Habitual recreational physical activity is associated with significantly improved survival in cancer patients: evidence from the Roswell Park Data Bank and BioRepository.

PURPOSE: The association of recreational physical activity (RPA) with mortality is well established only for breast and colon cancers and few studies have evaluated relationships for exercising before and after diagnosis, across multiple disease sites. We examined the joint associations of pre- and post- diagnosis RPA with mortality in a cohort of 5,807 patients enrolled in the Data Bank and BioRepository at Roswell Park. METHODS: Patients were classified into one of four activity categories (habitually active, increased activity after diagnosis, decreased activity after diagnosis, habitually inactive). Cox proportional hazards models were used to estimate the associations of activity status with mortality. RESULTS: In comparison to patients who were habitually inactive, habitually active patients experienced a 39% decreased hazard of all-cause mortality (HR = 0.61, 95% CI 0.54-0.69) and a 36% decreased hazard of cancer-specific mortality (HR = 0.64, 95% CI 0.56-0.73). Previously inactive patients who began exercising after diagnosis experienced a 28% decreased hazard of all-cause (HR = 0.72, 95% CI 0.59-0.89) and cancer-specific mortality (HR = 0.72, 95% CI 0.57-0.91) in comparison to patients who remained inactive. Patients engaging in 3-4 sessions/week experienced the greatest survival advantages, but 1-2 sessions/week also yielded significant survival advantages in comparison to inactivity. CONCLUSION: Low-to-moderate frequency pre- and post-diagnosis RPA was associated with significantly decreased mortality in patients diagnosed with a variety of malignancies. These observations solidify the clinical and public health importance of the message that some regular activity is better than inactivity, which is particularly encouraging, given that cancer survivors can be overwhelmed by current daily physical activity recommendations.

Whole body and local hyperthermia enhances the photosensitizing efficacy of 3-[(1'-hexyloxy)ethyl]-3-Devinylpyropheophorbide-a (HPPH).

BACKGROUND AND OBJECTIVES: In this study, we evaluated the impact of hyperthermia in photosensitizing efficacy of 3-[(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH or Photochlor) for the treatment of cancer by photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: The outcome of both whole body hyperthermia (WBH) and local hyperthermia (LH) in combination with HPPH-PDT was determined in BALB/c and nude mice bearing Colon26 and U87 tumors, respectively. LH was performed by using an indigenously designed heating device, that was heated to the required temperature using a circulating water bath. The device which has flexible membrane on one side was placed on skin above the tumor. The temperature of the tumor was monitored using a thermocouple sensor placed on the surface of the tumor capable of measuring the temperature within 0.1°C. Uptake of the photosensitizer in tumors was determined by fluorescence using an IVIS or a Nuance Imaging System. The PDT was performed by exposing the tumors to 665 nm laser loght, (135 J/cm2 , 75 mW/cm2 ) at the maximal uptake time of HPPH. Tumor size was measured daily using vernier calipers. RESULTS: The improved PDT efficacy (long-term percentage tumor cure) in combination with hyperthermia is possible due to an increase in tumor-uptake of the photosensitizer (PS), confirmed by in vivo fluorescence imaging and also by increased tumor perfusion and decreased hypoxia as have been reported previously (Sen et al. [2011] Cancer Res. 71:3872-3880 In Vivo. 20:689-695). Interestingly, compared to whole body hyperthermia, the 14 C- HPPH biodistribution data under local hyperthermia showed similar tumor-uptake in BALB/c mice bearing Colon26 tumors, but significantly lower uptake in other organs and in the blood. CONCLUSION: Our study demonstrates that both, fever range whole body and local hyperthermia in combination with HPPH-PDT enhances the long-term tumor cure of BALB/c and nude mice implanted with Colon26 and U87 tumors respectively. Lasers Surg. Med. 50:506-512, 2018. © 2018 Wiley Periodicals, Inc.

A pilot study of the effects of mild systemic heating on human head and neck tumour xenografts: Analysis of tumour perfusion, interstitial fluid pressure, hypoxia and efficacy of radiation therapy.

PURPOSE: The tumour microenvironment is frequently hypoxic, poorly perfused, and exhibits abnormally high interstitial fluid pressure. These factors can significantly reduce efficacy of chemo and radiation therapies. The present study aims to determine whether mild systemic heating alters these parameters and improves response to radiation in human head and neck tumour xenografts in SCID mice. MATERIALS AND METHODS: SCID mice were injected with FaDu cells (a human head and neck carcinoma cell line), or implanted with a resected patient head and neck squamous cell carcinoma grown as a xenograft, followed by mild systemic heating. Body temperature during heating was maintained at 39.5 ± 0.5 °C for 4 h. Interstitial fluid pressure (IFP), hypoxia and relative tumour perfusion in the tumours were measured at 2 and 24 h post-heating. Tumour vessel perfusion was measured 24 h post-heating, coinciding with the first dose of fractionated radiotherapy. RESULTS: Heating tumour-bearing mice resulted in significant decrease in intratumoural IFP, increased the number of perfused tumour blood vessels as well as relative tumour perfusion in both tumour models. Intratumoural hypoxia was also reduced in tumours of mice that received heat treatment. Mice bearing FaDu tumours heated 24 h prior to five daily radiation treatments exhibited significantly enhanced tumour response compared to tumours in control mice. CONCLUSIONS: Mild systemic heating can significantly alter the tumour microenvironment of human head and neck tumour xenograft models, decreasing IFP and hypoxia while increasing microvascular perfusion. Collectively, these effects could be responsible for the improved response to radiotherapy.

Simple solution phase synthesis of 3-D assembly of ZnO nanoneedles and its efficient field emission.

Three dimensional (3-D) assemblies of ZnO nanoneedles have been synthesized on silicon substrate by a unique chemical process. Each nanoneedle in the assemblies was hexagonal faceted having [001] growth direction and tip diameter approximately 20 nm. The growth of 3-D assemblies was governed by the initial nuclei formation, followed by their aggregation and subsequently nanoneedle formation from each nucleus. Room temperature photoluminescence (PL) spectrum of the assemblies showed two prominent peaks, one narrow peak in the ultraviolet region (385 nm) and another broad peak in the visible region (440 nm-600 nm). The 3-D assemblies of ZnO nanoneedles showed very good field emission property with turn-on voltages 390 V, 530 V and 680 V for the anode-emitter distances of 100 microm, 200 microm and 300 microm respectively. The turn-on voltages showed a linear relationship with the anode-emitter distance. Field enhancement factor (beta) for the nanostructure was calculated to be 2873. The high beta value and the low turn-on field are attributed to the sharp needle like structure and their interesting three dimensional assemblies.

Tumor Priming by SMO Inhibition Enhances Antibody Delivery and Efficacy in a Pancreatic Ductal Adenocarcinoma Model.

Despite frequent overexpression of numerous growth factor receptors by pancreatic ductal adenocarcinomas (PDAC), such as EGFR, therapeutic antibodies have not proven effective. Desmoplasia, hypovascularity, and hypoperfusion create a functional drug delivery barrier that contributes to treatment resistance. Drug combinations that target tumor/stroma interactions could enhance tumor deposition of therapeutic antibodies, although clinical trials have yet to support this strategy. We hypothesize that macromolecular or nanoparticulate therapeutic agents may best exploit stroma-targeting "tumor priming" strategies, based on the fundamental principles of the Enhanced Permeability and Retention phenomenon. Therefore, we investigated the molecular and pharmacologic tumor responses to NVP-LDE225, an SMO inhibitor of sonic hedgehog signaling (sHHI), of patient-derived xenograft models that recapitulate the desmoplasia and drug delivery barrier properties of PDAC. Short-term sHHI exposure mediated dose- and time-dependent changes in tumor microvessel patency, extracellular matrix architecture, and interstitial pressure, which waned with prolonged sHHI exposure, and increased nanoparticulate permeability probe deposition in multiple PDAC patient-derived xenograft isolates. During sHHI-mediated priming, deposition and intratumor distribution of both a nontargeted mAb and a mAb targeting EGFR, cetuximab, were enhanced. Sequencing the sHH inhibitor with cetuximab administration resulted in marked tumor growth inhibition compared with cetuximab alone. These studies suggest that PDAC drug delivery barriers confound efforts to employ mAb against targets in PDAC, and that short-term, intermittent exposure to stromal modulators can increase tumor cell exposure to therapeutic antibodies, improving their efficacy, and potentially minimize adverse effects that may accompany longer-term, continuous sHHI treatment.

Publisher Correction: Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Influence of DMPS on the water retention capacity of electroporated stratum corneum: ATR-FTIR study.

Anionic lipids like phosphatidylserine are known to significantly enhance electroporation mediated transepidermal transport of polar solutes of molecular weights up to 10kDa. The underlying mechanism of the effect of anionic lipids on transdermal transport is not fully understood. The main barrier to transdermal transport lies within the intercellular lipid matrix (ILM) of the stratum corneum (SC) and our previous studies indicate that dimyristoyl phosphatidylserine (DMPS) can perturb the packing of this lipid matrix. Here we report on our investigation on water retention in the SC following electroporation in the presence and the absence of DMPS. The water content in the outer most layers of the SC of full thickness porcine skin was determined using ATR-FTIR-spectroscopy. The results show that in the presence of DMPS, the SC remains in a state of enhanced hydration for longer periods after electroporation. This increase in water retention in the SC by DMPS is likely to play an important role in trans-epidermal transport, since improved hydration of the skin barrier can be expected to increase the partitioning of polar solutes and possibly the permeability.

Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment.

Local acidification of stroma is proposed to favour pre-metastatic niche formation but the mechanism of initiation is unclear. We investigated whether Human Melanoma-derived exosomes (HMEX) could reprogram human adult dermal fibroblasts (HADF) and cause extracellular acidification. HMEX were isolated from supernatants of six melanoma cell lines (3 BRAF V600E mutant cell lines and 3 BRAF wild-type cell lines) using ultracentrifugation or Size Exclusion Chromatography (SEC). Rapid uptake of exosomes by HADF was demonstrated following 18 hours co-incubation. Exposure of HDAF to HMEX leads to an increase in aerobic glycolysis and decrease in oxidative phosphorylation (OXPHOS) in HADF, consequently increasing extracellular acidification. Using a novel immuno-biochip, exosomal miR-155 and miR-210 were detected in HMEX. These miRNAs were present in HMEX from all six melanoma cell lines and were instrumental in promoting glycolysis and inhibiting OXPHOS in tumour cells. Inhibition of miR-155 and miR-210 activity by transfection of miRNA inhibitors into HMEX reversed the exosome-induced metabolic reprogramming of HADF. The data indicate that melanoma-derived exosomes modulate stromal cell metabolism and may contribute to the creation of a pre-metastatic niche that promotes the development of metastasis.

Resealing of electroporation of porcine epidermis using phospholipids and poloxamers.

The resealing of porcine epidermis after electroporation is investigated. Porcine epidermis was subjected to electroporation (30 pulses at 100 V, 1 ms and at 1 Hz) in a vertical diffusion apparatus, in the presence of 2 mg/ml dimyristoylphosphatidylserine, to produce a long lasting permeable state. Resealing treatments include incubation in 0.0625-0.25 mM poloxamer 188 (P188), or incorporation of phosphatidylcholines (PC) and/or cationic lipids with additional pulses. The recovery of electric resistance of the epidermis samples after electroporation with or without resealing treatments was monitored. The transports of carboxyfluorescein and glucose were measured during the recovery process. Both P188 and PC were effective in resealing in terms of electric conductance and transport, with P188 reacting more rapidly and completely. P188 mediated lipid exchange between stratum corneum lipid particles was measured by fluorescence resonance energy transfer (FRET). Lipid reorganization facilitated by P188 and PC is suggested to be a major resealing mechanism of electroporation damage.

Lipid and electroosmosis enhanced transdermal delivery of insulin by electroporation.

Transdermal transport of insulin and extraction of interstitial glucose under anodal iontophoresis (electroosmosis) following electroporation in the presence of 1,2-dimyristoylphophatidylserine (DMPS) was studied. An earlier study showed that DMPS increased the transport of insulin across porcine epidermis under electroporation by approximately fourfold. It was suggested that DMPS increased the lifetime of electropores in the epidermis resulting in an enhanced transport of permeants. When electroosmosis was applied across the epidermis following electroporation with DMPS, the enhancement of insulin transport was approximately 18-fold over electroporation alone. When the same strategy was applied to extract interstitial glucose, the enhancement was approximately 23-fold over electroporation alone. Real-time transdermal insulin transport kinetics was measured using FITC-labeled insulin and a custom-made vertical diffusion apparatus that had a fluorescence cuvette as the receiver compartment. Insulin transport by electroporation alone showed a nonlinear kinetics that is most likely due to the resealing of the electropores with time. The transport kinetics when electroporation was carried out in the presence of DMPS was more linear, confirming earlier studies that suggested the DMPS stabilizes transport paths formed by electroporation. The data suggests that in vivo, noninvasive insulin delivery to therapeutic levels and glucose extraction may be achieved by combining electroporation with anionic lipids and electroosmosis.

Synergistic effect of anionic lipid enhancer and electroosmosis for transcutaneous delivery of insulin.

A lipid formulation consisting of 1,2-dimyristoyl-sn3-phosphatidylserine (DMPS) in a 0.2% sodium dodecylsulfate (SDS) solution was tested as an in vivo enhancer for the transcutaneous delivery of insulin. The formulation when applied to for 15 min was found to permeabilize porcine epidermis and prolong the permeable state as evidenced by electric resistance measurement. The formulation enhanced the transport of insulin through the epidermis by 40- to 100-fold, as compared to epidermis that was treated with SDS or DMPS alone. Application of electroosmosis across the formulation-treated epidermis enhanced the transport of insulin by an additional 10-fold. Pharmacokinetic studies were carried out in Sprague-Dawley rats. Transcutaneous delivery of insulin with formulation treatment and electroosmosis increased the plasma level of insulin by approximately 10-fold over delivery by formulation treatment alone. With the above protocol plasma insulin concentration remained relatively constant for up to 4h. The synergistic application of anionic lipid formulation and electroosmosis offers a promising non-invasive technique to deliver insulin transcutaneously.

Transdermal insulin delivery using lipid enhanced electroporation.

Transdermal insulin transport by electroporation was measured using porcine epidermis and fluorescein-labeled insulin. Previous studies have shown that anionic lipids can enhance the electroporative transport of molecules up to 10 kDa in size. It was also shown that it is the charge and not the type of the phospholipid head group that influences transdermal transport under electroporation. Moreover, phospholipids with saturated acyl chains enhance the transport of larger molecules more as compared to those with unsaturated chains. In the current study, based on those earlier findings, the effect of 1,2-dimyristoyl-3-phosphatidylserine (DMPS) on the transdermal transport of insulin by electroporation was examined. Porcine epidermis was used as a model for skin. Transport was measured using glass vertical diffusion apparatus in which the epidermis separated the donor and receiver compartments. Negative pulses were applied across the epidermis using platinum electrodes. Results show that when electroporation was carried out in the presence of DMPS, there was greater than 20-fold enhancement of insulin transport. Furthermore, while in the presence of the phospholipid, almost all the transported insulin was detected in the receiver compartment; in the absence of added lipids, only about half the insulin transported was in the receiver compartment and an almost equal amount of insulin remained in the epidermis. Fluorescence microscopy revealed that the insulin transport was mainly through the lipid multilayer regions that surround the corneocytes.

Utilizing temperature-sensitive association of Pluronic F-127 with lipid bilayers to control liposome-cell adhesion.

The temperature sensitive properties of Pluronic F-127 (MW approximately 12600, PEO(98)-PPO(67)-PEO(98)), a block co-polymer or poloxamer, was used to control liposome-cell adhesion. When associated with liposomes, the PEO moiety of the block co-polymer is expected to inhibit liposome-cell adhesion. Liposomes were made using egg phosphatidylcholine and different mole% of Pluronic F-127. Size measurement of the liposomes at different temperatures, in the presence and absence of Pluronic F-127, shows significant reduction in the size of multilamellar vesicles, at higher temperatures, by the Pluronic molecules. Negative stain electron microscopy study showed the presence of individual molecules and micelles of Pluronic, respectively at temperatures below and above the critical micellar temperature (CMT). Measurement of the surface associated Pluronics indicated that they associated with liposomes when the sample was heated above the Pluronic CMT, and dissociated from liposomes when cooled below the CMT. Attachment of the Pluronic containing liposomes to CHO cells was inhibited at temperatures above the CMT, but not at temperatures below CMT, indicating that temperature-sensitive control of liposome-cell adhesion is achieved.

Electroporation and transcutaneous extraction (ETE) for pharmacokinetic studies of drugs.

The therapeutic activity and toxicity of drugs often depends on the accumulation of drugs in the peripheral anatomical compartment rather than the central compartment. In the routine practice of therapeutic drug monitoring (TDM) and pharmacokinetic studies, drug concentration determined by intermittent blood sampling is used as a surrogate for calculating the drug concentration in the peripheral compartment tissues. Microdialysis, a relatively less invasive procedure, has been used for estimation of free drug levels in dermal, subcutaneous and muscle tissues. Transcutaneous extraction of drugs from the dermal tissue is a good noninvasive alternative to phlebotomy and microdialysis. This requires a technique, which can facilitate the extraction of significant and reproducible amounts of drugs from the dermal extracellular fluid (ECF) within a short sampling duration. In the present work, we assessed the feasibility of electroporation and transcutaneous extraction (ETE) method for determining the time course of drugs in dermal ECF, using salicylic acid (SA) as a test drug. Electroporation protocol was optimized based on the in vitro diffusion studies of salicylic acid across rat skin. The concentration-time profile of total SA was determined in rats after a single i.v. bolus administration. The in vivo permeability coefficient (P(in vivo)) of rat skin was determined under steady state plasma concentration of drug created by i.v. bolus followed by constant rate infusion of SA. The pharmacokinetic parameters of the drug were determined using a two-compartment pharmacokinetic model. The theoretical predicted time course of free SA in the dermal ECF after a single i.v. bolus administration was calculated using standard formulae. The concentration of free SA determined by ETE is in good agreement with that calculated using two-compartment pharmacokinetic model. This study thus provides a credible evidence for the validity of ETE technique for determining the concentration of SA in the dermal ECF.

Tumor priming by Apo2L/TRAIL reduces interstitial fluid pressure and enhances efficacy of liposomal gemcitabine in a patient derived xenograft tumor model.

Interstitial fluid pressure (IFP) is elevated in tumors and high IFP, a negative cancer prognosticator, is known to limit the uptake and efficacy of anti-tumor therapeutics. Approaches that alter the tumor microenvironment and enhance uptake of therapeutics are collectively referred to as tumor "priming". Here we show that the cytotoxic biological therapy Apo2L/TRAIL can prime the tumor microenvironment and significantly lower IFP in three different human tumor xenograft models (Colo205, MiaPaca-2 and a patient gastrointestinal adenocarcinoma tumor xenograft). We found that a single dose of Apo2L/TRAIL resulted in a wave of apoptosis which reached a maximum at 8h post-treatment. Apoptotic debris subsequently disappeared concurrent with an increase in macrophage infiltration. By 24h post-treatment, treated tumors appeared less condensed with widening of the stromal areas which increased at 48 and 72h. Analysis of tumor vasculature demonstrated a significant increase in overall vessel size at 48 and 72h although the number of vessels did not change. Notably, IFP was significantly reduced in these tumors by 48h after Apo2L/TRAIL treatment. Administration of gemcitabine at this time resulted in increased tumor uptake of both gemcitabine and liposomal gemcitabine and significantly improved anti-tumor efficacy of liposomal gemcitabine. These results suggest that Apo2L/TRAIL has a potential as a tumor priming agent and provides a rationale for developing a sequencing schema for combination therapy such that an initial dose of Apo2L/TRAIL would precede administration of gemcitabine or other therapies.

Surfactant-enhanced transdermal delivery by electroporation.

The objective of the experiment was to study the influence of sodium dodecyl sulfate (SDS) on transdermal transport of diffusants by electroporation. The resistance of porcine epidermis in contact with SDS solution (0.2% w/v) dropped by 40% within 24 h. SDS improved the efficiency of transdermal delivery of glucose, dextrans of molecular weight (MW) 4 kDa (FD4K) and 10 kDa (FD10K) by electroporation. However, the transport of dextran MW 35 kDa (FD35K) was not influenced significantly. Pretreatment of epidermis with SDS solution reduced its electroporation threshold from 80 to 60 V. It appears that presence of SDS during electroporation helps in achieving the desired transport with less electrical exposure dose. SDS enhanced the transdermal delivery of molecules by electroporation most likely by facilitating the barrier disruption during pulse application and also by prolonging the lifetime of electropores created by the pulse.

Cyclodextrin enhanced transdermal delivery of piroxicam and carboxyfluorescein by electroporation.

The transdermal transport of cyclodextrins (CD) across porcine epidermis by electroporation was studied. Electroporation increased the permeation of beta-cyclodextrin (BCD) and hydroxy propyl beta-cyclodextrin (HPCD) by several orders of magnitude, relative to passive transport. The presence of BCD and HPCD enhanced the total transport of the test permeants piroxicam and carboxyfluorescein (CF), respectively, from both permeant solutions and suspensions. BCD enhanced the fraction of piroxicam transported across the epidermis into the receiver compartment medium. This was most likely due to the prolonged post-pulse permeability state of the epidermis. The fraction of CF retained in the epidermis was increased by HPCD. The rate of diffusion of CF from epidermis into the receiver compartment was decreased by the presence of HPCD, apparently due to the aggregate forming tendency of HPCD. The in vivo delivery of CF by electroporation in mice demonstrated the potential of HPCD for sustaining the transdermal absorption rate of hydrophilic molecules.

Enhanced transdermal transport by electroporation using anionic lipids.

Transdermal drug delivery is an attractive approach for either local or systemic treatment in medicine. In the last decade, different active transdermal delivery methods have been further investigated such as cationic liposomal delivery and electroporation-enhanced delivery. In light of gaining a synergistic effect of lipid and electroporation, a new method of using anionic lipids to enhance the transdermal transport of molecules under electroporation is reported here. Heat-stripped porcine epidermis was used for measurement of transdermal transport using an in vitro vertical diffusion apparatus. Lipid vesicles were prepared using a 1:1 mole ratio mixture of 1,2-dioleoyl-3-phosphatidylglycerol (DOPG) and 1,2-dioleoyl-3-phosphatidylcholine (DOPC). When the lipids were mixed with (but not encapsulating) the transport target molecule, the electroporation-induced transport through porcine epidermis was increased as compared to that without the lipids. The enhancement in transport was dependent upon the size and the charge of the transported molecule. Methylene blue (MB), protoporphyrin IX (PpIX) and dimethyl-protoporphyrin IX (DM-PpIX) were used as small target molecules, and FITC-dextrans (4 to 155 kDa) were used as large target molecules in our studies. Enhancement of transport, to varying degree, was observed for all three small molecules (molecular weights <1 kDa), in the presence of DOPG:DOPC vesicles. In the case of large molecules, lipid-enhanced transport was only observed for the 4 kDa dextran, and not for the larger ones (M(w)>10 kDa). Neutral or cationic lipids alone did not enhance the transdermal transport under the electroporation conditions we used.

pH influences the postpulse permeability state of skin after electroporation.

The pH dependence of porcine epidermis permeability and the influence of pH on the electroporation transport of molecules were studied. The resistance was maximum at pH 5 and decreased with an increase or decrease in the pH of the donor medium. The permeability coefficient of glucose was significantly higher at pH 7.5, compared to pH 5. On electroporation, the resistance recovery rate of porcine epidermis was rapid below pH 5 and slower at above pH 7.5. The transport studies revealed that a donor medium pH above 7.5 helps to maintain the postpulse permeability state of the skin. By changing the donor medium pH from 5 to 7.5, the postpulse transport of glucose and fluorescein isothiocyanate (FITC)-labeled dextran (MW 10 kDa) (FD10K) was enhanced by about threefold. The lipids extracted from porcine epidermis showed pI values of 4.3 and 5.9. Vesicles of these lipids fused more rapidly at pH 5 than at pH 3, 7, and 10. The results imply that pH-sensitive postpulse resistance recovery and molecular transport are due to the charge states of epidermal lipids.

Temperature influences the postelectroporation permeability state of the skin.

The influence of temperature on the electrical conductance and transport of macromolecules across porcine epidermis during and after electroporation were studied. The passive diffusion of fluorescein isothiocyanate labeled dextran (molecular weight 10 kDa, FD10K), across the epidermis did not differ much at temperatures below 37 degrees C, but became significantly higher above 40 degrees C. The resistance drop during pulse application was less sensitive to temperature within the temperature range (10-50 degrees C) of this study. The kinetics of decrease in postpulse conductance of the electroporated epidermis was fit to a monoexponential function. The rate of decrease in postpulse conductance was significantly less and FD10K transport was markedly high at temperature over 40 degrees C relative to those observed at temperatures less than 37 degrees C. This jump in transport cannot be explained by electrophoresis induced by the pulse, or by the increased diffusion kinesis of the molecules. The enhanced transport is most likely due to the prolonged postpulse permeable state of the skin. Electroporation at mild hyperthermia temperatures resulted in delivering much higher quantities of macromolecules.