biospec 9.4T spectrometer. MR images were acquired before, 30 min, and 23 hrs post-i.v. administration of Lip-Gd/Fe/Rho. To identify iron particles, a 3D fast low-angle shot (FLASH) sequence was used, while a 3D fast spin echo (RARE: Rapid Acquisition with Relaxation Enhancement) sequence with an effective echo time of 50 ms and five different repetition times was acquired to track GdDTPA released from liposomes. After completion of the MRI study, tumors were excised, fixed and were cut into 10μm sections for imaging with second harmonic generation multiphoton microscopy. Region of interest analysis were carried out on the MRI data. Results/Discussion: In vivo MRI results demonstrated that a decrease in T1 of the tumors was observed following i.v. administration of the Lip-Gd/Fe/Rho, indicating successful delivery and degradation of liposomes in the tumor. The comparison of differences in liposome delivery and its correlation with collagen-I density in the ECM of MDA-MB-231 and MCF-7 tumors is currently underway. Our results demonstrate the feasibility if using complementary imaging techniques to characterize the factors affecting intratumoral distribution of drug molecules after a release from nanocarriers. Acknowledgment: Supported by NIH grant R21 EB008162 (YK). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5219.

Drug Delivery Systems for Intraperitoneal Therapy

Disorders associated with the peritoneal cavity include peritoneal adhesions and intraperitoneal (IP) malignancies. To prevent peritoneal adhesions, physical barrier devices are used to prevent organs from contacting other structures in the abdomen and forming adhesions, or pharmacological agents that interfere with adhesion formation are administered intraperitoneally. IP malignancies are other disorders confined to the peritoneal cavity, which are treated by combination of surgical removal and chemotherapy of the residual tumor. IP drug delivery helps in the regional therapy of these disorders by providing relatively high concentration and longer half-life of a drug in the peritoneal cavity. Various studies suggest that IP delivery of anti-neoplastic agents is a promising approach for malignancies in the peritoneal cavity compared to the systemic administration. However, IP drug delivery faces several challenges, such as premature clearance of a small molecular weight drug from the peritoneal cavity, lack of target specificity, and poor drug penetration into the target tissues. Previous studies have proposed the use of micro/nanoparticles and/or hydrogel-based systems for prolonging the drug residence time in the peritoneal cavity. This commentary discusses the currently used IP drug delivery systems either clinically or experimentally and the remaining challenges in IP drug delivery for future development.

Self-Assembled Hydrogel Nanoparticles for Drug Delivery Applications

Hydrogel nanoparticles—also referred to as polymeric nanogels or macromolecular micelles—are emerging as promising drug carriers for therapeutic applications. These nanostructures hold versatility and properties suitable for the delivery of bioactive molecules, namely of biopharmaceuticals. This article reviews the latest developments in the use of self-assembled polymeric nanogels for drug delivery applications, including small molecular weight drugs, proteins, peptides, oligosaccharides, vaccines and nucleic acids. The materials and techniques used in the development of self-assembling nanogels are also described.

Effect of physicochemical properties on intranasal nanoparticle transit into murine olfactory epithelium

Small molecular weight drugs, peptides, and nanoparticles have previously been shown to localize in the central nervous system after intraneural administration. A basic understanding of direct nose-to-brain drug delivery, particularly for nanoparticles with different physicochemical characteristics, remains unclear. In this study, fluorescence microscopy and stereology were used to track intranasally administered chitosan-coated polystyrene (C-PS) or polysorbate-coated polystyrene (P80-PS) nanoparticles (100 nm or 200 nm in diameter) in olfactory and respiratory nasal epithelia and olfactory bulbs in mice. Chitosan coating caused particles to adhere to the extracellular mucus which could provide useful modality for paracellular drug transport. Nanoparticle transport was exclusively transcellular. None of the nanoparticle formulations showed preference for uptake into olfactory axons over other nasal epithelial cells. Both 100 nm PS and 100 nm P80-PS were observed in olfactory epithelial cells but were absent from the olfactory bulbs; therefore, it is speculated that an optimal nanoparticle diameter for axonal transport is <100 nm in mice.

Gene Modulation for Treating Liver Fibrosis

Despite tremendous progress in our understanding of fibrogenesis, injury stimuli process, inflammation, and hepatic stellate cell (HSC) activation, there is still no standard treatment for liver fibrosis. Delivery of small molecular weight drugs, proteins, and nucleic acids to specific liver cell types remains a challenge due to the overexpression of extracellular matrix (ECM) and consequent closure of sinusoidal gaps. In addition, activation of HSCs and subsequent release of inflammatory cytokines and infiltration of immune cells are other major obstacles to the treatment of liver fibrosis. To overcome these barriers, different therapeutic approaches are being investigated. Among them, the modulation of certain aberrant protein production is quite promising for treating liver fibrosis. In this review, we describe the mechanism of antisense, antigene, and RNA interference (RNAi) therapies and discuss how the backbone modification of oligonucleotides affects their in vivo stability, biodistribution, and bioactivity. Strategies for delivering these nucleic acids to specific cell types are discussed. This review critically addresses various insights developed with each individual strategy and for multipronged approaches, which will be helpful in achieving more effective outcomes.

Formulation and Physiological Factors Influencing CNS Delivery upon Intranasal Administration

The treatment of central nervous system (CNS) disorders is particularly challenging because of a variety of formidable barriers to effective and persistent delivery of therapeutic compounds. This review discusses the potential of intranasal drug administration as a means to bypass a major barrier, the blood-brain barrier, and allow for direct delivery of drugs into the CNS. The article emphasizes physicochemical properties of intranasal drug formulations as well as relevant anatomical and physiological factors in intranasal delivery of drugs for CNS therapy. Published examples of intranasal administration of small molecular weight drugs, peptides and proteins, and novel formulations for delivering a broad spectrum of molecules are discussed. Finally, the article provides several strategies for effectively enhancing nose-to-brain transport of drug molecules through rational formulation design and optimization.

Block copolymer micelles as delivery vehicles of hydrophobic drugs: Micelle–cell interactions

One-third of drugs in development are water insoluble and one-half fail in trials because of poor pharmacokinetics. Block copolymer micelles are nanosized particles that can solubilize hydrophobic drugs and alter their kinetics in vitro and in vivo. However, block copolymer micelles are not solely passive drug containers that simply solubilize hydrophobic drugs; cells internalize micelles. To facilitate the development of advanced, controlled, micellar drug delivery vehicles, we have to understand the fate of micelles and micelle-incorporated drugs in cells and in vivo. With micelle-based drug formulations recently reaching clinical trials, the impetus for answers is ever so strong and detailed studies of interactions of micelles and cells are starting to emerge. Most notably, the question arises: Is the internalization of block copolymer micelles carrying small molecular weight drugs an undesired side effect or a useful means of improving the effectiveness of the incorporated drugs?

Pluronic-g-poly(acrylic acid) copolymers as novel excipients for site specific, sustained release tablets

Potential utility of copolymers comprising Pluronic ® (PEO–PPO–PEO) surfactants covalently conjugated with poly(acrylic acid) (PAA) as excipients for sustained-release tablets was explored. Apparent particle density, particle size distribution, Carr index, thermal stability, and compression behavior of the Pluronic–PAA copolymers were characterized. Tablets prepared by direct compression of blends of Pluronic–PAA copolymers were evaluated on the basis of their thermomechanical profile, crushing strength, friability, and drug release properties. Small molecular weight drugs of aqueous solubility decreasing in the order theophylline > hydrochlorothiazide > nitrofurantoin were incorporated to the tablets. For comparison purposes, tablets were also prepared from PAA of Carbopol ® 71G (C71G), and mixtures of C71G and Pluronic ® F127, with each of the above three drugs. The Pluronic–PAA aggregates are stabilized by hydrophobic associations between poly(propylene oxide) (PPO) segments in aqueous solutions, and thus require higher ionization of the carboxylic groups to overcome the associations and swell. The swelling pattern of the Pluronic–PAA copolymers is more dramatically pH-dependent than that of Carbopol lacking any hydrophobic associations. The drug retention in and release from the Pluronic–PAA based tablets is profoundly pH-dependent and hence specific to the pH exceeding that of the p K a > 5 of these copolymers. Theophylline- and hydrochlorotiazide-containing tablets made with Pluronic–PAA copolymers showed a reduced release rate under acidic conditions compared to the neutral or alkaline conditions, while the opposite pattern was observed with the Carbopol-based tablets due to the different pH-dependent swelling behavior of the polymers. Nitrofurantoin-containing tablets showed a remarkably low drug release rate owing to the strong hydrophobic character of nitrofurantoin and of its complexes with the copolymers. Integrity of the nitrofurantoin-containing tablets was maintained during the 24 h release test. Zero-order kinetics of the cumulative release profile of all drugs under study was observed with the Pluronic–PAA as a tablet excipient. Adequate mechanical properties, the self-assembling behavior, and the pH-sensitiveness of the Pluronic–PAA copolymers make them promising excipients for tablets with preferential delivery into a neutral to alkaline pH environment.

Progressive Transforming Growth Factor β1–induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor

Pulmonary fibrosis is characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function and respiratory failure. Idiopathic pulmonary fibrosis (IPF) is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta (TGF-beta) is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases (ALK). We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of ALK5, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.

Pre-clinical methods for detecting the hypersensitivity potential of pharmaceuticals: regulatory considerations

Immune-based systemic hypersensitivities account for a significant number of adverse drug reactions. There appear to be no adequate nonclinical models to predict systemic hypersensitivity to small molecular weight drugs. Although there are very good methods for detecting drugs that can induce contact sensitization, these have not been successfully adapted for prediction of systemic hypersensitivity. Several factors have made the development of adequate models difficult. The term systemic hypersensitivity encompases many discrete immunopathologies. Each type of immunopathology presumably is the result of a specific cluster of immunologic and biochemical phenomena. Certainly other factors, such as genetic predisposition, metabolic idiosyncrasies, and concomitant diseases, further complicate the problem. Therefore, it may be difficult to find common mechanisms upon which to construct adequate models to predict specific types of systemic hypersensitivity reactions. There is some reason to hope, however, that adequate methods could be developed for at least identifying drugs that have the potential to produce signs indicative of a general hazard for immune-based reactions.

The Ascent of Pulmonary Drug Delivery

The origins of inhalation therapy can be traced back to the early civilizations but this route of administration was relatively uncommon until recently. Direct delivery of drugs to the lung by inhalation for the treatment of respiratory disease grew rapidly in the second half of the 20th century as a result of the availability of effective asthma drugs in convenient, portable delivery systems. In the search for non‐invasive delivery of biologics, it was discovered that the large highly absorptive surface area of the lung could be used for systemic delivery of proteins such as insulin. New delivery systems with efficiency and reproducibility to match the high cost and therapeutic constraints of biologics are currently in late stage clinical trials. Even small molecular weight drugs previously administered by injection are tested via the inhalation route either to provide non‐invasively rapid onset of action, or to improve the therapeutic ratio for drugs acting in the lung. Gene therapy of pulmonary disease is still in its infancy but could provide valuable solutions to currently unmet medical needs. The beginning of the new millennium is therefore likely to witness development of many valuable therapeutic products delivered by inhalation. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 940–945, 2000

Enhancing the uptake of chemotherapeutic drugs into tumors using an "artificial lymphatic system".

This paper presents findings from uptake studies to evaluate the ability of an "artificial lymphatic system" (ALS) to enhance large and small molecular weight drug transport into solid tumors and the therapeutic effect of the additional drug on their growth. These studies also served to test the effectiveness of an implantable multidrain ALS. Walker 256, Neuroblastoma, and Sarcoma dual-tumor models were used to evaluate the effect of ALS aspiration on the uptake of 3F8 monoclonal antibody, and doxorubicin. A tumor shrinkage experiment using Walker 256 dual tumors was used to evaluate the efficacy of an implantable ALS with cyclophosphamide chemotherapy. Drug uptake significantly increased in all aspirated tumors; 3F8 uptake was enhanced 37.4% in the Walker and 93.1% in the Neuroblastoma tumor lines (p<0.05). Doxorubicin uptake increased 23.2% in Sarcoma tumor (p<0.05). The shrinkage study demonstrated that one-drain aspirated tumors shrank 90% faster (p<0.01) than control tumors, while three-drain aspirated tumors shrank 123% faster than control tumors (p<0.01).