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Mucin, a glycosylated protein, is aberrantly overexpressed in a variety of tumor cells. The glycoprotein mesh decreases the rate of intracellular drug uptake and effectiveness. We investigated the influence of the mucin mesh on the cellular uptake of anti-MUC1 antibody and nanoparticles by fluorescence spectroscopy and microscopy. A glycosylation inhibitor (benzyl-α-GalNAc) was employed to regulate mucin glycosylation events. In our panel of pancreatic cell lines, only PANC-1 cells exhibited a significant increase in the uptake of liposomes following glycosylation inhibition, resulting in improved cytotoxicity of gemcitabine-loaded liposomes. Interestingly, areas devoid of liposome uptake were observed for pancreatic cancer cell lines PANC-1, Capan-1, and Capan-2; however, these restricted regions could be diminished for PANC1 cells only. In conclusion, investigating the reason(s) for differential cellular uptake of nanoparticles, in association with the production of mucin glycosylation mesh, should provide valuable leads to the future development of nanomedicine for cancer treatment.

Nanotechnology has brought about the advent of personalized medicine in the era of targeted therapeutic strategies for cancer therapy. The ability to exploit tumor features for therapeutic gain has made it possible to manufacture more effective nanomedicines for cancer treatment. However, known obstacles, including the inability to overcome pathophysiological barriers of tumors, have impeded disease management. In spite of this, recent efforts have been made to develop more functionalized nanosystems that utilize the active-targeting approach. This article reviews the FDA-approved cancer drug delivery systems in the general framework of personalized nanomedicine. We discuss the latest efforts in the development of functionalized nano-systems, and summarize relevant ongoing preclinical and clinical trials.

Background: Liposome-encapsulated doxorubicin has proven to be an effective drug delivery method to cancer cells. Lipid extracts derived from human prostate cancer cells along with conventional components were employed to develop cell membrane lipid-extracted nanoliposomes (CLENs) for prostate cancer treatment. In an effort to balance efficiency of drug loading with cellular targeting efficiency we report on physicochemical characteristics (i.e., particle size, zeta potential, drug loading efficiency) and cellular uptake studies. Methods: Five preparations of CLENS were prepared consisting of variable concentrations of DOPC and CRL-1740 lipid extract material varying as a function of optimized fixed ratios of conventional components (Cholesterol and DSPE-PEG5000). The controls used to investigate the effect of the different components on drug incorporation efficiency were preparations of DOPC (100%) and CRL-1740 (100%). Doxorubicin hydrochloride (5 mol%) was employed during the preparation of all formulations. Samples were readily prepared by thin film evaporation. For cellular uptake studies CRL-1740 cells were seeded at 1 x 104 mL in 48-well plate and incubated for 24 hours prior to use. The cells were next exposed to various amounts of rhodamine labeled CLENS for 24 hrs. Cellular uptake was determined using fluorescence intensity values determined by a fluorescence microplate reader. Fluorescence microscopy supplement cellular uptake studies. Results: The DOPC drug-loaded liposome preparation consistently achieved the lowest percent of drug incorporation. Likewise, 100% CRL-1740 CLENs demonstrated a significant degree of formulation instability, resulting in a relatively low percent of drug incorporation compared to preparations that consisted of lipid extract and conventional components. The finding were supported by values determined for zeta potential and particle size. Cellular uptake studies also favored the preparations that consisted of lipid extract material and conventional components compared to each alone. The results collectively support the importance of balancing lipid extract material derived from prostate cancer target cells with cholesterol and DSPE-PEG5000 for formulation development and cellular uptake. Conclusion: We formulated seven preparations of CLENS as part of the drug platform. The most promising candidates were determined following completion of the study. Future studies should evaluate the cytotoxicity and safety profile of the most promising formulations vivo. Citation Format: Abubker Omaer, Ali Alqarni, Carlos Randulfe, Hanan Alharbi, Robert Campbell. Formulating a cell membrane lipid-extracted nanoliposome (CLENS) drug platform for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3881.

Mucins are high molecular weight glycoproteins expressed on the apical surface of normal epithelial cells. In cancer disease mucins are overexpressed on the entire cellular surface. Overexpression of MUC1 mucin in pancreatic tumours has been correlated with poor patient survival. Current chemotherapeutic approaches such as 5-fluorouracil (5-FU) has produced limited clinical success. In this study we investigated the role of mucin in cytotoxic drug treatment to determine whether the extracellular domain of mucin impedes cytotoxic drug action of 5-FU. Human pancreatic cancer cells revealed high and relatively moderate MUC1 levels for Capan-1 and HPAF-II, respectively, compared to MUC1 negative control (U-87 MG glioblastoma) that showed relatively non-specific anti-MUC1 uptake. Benzyl-alpha-GalNAc (O-glycosylation inhibitor) was used to reduce mucin on cell surfaces, and neuraminidase was used to hydrolyse sialic acid at the distal end of carbohydrate chains. Benzyl-alpha-GalNAc had no effect on cell morphology or proliferation at the concentrations employed. The inhibition of O-glycosylation resulted in significant 5-FU antiproliferative activity against Capan-1 and HPAF-II, but not against U-87 MG. However, the exposure of cells to neuraminidase failed to improve the cytotoxic action of 5-FU. Our experimental findings suggest that the overexpression of mucin produced by human pancreatic tumours might limit the effectiveness of chemotherapy.

Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors.

Paclitaxel (taxol) is a poorly soluble anticancer agent that is in widespread clinical use. Liposomes provide a less toxic vehicle for solubilizing the drug and increasing the therapeutic index of paclitaxel in model tumor systems. The role of liposome membrane composition in the stability of paclitaxel-containing formulations is understood partially for neutral and anionic liposomes, but poorly for other compositions. We investigated the effect of dialkyl cationic lipids on the stability and physical properties of paclitaxel-containing liposomes, using circular dichroism (CD), fluorescence spectroscopy, and differential interference contrast microscopy (DIC). DOTAP (1,2-dioleoyl-3-trimethylammonium propane), a cationic lipid used frequently for gene delivery, was combined at various ratios with dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or distearoylphosphatidylcholine (DSPC). In the absence of DOTAP, the stability of liposomes containing > or =3 mol% paclitaxel was observed to follow the following rank order: DPPC >DSPC > DMPC. Increasing concentrations of DOTAP increased the physical stability of all compositions, and maximal stabilization was achieved at 30-50 mol% DOTAP, depending on the paclitaxel concentration and the acyl chain length of the phosphatidylcholine. The relationship between stability and mole fraction of DOTAP was complex for some compositions. DOTAP exerted a major fluidizing effect on DMPC, DPPC, and DSPC membranes, and the addition of paclitaxel at 3-8 mol% did not increase fluidity further. Studies of membrane phase domain behavior using the probe Laurdan (6-dodecanoyl-2-dimethylaminonaphthalene) indicated that both paclitaxel and DOTAP were miscible with the phosphatidylcholine phase. The physical events leading to destabilization of formulations are hypothesized to arise from concentration-dependent paclitaxel self-association rather than immiscibility of the membrane lipids. Given the increased incorporation and stability of paclitaxel in DOTAP-containing membranes and the potential for enhanced interaction with cells, cationic liposomes may provide a therapeutic advantage over previously described liposome formulations.

Liposomes composed of synthetic dialkyl cationic lipids and zwitterionic phospholipids such as dioleoylphosphatidylethanolamine have been studied extensively as vehicles for gene delivery, but the broader potentials of these cationic liposomes for drug delivery have not. An understanding of phospholipid-cationic lipid interactions is essential for rational development of this potential. We evaluated the effect of the cationic lipid DOTAP (N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium) on liposome physical properties such as size and membrane domain structure. DSC (differential scanning calorimetry) showed progressive decrease and broadening of the phase transition temperature of dipalmitoylphosphatidylcholine (DPPC) with increasing fraction of DOTAP, in the range of 0.4–20 mol%. Laurdan (6-dodecanolyldimethylamino-naphthalene), a fluorescent probe of membrane domain structure, showed that DOTAP and DPPC remained miscible at all ratios tested. DOTAP reduced the size of spontaneously-forming PC-containing liposomes, regardless of the acyl chain length and degree of saturation. The anionic lipid DOPG (dioleoylphosphatidylglycerol) had similar effects on DPPC membrane fluidity and size. However, DOTAP/DOPC (50/50) vesicles were taken up avidly by OVCAR-3 human ovarian tumor cells, in contrast to DOPG/DOPC (50/50) liposomes. Overall, DOTAP exerts potent effects on bilayer physical properties, and may provide advantages for drug delivery.

Aims: The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. Materials & methods: MCLs (with incorporated high SPION cargo) were administered to a severe combined immunodeficiency mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre- and post-injection magnetic resonance (MR) images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by 111In-labeled MCLs and the amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations. Results: We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. Conclusion: MR and biodistribution analysis clearly show the efficacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.

Aims: Cationic liposomes have been shown to preferentially target the tumor vasculature, but not uniformly. Bevacizumab antibody selectively accumulates in tumors expressing VEGF. We thus developed bevacizumab-modified, pegylated cationic liposomes (PCLs) to improve the distribution of liposomes along tumor vessels, and to enhance tumor targeting. Materials & methods: We evaluated the delivery vehicle both in the absence and presence of VEGF, using human pancreatic cancer (Capan-1, HPAF-II and PANC-1) and endothelial (MS1-VEGF and HMEC-1) cell lines. Results: All cell lines except for HMEC-1 secreted VEGF. Modification of PCLs with bevacizumab did not alter ζ-potential, but increased overall liposome size. The toxicity profile for bevacizumab-modified PCLs was cell line dependent and, in general, bevacizumab improved cellular uptake and tumor targeting of PCLs. Conclusion: Bevacizumab-modified PCLs represent a potential improvement over the unmodified variety, supporting their future development for the treatment of cancer.

Using cationic liposomes to deliver cytotoxic molecules to the tumor microvasculature is currently being developed for the treatment of cancer and other angiogenesis-related diseases. To improve on their beneficial properties, the authors have examined whether the particular cationic lipid type and lipid content employed are important factors influencing cellular interactions and formulation effects. The authors prepared different PEG (polyethylene glycol)-modified cationic liposomes (PCLs) with varying percent cationic lipid content and lipid type, and evaluated liposome size, surface charge (zeta) potential, and cellular properties in vitro. The cell lines used were human umbilical vein (HUVEC), lung microvascular (HMVEC-L and HPVE-26), coronary microvascular (HMVEC-C), dermal microvascular (HMVEC-D), and immortalized dermal microvascular (HMEC-1) endothelial cells. In vitro experiments consisted of cellular uptake and cytotoxicity studies, fluorescence-activated cell sorting (FACS) analysis, fluorescence, and transmission electron microscopic analysis. Liposome size and zeta potential analysis of five different PCLs revealed significant differences in their physicochemical properties. Some cationic lipids formed relatively toxic liposomes compared to others. The efficiency of loading chemotherapeutic drugs (doxorubicin hydrochloride, etoposide), affinity of PCLs for endothelial cells, and formulation effects varied according to cationic lipid content and the lipid type. Cellular uptake was observed in lung, dermal, and coronary endothelial cells. Heparan sulfate proteoglycans were found present on HMEC-1 cells, which may have enabled PCL uptake. In conclusion, physicochemical properties of cationic liposomes and their ability to interact with endothelial cells are important factors to consider during the early stages of formulation development for the treatment of cancer and other angiogenesis-dependent diseases.

Chemotherapy is a popular treatment approach against cancer but significant uptake of drugs by normal tissues is still a major limitation. Magnetic drug targeting (MDT) has been used to improve localized drug delivery to interstitial tumor targets. MDT is now being developed to improve drug delivery to tumor vessels. We thus seek to understand the role of magnetite (MAG-C) in drug loading, influence on cytotoxicity and vascular targeting characteristics. The inclusion of MAG-C at lower concentrations (0.5 mg/ml) in cationic liposomes did not alter the efficiency of loading etoposide, but at higher concentrations (2.5 mg/ml) incorporation decreased from 80±3.4% to 44±4.26%. MAG-C reduced the incorporation of dacarbazine. The incorporation was significantly lower compared to liposomal etoposide, both in the presence and absence of MAG-C. The incorporation efficiency of vinblastine sulfate in cationic liposomes was similar for low and relatively high MAG-C content; values for incorporation were 21±0.11 and 23±2, respectively. Polyethylene-glycol improved the efficiency of loading chemotherapeutic agents regardless of drug type. Additionally, cytotoxicity and tumor vascular targeting characteristics of liposome therapeutics were not influenced by MAG-C. The components used to prepare magnetic liposomes for MDT should be optimized for maximum therapeutic benefit.

Breast cancer is a major cause of cancer death in women worldwide. Breast cancer is a heterogeneous disease characterized by variant pathological features, disparate responses to therapeutics, and substantial differences in patient's long-term survival. The use of drug delivery systems such as liposomes can favorably alter the pharmacokinetic and biodistribution profile of commonly used drugs used to treat breast cancer disease. An important feature of a drug delivery system is its ability to recognize and selectively target tumor cells with relatively high affinity when compared to healthy tissues. For this reason, the goal of this study was to develop a novel nanoliposome system that would target tumor cells to a significantly greater extent when compared to more conventional liposome systems. In this study, natural lipids extracted directly from breast cancer cells were used to prepare cellular lipid-extracted nanoliposomes (CLENs). The rationale is that an array of different lipids with a unique composition profile would represent a more relevant source of lipid material when compared to more traditional methods of liposome preparation. We therefore investigated whether the inclusion of extracted lipids derived from breast cancer cells would improve the selective uptake of liposomes by breast cancer cells, and related formulation features. To achieve these goals, three breast cancer cell lines were used (4T1, BT-20, and SK-BR-3), a normal breast fibroblast (CRL-2089), and an ovarian cancer cell line (SK-OV-3- used as a negative control). The size of CLENs fell within the size range of 120- 203 nm and possessed a negatively-charged liposome surface charge potential (ranging between -10.97 and -20.97 mV). The nanoliposomes were also non-toxic to cells within the concentration range evaluated (up to 1μmol). Furthermore, without exception, the cellular uptake of CLENs was greatest when the extracted material used to prepare CLENs was the same as the target cell from which the lipids were extracted. In addition, when the breast cancer cell lines (4T1, SK-BR-3 and BT-20) were used to prepare CLENs, SK-OV-3 and CRL-2089 cell lines took up CLENs to a lesser extent, suggesting a more selective and differential cellular uptake. In conclusion, the novel nanoliposome platform represents a promising drug delivery alternative to more conventional nano drug delivery systems. Additional formulation studies are currently underway. Citation Format: Hanan M. Alharbi, Robert B. Campbell. Employing a unique panel of breast cancer cellular lipids extracts in the development of a novel nanoliposome drug platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5513. doi:10.1158/1538-7445.AM2015-5513

MUC1 is a transmembrane glycoprotein that is overexpressed in epithelial ovarian cancer. Due to extensive O-glycosylation, mucins form a physical barrier that limits the intracellular accumulation and cytotoxic effect of chemotherapeutic drugs. Our investigation represents a key step in determining if drug resistance in ovarian cancer develops due to altered MUC1 expression and glycosylation. Immunoblotting and ELISA techniques were utilized to characterize the extent of membrane-bound and shed MUC1 expression in drug-resistant and drug-sensitive ovarian cancer cells. An (anti-MUC1) antibody-based in vitro model was employed to determine if the inhibition of O-glycosylation enhanced functional access of small molecule drugs using FACS and fluorescence microscopic analyses. Expression of MUC1 was detected in both the drug resistant ovarian cancer cell line SK-OV-3 (MDR) and the parent cell line SK-OV-3 (WT), with the highest levels observed in the drug resistant sub-clone. The greatest improvement in functional anti-MUC1 antibody access following inhibition of O-glycosylation was observed in the drug-resistant ovarian cancer cells. Our results provide evidence to support drug resistance in ovarian cancer due in part to a mucin barrier mesh. The inhibition of mucin O-glycosylation may be a viable strategy to improve drug delivery and efficacy of small molecule delivery to ovarian carcinomas. Citation Format: Steven M. Richards, Robert B. Campbell. An evaluation of the role of Mucin in drug resistant ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4554. doi:10.1158/1538-7445.AM2015-4554

Over the past few decades significant advances have been made in the development of nanopharmaceuticals (including phospholipid and polymer-based therapeutics) against cancer. There is still, however, room for improvement. Today, many researchers are focusing on the development of innovative approaches to selectively deliver drugs to solid tumors, while minimizing insult to healthy tissues. Unfortunately, the majority of these efforts are confronted by physiological barriers that reduce the clinical dose required to effectively manage the disease state. In an effort to develop promising nanopharmaceutical products of the future, we review the most important problems facing drug delivery experts today. We discuss here, the physiological role of solid tumors in delivery and transport of nanopharmaceutical products. The nature of tumors in terms of their unique anatomical structure and functions is also discussed. Finally, an overview of ways to overcome physiological barrier functions and exploit tumor pathogenesis for therapeutic gain is provided.

Introduction: Solid tumors comprise more than 85% of cancers that affect humans. The presence of the extracellular matrix, namely mucin, on the tumor cell is considered one of the barriers against effective treatment of solid tumors. In tumor cells, mucin is aberrantly overexpressed producing a mucin mesh which may impede the rate of entry of chemotherapy medications. The type O-glycosylation inhibitor, benzyl-α-GalNAc, significantly reduces mucin type O-glycosylation in mucin-producing tumor cells resulting in enhanced cytotoxic drug action. We next seek to determine the role of mucin in the delivery of nano-sized drug delivery systems. Methods: The cell lines used were derived from tumor or normal tissues representing multiple organ environments. These cell lines include: Capan-1, Capan-2, PANC-1, HPAF-II (human adenocarcinoma), hTERT-HPNE (normal human pancreas), CRL-1777 (normal murine pancreas), ZR-75-1 (breast cancer), and CRL-2089 (normal breast). Evaluation of MUC1 protein expression was done by western blot analysis in addition to fluorescence microplate reader using CD227 (anti-MUC1 antibody). Furthermore, we investigated the cellular uptake of the fluorescently labeled polystyrene microsphere beads and liposomes in the different cell lines. Finally, FACS analysis was used to determine cellular uptake following inhibition of mucin type O-glycosylation and compared to control. Results: Different levels of mucin expression were observed among the various cell lines. By investigating the antibody association with the MUC1 protein core, Capan-1and ZR-75-1have shown the greatest cellular uptake following inhibition of glycosylation. To evaluate the cellular uptake of the microsphere beads and liposomes we used cell lines derived from the pancreas. The glycosylation inhibitor had little to no effect on the uptake of the microsphere beads, regardless of cell line employed. However, the overall uptake of the large beads (990 nm) was significantly greater in comparison to the uptake of the smaller beads (67 and 116 nm). Next, we carried out the same procedure using liposomes that were made in the size range of 60-80nm, 100-120nm, and 350-550nm. Out of the 6 pancreatic cell lines examined, PANC-1 cell line showed that the uptake of each liposome preparation type was significantly greater following the inhibition of mucin glycosylation. In addition, we observed that the uptake of liposomes increased as a function of liposome size. This was confirmed by FACS analysis as well. Conclusion: Our results suggest that inhibiting the mucin type O- glycosylation alters the uptake of the microsphere beads in all the cell lines examined. As for the liposomes, however, the effect of inhibiting glycosylation is cell line dependent. Further studies will be performed to investigate the factors underlying the differential uptake observed with liposomes following inhibition of glycosylation. This might be helpful in developing a better nano-therapeutic approach to treat cancer. Citation Format: Musaed A. Alkholief, Robert Campbell. An evaluation of the role of mucin in nano drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4469. doi:10.1158/1538-7445.AM2014-4469

Conventional epifluorescence microscopy coupled with chronic animal window models has provided stunning insight into tumor pathophysiology, including gene expression, angiogenesis, interstitial transport, and drug delivery. However, the findings to date have been limited to the tumor surface (

We have developed magnetic nano-liposomes (MNL), incorporating superparamagnetic iron oxide nanoparticles (SPION), that are versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. MNL are prepared with a formuation of DPPC:DOTAP:CHOL and DOPE-PEG5000. Incorporation of SPIONs results in MNL with mean diameter of 150-250 nm. MNL are easily taken up by B16-F10 melanoma, HUMVEC-D and breast cancer cell lines. They preferentially target the tumor vasculature as shown in a dorsal skin fold chamber using fluorescently labeled MNL. MNL display superparamagnetic response that is essential for magnetic targeting, MR contrast enhancement and magnetic heating. MNL was administrated to SCID mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre-injection and post-injection MR images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by 111In labeled MNL and amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations. We have shown that tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2-fold greater accumulation by magnetic targeting. 111In radio-labeled MNL have been shown to enable multi-modal imaging in vivo using MRI and SPeCT/CT. The images show that an MNL bolus injected intra-tumorally was retained in the tumor 24 hours after injection. Application of a magnetic field enables redistribution of the MNL in the tumor. These MNL are also responsive to ac magnetic fields applied using a Copper coil at 360 kHz and 170A driving current. Both hyperthermia (upto 45C) and thermo-ablative temperatures upto 90C were achieved in 10 – 30 minutes ex vivo in buffer. The results indicate high efficiency for magnetic heating using MNL (Specific Absorption Rate ∼ 104 W/kg) and demonstrate the capability to couple ac magnetic fields to MNL to achieve any set of temperatures needed for hyperthermia and thermal ablation. To date there are no truly theranostic platforms that have been approved for clinical use that combine targeting, thermal heating and MRI imaging capabilities. Existing FDA approved magnetic nanoparticle formulations like ferridex and ferumoxytol, are optimized for MR imaging, and have not been shown to be usable for thermal therapy.The MNL platform is a novel nanoplatform combining multi-modal imaging capabilities, with magnetic targeting and thermal therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2011-380

Uptake of cytotoxic drugs by typical tumor cells is limited by the dense dendritic network of oligosaccharide mucin chains that forms a mechanical barrier. Atomic force microscopy is used to directly measure the force needed to pierce the mucin layer to reach the cell surface. Measurements are analyzed by de Gennes’ steric reptation theory. Multidrug resistant ovarian tumor cells shows significantly larger penetration load compared to the wide type. A pool of pancreatic, lung, colorectal, and breast cells are also characterized. The chemotherapeutic agent, benzyl-α-GalNac, for inhibiting glycosylation is shown to be effective in reducing the mechanical barrier.

Purpose: The development of non‐invasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. Magnetic Cationic Liposomes (MCL) that carry a cargo of anti‐cancer drugs and magnetic nanoparticles that will selectively target primary and metastatic cancertumorsdeliver drugs to them and visualize their effects through magnetic resonance imaging(MRI)single photon emission computed tomography(SPECT) and fluorescence spectroscopy. The aim of the present study is to evaluate MCL as a versatile theranostic nanoplatform for enhanced drug deliveryimaging and monitoring of cancer treatment. Materials and Method: Poly‐ethyleneglycol (PEG) coated cationic liposomes are loaded with superparamagnetic iron oxide nanoparticles (SPIONS) and tagged with the radioisotope Indium‐111. MCL was administered to SCID mouse with metastatic (B16‐F10) melanoma grown in the right flank. Pre‐injection and post‐injection MR and SPECT/CT images were used to assess response to magnetic targeting effects and tumor and organ distribution. Results:Tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2‐fold greater accumulation by magnetic targeting. SPECT/CT images showed the localization and distribution of MCL in the tumor.Conclusion: MR SPECT/CT and biodistribution analyses clearly show the efficacy of MCL as MRI contrast agents prove the use of magnetic guidance and demonstrate the potential of MCL as agents for imaging guidance and therapeutic delivery.